July- August June 2012

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Pan-ErbB blocker tops standard chemo in lung cancer

NEWS Asian study unveils mechanism of HBV integration in HCC

CONFERENCE Better strategies needed for ALL in adolescents and young adults

INDUSTRY UPDATE First-line temsirolimus improves survival in poor-prognosis mRCC patients

CASE STUDY Capecitabine in advanced gastric cancer

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Jul-Aug 2012

Pan-ErbB blocker tops standard chemo in lung cancer
Christina Lau

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fatinib, an investigational drug that irreversibly blocks EGFR (ErbB1), HER2 (ErbB2), HER3 (ErbB3) and HER4 (ErbB4), significantly extended progression-free survival (PFS) vs pemetrexed plus cisplatin in the largest phase III trial in EGFR mutation-positive advanced lung adenocarcinoma. [ASCO 2012; abstract LBA7500] The oral pan-ErbB inhibitor was particularly beneficial for patients with deletion 19 or L858R – common mutations that together accounted for 89 percent of all EGFR mutations in the trial. “Unlike reversible EGFR tyrosine kinase inhibitors such as gefitinib and erlotinib, afatanib blocks the entire ErbB family of receptors permanently,” said lead investigator Dr. James Yang of the National Taiwan University Hospital. “While gefitinib and erlotinib have demonstrated significant benefits vs first-line chemotherapy, LUXLung3 is the first trial in EGFR mutation-positive lung cancer to use pemetrexed/cisplatin as a chemotherapy comparator.” The global trial included 345 treatmentnaïve patients from 25 countries who had stage IIIB (wet) or IV disease (median age, 61 years; ECOG performance status, 0-1; East Asians, 72 percent; never-smokers, 68 percent). Patients were randomized 2:1 to receive afatinib (40 mg) once daily or pemetrexed (500 mg/m2) plus cisplatin (75 mg/m2) q21d until progression. “The trial met its primary endpoint of PFS.

After a median follow-up of 8 months, patients receiving afatinib had a significant 4.2-month improvement in PFS. Median PFS was 11.1 months with afatinib vs 6.9 months with pemetrexed/cisplatin [hazard ratio (HR), 0.58; p=0.0004],” Yang reported. “Twelve-month PFS rate was 47 vs 22 percent.” Importantly, the PFS benefit of afatanib was consistent in all relevant subgroups, including gender, age at baseline, race (Asian or non-Asian), baseline ECOG performance status, and smoking history (never smoked, or smoked <15 pack-years and stopped >1 year). “The benefit of afatinib was even greater in patients with deletion 19 or L858RV [n=308],” he continued. “In these patients, afatinib doubled PFS to 13.6 months vs 6.9 months with pemetrexed/cisplatin [HR, 0.47; p<0.0001]. PFS rate at 12 months was 51 vs 21 percent.” Patients treated with afatinib also had a significantly higher objective response rate (56.1 vs 22.6 percent with pemetrexed/cisplatin; p<0.001), a longer duration of response (11.1 vs 5.5 months), and a higher disease control rate (90 vs 81 percent). In patients with deletion 19 or L858R, objective response rate was 60.8 vs 22.1 percent (p<0.0001). In addition, afatinib significantly prolonged the time to deterioration of cough and dyspnea, resulting in a better quality of life. “Grade 3/4 adverse events that were increased with afatinib included diarrhea [14.4 vs 0 percent], rash/acne [16.2 vs 0 percent], stomatitis/mucositis [8.7 vs 0.9 per-

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Jul-Aug 2012 pemetrexed/cisplatin arm.” In LUX-Lung3, only 7.9 percent of patients discontinued afatinib due to treatment-related adverse events (vs 11.7 percent with pemetrexed/cisplatin), and only about 1 percent discontinued the drug due to diarrhea.

cent], paronychia [11.4 vs 0 percent], and dry skin [0.4 vs 0 percent],” said Yang. “These adverse events were as expected with EGFR-targeting therapies, and were manageable and reversible. It is also important to note that patients in the afatinib arm received 16 cycles of therapy, vs 6 cycles in the

PERSPECTIVES Dr. Kwok-Chi Lam

Department of Clinical Oncology, Prince of Wales Hospital

The LUX-Lung3 trial has echoed what we have seen in other randomized phase III trials, with consistent HR for progression-free survival. It is difficult to compare the treatment efficacy of different EGFR TKIs across different trials. Afatinib can be one of the treatment options for patients with EGFR mutation-positive tumors. We might know which EGFR TKI is better as results of the LUX-Lung7 trial (comparing afatinib with gefitinib in EGFR mutation-positive chemonaïve non-small cell lung cancer) become available in future.

Cancer drug shortages a global problem
Naomi Rodrig

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he European Hematology Association (EHA), the American Society of Hematology (ASH) and the European Cancer Patient Coalition (ECPC) issued a joint call to action to address the looming crisis of cancer drug shortage. The announcement, issued at the recent 2012 EHA Congress, comes on the footsteps of the American Society of Clinical Oncology (ASCO) 2012 Annual Meeting, which also highlighted the problem. According to ASCO officials, disrupted manufacturing and quality control are the main culprits behind the shortages that have left many cancer patients without necessary treatments. “We’re never sure when a generic drug is suddenly going to go out of supply,” said Dr. Richard Schilsky, Chair of the ASCO

Government Relations Committee. Hundreds of drugs have been in short supply in the US over the past year, including methotrexate, used frequently for leukemia; liposomal doxorubicin, which treats ovarian cancer; paclitaxel, used in a variety of cancers; mustargen, used to treat lymphoma; and 5-fluorouracil (5-FU), a key component of adjuvant therapy for colorectal and other cancers. The situation in Europe seems to be even more serious. “In the US, legislation is under way that may curb drug shortages, but in Europe we do not even have a proper understanding of the scope of the problem,” remarked EHA President, Dr. Ulrich Jager. The US FDA is drafting legislation requiring mandatory 6-month advance notification

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Jul-Aug 2012 epirubicin and 5-FU – were out of supply in HA hospitals. The solution was substitution; for example, epirubicin was used to substitute doxorubicin and vice versa. For 5-FU, we used other brands.” While the supply of these drugs has been back to normal now, liposomal doxorubicin, which is commonly used in second-line treatment of recurrent ovarian cancer, has been out of supply for almost a year. “We have to use topotecan, a more toxic drug, for this indication,” she said. “I guess the main reason for the shortages is on the manufacturing side, such as lack of raw materials. In other situations, the drug company ceased to produce the drug because it is not commonly used, such as mitotane for adrenocortical carcinoma, a very rare cancer,” Kwok suggested.

by drug companies for withdra-wals or manufacturing interruption, with penalties for non-reporting. Early alerts may enable government agencies to source the same or alternative drugs from overseas manufacturers. “The situation in Europe is undoubtedly more complex. We are not one country; we are 27 countries, each with its own rules and regulations,” noted Dr. Anton Hagenbeek, The Netherlands, who emphasized that drug supply and pricing are subject to government policies. Asian countries have not been spared either. “In my opinion, cancer drug shortage is a global problem, and Hong Kong is affected as well,” commented Dr. Carol Kwok of the Department of Oncology, Princess Margaret Hospital. “Just a few months ago, three commonly used cytotoxic drugs – doxorubicin,

Big strides in cancer genetics research in Asia

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ncreasing numbers of high-quality cancer genetics studies conducted in Asia are making it into prestigious journals, affirming the region’s position as an upcoming hub of advanced oncology research. In the current issue, we report three stories of innovative research from Asia, as investigators from Hong Kong, China and Singapore are shedding new light on carcinogenesis pathways. One of the studies focused on reversal of apoptosis, which may induce oncogenic transformation in various cell types, while the others looked at specific cancers – hepatocellular carcinoma and an aggressive type of lymphoma that is common in China and Korea. The expanding industry funding for basic research in Asia also reflects increasing confidence in its quality as well as a fresh enthusiasm for long-term R&D investment in the region. Although many of these studies are still at the preclinical stage, some may eventually lead to new therapeutic or diagnostic products. The global pharma industry is now willing to stay the course, which may give an even greater boost to Asian medical and life-science research. The Editor

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Jul-Aug 2012

News

Asian study unveils mechanism of HBV integration in HCC
Naomi Rodrig

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he Asian Cancer Research Group (ACRG) in collaboration with the Shenzhen-based genomics company BGI recently published the results of a genome-wide study unveiling the mechanism of recurrent hepatitis B virus (HBV) integration in hepatocellular carcinoma (HCC) genomes. [Nature Genetics 2012. DOI: 10.1038/ng.2295] HBV integration is thought to be one of the major causes underlying HCC development, as previous studies have shown that it may induce chromosomal instability, leading to carcinogenesis and tumor recurrence. “However, this is the first whole-genome sequencing study to systematically investigate the breakpoints of HBV DNA and the human genes which are affected by such integration in a large sample of 88 pairs of HCC tumor and non-tumor liver tissue obtained from 88 patients operated at Queen Mary Hospital [QMH],” said Professor Ronnie Poon, Chief of the Division of Hepatobiliary & Pancreatic Surgery at the University of Hong Kong (HKU) who was one of the study investigators. “The study was initiated by Dr. John Luk, a corresponding author of the paper,  when he was working at HKU. He subsequently moved to the National University of Singapore where he recruited talents in bioinformatics analysis for the project.” In the study, which enrolled 81 HBV-positive and seven HBV-negative patients with HCC, HBV integration was observed more frequently in tumors than in normal tissues (86.4 vs 30.7 percent).

The researchers also identified a specific region of the viral genome that is most commonly cleaved during integration into the host genome. “Approximately 40 percent of HBV breakpoints within the HBV genome were located at a 1,800-bp region where the viral enhancer, X gene and core gene are located,” they wrote. In addition to the previously reported human genes TERT and MLL4, they discovered three novel genes associated with recurrent HBV integration – CCNE1, SENP5 and ROCK1. All these genes are known to play an important role in cancer development and progression, and showed upregulated expression in tumor vs normal tissue. Another observation was that the number of HBV integration events was positively correlated with tumor size, and serum levels of hepatitis B surface antigen (HBsAg) and alpha-fetoprotein. The number of HBV integrations was also associated with patient survival. Patients with <3 detected HBV integrations survived longer than those with >3 integrations, suggesting that the number of integrations may be a

“This  study provides insight into future drug development to prevent hepato-carcinogenesis by HBV. a higher frequency of HBV integration was observed in HCC patients who were in their twenties or thirties. and performed some experiments and  data analysis. ACRG not only provided funding support for the study. According to Poon.” said Poon. but its investigators were involved from the very early phase of study design.” he said.  ACRG is an independent.” he said. MSD and Pfizer to accelerate research on cancers that are common in Asia. over 6 percent of the 3. Poon noted that current drugs which inhibit HBV replication cannot completely eradicate the virus or prevent its re-integration into the human genome.500 primary HCC cases who presented to QMH between 2001 and 2010 were <40 years of age. provided the samples. and I appreciate such effort by pharmaceutical companies. HKU initiated the study. prognostic indicator in HCC patients.” Poon told Oncology Tribune. “The median survival of these young patients is much poorer compared with older patients [8.6 Jul-Aug 2012 News integration into the human genome. He stressed that such genome-wide cancer study is very demanding in terms of technology platforms and bioinformatics analysis. not-for-profit company established in 2010 by Eli Lilly. “This is the first study that correlated the HBV integration patterns with clinical outcome in patients with HBV-related HCC. especially the clinical correlation.3 vs 16. “Collaboration among institutes and with pharmaceutical companies is very important. which may explain the development of the tumors in younger individuals without chronic hepatitis or cirrhosis. and would have been very difficult for a single academic institution to perform. The mapping and sequencing analysis and several other experiments were performed by BGI.1 months]. Their sequencing ability is obviously important to this study. and this may be explained by the increased number of viral integrations as shown in this study. Notably. although there is no drug being developed yet to disrupt HBV DNA . This is really a collaborative effort and the credit should go to all parties and investigators involved.

while promoting anastasis may facilitate tissue recovery. new mutations may develop.7 Jul-Aug 2012 News changes may cause new tumors to form after cancer therapy.” The researchers proposed naming the reversal of apoptosis as ‘anastasis’. “While recent research indicates that cancer stem cells [CSCs] are resistant to chemotherapy and implicated in metastasis. [Mol Biol Cell 2012. Ho-Lam Tang of CUHK’s School of Life Sciences and John Hopkins University School of Medicine. this unanticipated rescue mechanism – observed in both normal and malignant cells – may have important applications in cancer treatment. some cells acquired permanent genetic changes and underwent oncogenic transformation after the reversal of apoptosis. “This effect was observed at non-toxic concentrations of 2. mitochondrial fragmentation.” said principal investigator Dr. including cell shrinkage. causing the cancer to become more aggressive or metastatic. cervical cancer HeLa cells and brain cells with apoptosis inducers. In cancer cells that undergo reversal of apoptosis after treatment. embryonic NIH 3T3 fibroblasts. “It is generally believed that apoptosis – which is a protective mechanism that eliminates damaged cells through programmed cell death – is irreversible once cells pass certain checkpoints. Fung and colleagues treated primary liver and heart cells.23:2240-2252] Accor ding to the researchers. our observation is that anastasis occurs not only in CSCs. nucleus condensation. a Greek term for ‘rising to life’. For example. but also in most cancer cells.” [Br J Cancer 2009. “Genistein had a synergistic anti-cancer effect in combination with chemotherapy. Fung warned against improper use of herbal medicine with potential anticancer properties. as they may drive cancer progression or oncogenic transformation in normal cells.” Fung told Oncology Tribune.” Fung pointed out. and this may be one of the causes of cancer recurrence.” “Although carcinogenesis represents a harmful side effect of anastasis.” said Professor Ming-Chiu Fung of the Department of Biology. the vast majority of dying cells arrested the apoptotic process and recovered when the inducer was washed away. “Further study is needed on the relationship between CSCs and anastasis. Reversal of apoptosis may drive carcinogenesis Christina Lau A recent study from the Chinese University of Hong Kong (CUHK) demonstrated that the process of apoptosis can be reversed even after passing the critical checkpoints of no return. anastasis may be conducive to tissue repair and formation of new genetic combinations. ongoing studies demonstrated that genistein – a predominant isoflavone in soybean with well-documented anticancer effects – could inhibit anastasis in cancer cells.” However. “In normal cells. “More importantly. Further investigation will be carried out on the mechanism.100:118-122] In their current study.” said Fung.5-25 µg/mL in our work with CUHK’s Center for Soybean Research. these genetic . which may lead to genetic changes that contribute to carcinogenesis or resistance to cancer treatments. “Our previous work showed that human cancer cells could evade the apoptotic process even after passing the presumed point of no return. Our findings suggest that inhibiting anastasis may enhance the effect of chemotherapy. macrophages. DNA breakdown and caspase-3 activation. Surprisingly.

” said lead author Dr. At 5 years. respectively.4 percent. 501 (20 percent) were aged 16-30 years. “In the Children’s Oncology Group [COG] study ALL0232. patients aged 21-30 years were eligible for enrollment in an ALL study.” he said. Eric Larsen of the Maine Children’s Cancer Program in Scarborough. According to the investigators. USA.0007]. Marrow relapse at 5 years was 15. Of 2.3 percent in patients aged 16-30 years.8 Jul-Aug 2012 Conference Covera ge American Society of Clinical Oncology (ASCO) 2012 Annual Meeting. p<0. according to new data from a major phase III study which highlights the need for better treatment strategies for this group of patients. USA Better strategies needed for ALL in adolescents and young adults Christina Lau A dolescents and young adults with high-risk acute lymphoblastic leukemia (ALL) have poorer survival and higher toxicity from treatment than their younger counterparts. we tested dexamethasone vs prednisone during induction and high-dose methotrexate vs escalating Capizzi methotrexate plus PEG asparaginase during interim maintenance 1 in a 2 x 2 factorial design.571 eligible patients. the treatment strategy of the . ALL patients older than 16 years have an inferior outcome compared with patients aged 1 to 15 years because older patients have higher rates of relapse and toxicity. vs 13. Chicago. patients aged 16-30 years had significantly poorer event-free survival (EFS) and overall survival (OS) than those <16 years (68 vs 80.4 percent in younger patients [p=0.2 vs 3.0001 for both). respectively [p=0.3 vs 9 percent. “Relapses were significantly more frequent in adolescent and young adult patients.8 vs 88.58).” reported Larsen. “The 5-year cumulative relapse rate was 21.” Central nervous system (CNS) relapse was similar between the two groups (5 years.” ALL0232 enrolled patients with newly-diagnosed B-precursor high-risk ALL. [Abstract CRA9508] “Historically. p=0. “This represents the largest cohort of adolescent and young adult ALL patients to date in a single clinical trial. primarily due to a higher rate of bone marrow relapse. 5.002].7 percent.9 percent and 79. Maine. For the fist time. 1-5 June 2012.

” remarked Larsen.0001). As ‘older’ ALL patients don’t tolerate chemotherapy as well as younger patients. p=0. their compliance is often lower and treatment protocols for them tend to be less intense in terms of the number of drugs. was also significantly lower in adolescent and young adult patients (97.4 vs 1. p<0.1 percent.8 percent. p=0. Mortality during post-induction remission was significantly higher among those aged 16-30 years vs those <16 years (5 years. dosages and treatment duration. As a result of our study. “Adolescent and young adult patients treated in ALL0232 had improved outcome .9 Jul-Aug 2012 Conference Covera ge compared with previous studies that showed EFS rates of 50-60 percent. the COG is considering several options to both enhance leukemia control and reduce the toxicity of treatment. 5.5 vs 2. “However. although there was no significant difference in induction mortality between the two groups (2. our results suggest that we need to find novel agents that improve leukemia control with reduced toxicity. Remission.36).0134).8 percent.” trial was to try to improve disease control in the CNS.2 vs 98. defined as <5 percent marrow blasts at the end of induction.

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Maha Hussain from the University of Michigan. according to a large multinational phase III study. Previous preclinical data have suggested that intermittent therapy can re-induce apoptosis and prolong time to castration resistance. the primary endpoint of overall survival (OS) was inferior in the intermittent therapy group (5. in patients with extensive disease spread. and a SWOG performance status of 0 to 2. increased risk of diabetes and altered lipid profiles.2 years. USA Continuous androgen deprivation still standard of care for prostate cancer Yen Yen Yip C ontinuous androgen deprivation remains standard of care in hormone-sensitive metastatic prostate cancer. USA. After a median follow-up of 9. “This preclinical concept [supporting intermittent therapy] must no longer be propagated. Oh noted. The subjects were treated with goserelin and bicalutamide for 7 months. many patients eventually progress to castration-resistant disease. The primary objective of the SWOG (Southwest Oncology Group) 9346 study. “However. USA.” said lead investigator Dr.2 years.” .” said Oh. 1. decreased cognitive function. was to determine if intermittent androgen deprivation was non-inferior to continuous therapy. believing it will reduce their risk of side effects without compromising outcome. The study included more than 1. New York. and those who achieved PSA ≤4 ng/mL at the 6th or 7th month were then randomized to receive continuous or intermittent therapy.034). commented Dr. “Neither SWOG 9346 nor any randomized trial has ever shown a superior cancer outcome with intermittent androgen deprivation therapy. p=0. HR. with prostate-specific antigen (PSA) levels ≥5 ng/mL prior to initiation of androgen deprivation therapy. Chicago.11 Jul-Aug 2012 Conference Covera ge American Society of Clinical Oncology (ASCO) 2012 Annual Meeting. However. which spanned 17 years.500 patients newly diagnosed with hormone-sensitive prostate cancer.” “The SWOG 9346 findings will be practice changing for many doctors who routinely use intermittent therapy. Among patients with minimal disease. Androgen deprivation therapy leads to significant setbacks in quality of life. [Abstract 4] “Some doctors recommend intermittent hormonal therapy to men with metastatic prostate cancer.1 vs 5. OS was significantly better for those who received continuous therapy (7.” said Hussain.8 years with continuous therapy. 1-5 June 2012. but our findings demonstrate a clear downside to this approach for certain men.09). and is also associated with increased fractures. [Cancer 1993. intermittent and continuous therapies were comparable.1 years vs 5.71:2782-2790] The advantages of the intermittent approach and its comparable efficacy were confirmed by at least 23 phase II trials. In addition. Ann Arbor. these studies were essentially underpowered to evaluate survival. William Oh from the Mount Sinai School of Medicine.

USA. 85-90 percent of patients ultimately develop resistance to these tyrosine kinase inhibitors [TKIs] that target KIT or PDGFRA. 0.27. with side effects similar to those of imatinib and sunitinib.” pointed out Demetri. 0.” .5 vs 1. Disease control and objective response also favored regorafenib.239. making it a potentially significant new option.5 percent. Dana Farber Cancer Institute. hypertension and diarrhea. Patients were randomized to receive regorafenib 160 mg once daily plus best supportive care (BSC) (n=133). If approved.9 months for placebo [HR. Regorafenib was generally well tolerated in the trial. with progression-free survival [PFS] being four times longer in the regorafenib arm. murine VEGFR-2.212 and 0. RET. Massachusetts. the most common mutations in GIST (HR. USA Regorafenib offers hope for GIST patients failing TKIs Christina Lau T he multi-kinase inhibitor regorafenib may represent the first targeted treatment option for patients with metastatic and/or unresectable gastrointestinal stromal tumor (GIST) who progressed despite prior use of both imatinib and sunitinib. On the next progression. The most common grade 3 adverse events were hand-foot skin reaction.” he suggested. on a 3-weeks-on 1-week-off schedule. at 52.12 Jul-Aug 2012 Conference Covera ge American Society of Clinical Oncology (ASCO) 2012 Annual Meeting. patients were taken off treatment. “Positive results of the trial were submitted to regulatory authorities in March 2012.” he noted.” The same PFS benefit was maintained in patients with KIT exon 11 (n=51) or exon 9 (n=15) mutation. The phase III GRID (Regorafenib in Progressive Disease) trial included 199 patients from 17 countries who failed at least imatinib and sunitinib – the only two drugs approved for GIST worldwide. PDGFR-b.0001]. “The side effects were all manageable with dose modifications. the difference between the two arms did not reach statistical significance as 85 percent of patients in the placebo arm crossed over to receive open-label regorafenib. Regorafenib is a structurally distinct oral inhibitor of KIT. “Although overall survival [OS] favored regorafenib [HR. “While imatinib and sunitinib have increased patient survival in metastatic GIST from 3-6 months to 5 years or more.77]. 0.” reported Dr. VEGFR-1. respectively. The trial was unblinded on disease progression.6 vs 9. “PFS rates at 3 and 6 months were 60 vs 11 percent and 38 vs 0 percent. Chicago. George Demetri.1 percent and 4. BRAF and FGFR-1 that appears to target GIST in a possibly more powerful way. [Abstract LBA10008] “The trial met its primary endpoint. respectively.8 months for regorafenib vs 0. regorafenib will fulfill an urgent unmet need for GIST patients who have exhausted all other treatment options. respectively). or placebo plus BSC (n=66). p<0. when placebo-treated patients were eligible for crossover to openlabel regorafenib and regorafenib-treated patients continued on their treatment. 1-5 June 2012. Median PFS was 4.

or platinum-based chemotherapy. Pain scores fell by half in 21 percent of patients on duloxetine vs 9 percent on placebo. A total of 220 patients with peripheral neuropathic pain associated with paclitaxel or oxaliplatin were randomized to receive duloxetine (30 mg daily in the first week. works by increasing amounts of pain-inhibiting neurotransmitters. we think patients who respond may have some abnormalities in the way their brain processes pain … and we have to identify who might respond so we can target the use of this drug. fewer patients on duloxetine experienced this effect compared with the placebo group.. duloxetine conferred a ≥30 percent reduction in pain score for 33 percent of patients.” Lavoie Smith said. a small proportion of patients felt more pain after receiving treatment. Fatigue. only 17 percent achieved a similar reduction in pain.” The drug was generally well tolerated. 59 percent of patients taking duloxetine achieved some degree of pain relief vs 38 percent of placebo recipients. Ann Arbor. Although mean pain scores fell in the placebo group as well. 1-5 June 2012. Seven percent of recipients experienced severe adverse events and 11 percent dropped out of the study as a result of side effects.. [Abstract CRA 9013] In the study. . University of Michigan School of Nursing. a randomized controlled trial has found the serotoninnorepinephrine reuptake inhibitor (SNRI) duloxetine to be effective against chronic neuropathic pain associated with taxane.” commented lead investigator Dr. In the placebo group. “Not everyone responded to duloxetine. insomnia. “A 30 percent decrease in pain is clinically significant and important to patients. somnolence and dizziness were the most common adverse events.13 Jul-Aug 2012 Conference Covera ge American Society of Clinical Oncology (ASCO) 2012 Annual Meeting.003). Overall. USA. However. USA Antidepressant relieves chemo-induced neuropathic pain Yen Yen Yip F or the first time. patients who received du- loxetine achieved a significantly greater degree of pain relief (p=0. nausea. Chicago. “Duloxetine. then 60 mg daily for 4 weeks) or placebo. Ellen Lavoie Smith.

“We still have no idea how to identify patients who are resistant to endocrine . and which do not need them. André Prof.” said André. However. Smith Dr. However. aromatase inhibitors (AIs) are the first-line treatment choice. This has led to the development of targeted therapies. Research on endocrine-resistant cells showed that selective inhibitors of the PI3K/ AKT/mTOR pathway provide significant growth inhibition in long-term estrogendeprived breast cancer cells. Novartis) in combination with exemestane more than doubled progression-free survival (PFS) in women with estrogen receptor positive (ER+). [Nat Rev Drug Discov 2005. [Clin Cancer Res 2010.16:1979-1987] “Molecular mechanisms of resistance are emerging. human epidermal growth factor receptor 2-negative Prof.4:988-1004] “Kinase activation induced by long-term estrogen deprivation and genomic alteration acquired during the natural course of the disease may lead to acquired resistance. “Activation of the AKT/mTOR pathway leads to resistance to endocrine therapy and their inhibition reverses the resistance. UK. In postmenopausal patients.” explained Dr. Overcoming endocrine resistance Over two-thirds of breast cancers express the ER which contributes to tumor growth and progression. France.14 Jul-Aug 2012 ASCO 2012 Sa tellite Symposium Everolimus plus exemestane improves PFS in advanced breast cancer Updated data from the BOLERO -2 trial demonstrate that everolimus (Afinitor®. such as anti-estrogens that target ERs. presented at a Novartis-sponsored symposium held in conjunction with the American Society of Clinical Oncology (ASCO) 2012 Annual Meeting. Fabrice André of the Institute Gustave Roussy Villejuif. Everolimus: Targeting the PI3K/ AKT/mTOR Pathway Abnormalities in the phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway have been implicated in several forms of human cancer. Rugo (HER2-) advanced breast cancer who are resistant to hormonal therapy. up to 25 percent of all breast cancer patients do not respond to endocrine therapy (de novo resistance). whereas others will eventually relapse despite an initial response due to either intrinsic or acquired resistance.” said Professor Ian Smith of the Royal Marsden Hospital and Institute of Cancer Research in London. confirm evidence from previous analyses on the survival benefits of adding everolimus to exemestane. Patients who are ER+ benefit from endocrine therapeutic agents. The data. the challenge is to define which patients will most likely benefit from these therapies.

conducted by the Groupe d’Investigateurs Nationaux pour l’Etude des Cancers Ovariens et du sein (GINECO Group.” said Professor Hope Rugo of the University of California. France).advanced breast cancer refractory to treatment with nonsteroidal AIs (NSAIs) such as letrozole or anastrozole.45 Log-rank p value <0. randomized phase III trial designed to evaluate everolimus in combination with exemestane vs exemestane alone in postmenopausal women with ER+ HER2. with median time to disease progression of 8.metastatic breast cancer with prior exposure to AIs.30(suppl): abstract 559. Everolimus. [Pharmacotherapy 2012.4 in the 12-month follow-up) vs 3. [J Clin Oncol 2012. It is very encouraging that there are numerically fewer deaths in the everolimus arm vs the placebo arm. Results showed that addition of everolimus to tamoxifen delayed disease progression compared to tamoxifen alone.2 months HR=0. was designed to evaluate the efficacy and safety of everolimus in combination with tamoxifen vs tamoxifen alone in patients with hormone receptorpositive (HR+). N Engl J Med 2012. BOLERO-2 18-month follow-up: PFS based on local assessment 100 80 60 40 20 0 0 Patients at risk EVE 10 mg + EXE PBO + EXE therapy before they relapse. San Francisco. respectively. [Cancer Res 2011. chemotherapy.2 percent of patients who died in the exemestane-only arm. et al. EVE = everolimus.0001 Censoring times EVE + EXE (n/N = 310/485) PBO + EXE (n/N = 200/239) 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 102 108 114 120 Time (weeks) 485 436 366 304 257 221 185 158 124 91 239 190 132 96 67 50 39 30 21 15 66 10 50 8 35 5 24 3 22 1 13 1 10 1 8 0 2 0 1 0 0 0 EXE = exemestane. USA.6 vs 4.0084 Censoring times EVE + EXE (n=485) PBO + EXE (n=239) 6 12 18 0 24 30 36 42 48 54 60 66 72 78 84 90 96 Patients at risk EVE 10 mg + EXE PBO + EXE Time to deterioration in QoL (months) 176 49 145 36 119 27 99 19 71 16 52 7 43 6 485 239 427 201 305 116 245 83 198 62 29 3 18 1 13 0 9 0 8 0 BOLERO-2 study New subgroup analyses BOLERO-2 (Breast cancer trials of OraL EveROlimus-2) is an international. [Ann Oncol 2012.71(24 suppl):abstract S37.8 months Log-rank p value=0. or patients who are more likely to respond to treatments that may reverse resistance.5 months.8 months PBO + EXE: 3. HR = hazard ratio. and this difference has continued with the latest analysis of data.366:520-529] Updated results of an 18-month followup showed a median PFS of 7. abstract 13O_PR] Probability (%) of event Median PFS: EVE + EXE: 7. HER2. The study included 724 advanced breast cancer patients from 189 sites worldwide. 23(suppl 2): ii17–ii24.1 months in the exemestane-only arm.” said Rugo.2 months for patients receiving exemestane alone (n=239). HER2-. “The clinical benefit of everolimus was observed in all subgroups in the BOLERO-2 study. PBO = placebo. an oral mTOR inhibitor.15 Jul-Aug 2012 ASCO 2012 Sa tellite Symposium Figure 1. Delaying bone progression “Subgroup analysis showed that everolimus delayed bone progression in patients with or without bone metastasis at baseline.8 months for patients receiving exemestane plus everolimus (n=485) (7. PFS = progression-free survival Adapted from Piccart MJ.3 months PBO + EXE: 5. has promising clinical activity in women with HER2+. “The delay was more .30(suppl): abstract 559] 100 80 60 40 20 0 Probability (%) of event Median time to QoL deterioration EVE + EXE: 8. (Figure 1) An independent review showed a PFS of 11 months in the combination arm vs 4. Eligible patients were randomized (2:1) to exemestane (25 mg/day) with everolimus (10 mg/day) or placebo. and ER+ breast cancer when combined with HER2-targeted therapy.4 percent in the combination arm died. 25. Compared to 32.” said Rugo. J Clin Oncol 2012. and hormonal therapy.32:383-396] The phase II TAMRAD trial.

3 months for everolimus plus exemestane vs 5. Results showed that bone turnover markers were reduced in the combination arm vs the exemestane-alone arm during the first 12 weeks of therapy.37. ASCO 2012. Everolimus.05). among Asian patients (HR=0. et al. . using the EORTC-QLQ-30 (European Organization for Research and Treatment of Cancer Core Cancer Quality of Life Questionnaire) Global Health Scale with minimal important difference of 5%.14 months) and nonAsian patients (median. QoL = quality of life Adapted from Beck JT.05).8 months Log-rank p value=0. 98 received everolimus plus exemestane and 45 received exemestane alone.83 months with the combination vs 4.advanced breast cancer. et al. Results demonstrate that median time to definitive deterioration in HRQoL was 8. in those <65 years (HR=0. BOLERO-2 18-month follow-up: QoL* 100 80 60 40 20 0 0 Patients at risk EVE 10 mg + EXE PBO + EXE Probability (%) of event Median time to QoL deterioration EVE + EXE: 8. when added to exemestane. respectively.48 vs 4. et al. ASCO 2012.8 for exemestane alone. A BOLERO-2 subanalysis evaluated the effect of everolimus in combination with exemestane vs exemestane alone on markers associated with bone formation and resorption.05). (Figure 2) [Beck JT. Combination therapy reduced the risk of disease progression by 44 percent vs exemestane alone Results of the 18-month follow-up of the BOLERO-2 trial are supportive of previously presented data from the 12-month follow-up. Therefore. [Noguchi S. 56 percent of Asian patients in the combination arm had experienced disease progression vs 76 percent in the exemestane-alone arm. compared with 8. p<0. At a median follow-up of 12.5 months.31 and 2. PFS was 6.0 0 EVE + EXE (n/N = 310/485) PBO + EXE (n/N = 200/239) 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 102 108 114 120 16 Jul-Aug 2012 ASCO 2012 Sa tellite Symposium Patients at risk EVE 10 mg + EXE PBO + EXE Time (weeks) 66 10 50 8 485 436 366 304 257 221 185 158 124 91 239 190 132 96 67 50 39 30 21 15 35 5 24 3 22 1 13 1 10 1 8 0 2 0 1 0 0 0 significant in patients with bone metastases at baseline.56. ASCO 2012.3 months PBO + EXE: 5. EXE = exemestane. 7.0084 Censoring times EVE + EXE (n=485) PBO + EXE (n=239) 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 Time to deterioration in QoL (months) 485 239 427 201 305 116 245 83 198 62 176 49 145 36 119 27 99 19 71 16 52 7 43 6 29 3 18 1 13 0 9 0 8 0 * QoL evaluated at baseline and every 6 weeks thereafter until progression. This combination is a step forward that offers good QoL.83 months).33 vs 2.92 months. abstract 551] Conclusion Of 143 Asian patients in the BOLERO-2 study.56. 8.48(suppl 1): abstract LBA3] NSAIs are associated with decrease in bone mineral density and increased risk of fractures. abstract 539. At the time of database lock. it is important to evaluate whether new therapies in combination with exemestane affect bone turnover. p<0. Maintaining quality of life (QoL) Figure 2. significantly improves PFS in patients with ER+ HER2. abstract 540] Elderly vs younger patients A subgroup of patients was assessed to determine whether any disruption in health-related quality of life (HRQoL) occurred with the everolimus-exemestane combination. [Pritchard KI. p<0. et al. EVE = everolimus.01 months with exemestane alone in elderly patients (HR=0. suggesting that adding everolimus to exemestane maintained QoL in the patients.” [Eur J Cancer 2012. The PFS benefit with everolimus plus exemestane vs exemestane alone was similar in Asian patients (median. ASCO 2012. The PFS benefit was demonstrated across various subgroups of patients. suggesting clinical benefits on bone health. abstract 539] In Asian patients Adding everolimus to exemestane was beneficial for both elderly (≥65 years) and younger (<65 years) patients.

As Professor Bernard Escudier of the Institut Gustave Roussy. with comparable efficacy but differences in terms of safety profile. during the 2-week washout period. pazopanib was less toxic. or even years. good or intermediate prognosis. measurable or non-measurable disease.17 Jul-Aug 2012 ASCO 2012 Meeting Highlights PISCES study: mRCC patients favor pazopanib for better QoL Pazopanib is an oral multi-kinase angiogenesis inhibitor which significantly improves progression-free survival (PFS) in patients with metastatic renal cell carcinoma (mRCC). a strong association between adverse events and HRQoL suggests that patient preference is a legitimate and useful endpoint. Escudier Pazopanib and sunitinib: Comparable efficacy. different safety erability and HRQoL on a patient’s choice of treatment. It has also demonstrated a unique safety profile compared with other approved agents for mRCC. drug tolerability is a major determinant of health-related quality of life (HRQoL). followed by a 2-week washout period.” said Escudier. An indirect comparison suggested that PFS rates associated with pazopanib in treatment-naïve subjects were not significantly different from sunitinib (hazard ratio [HR]. [Abstract CRA4502] The subjects were stratified based on their ECOG performance status and the number of metastatic sites (1 vs ≥2). and again at the end of the second . where patients may have to be treated for many months. and adequate cardiac and renal function. and then sunitinib 50 mg for 10 weeks. or vice versa (sunitinib then pazopanib). with lower rates of grade 3 or 4 adverse events (44 percent) as compared with sunitinib (67 percent). However.” noted Escudier. Patients were eligible if they had previously untreated mRCC. 0. Prof. elaborated at the American Society of Clinical Oncology (ASCO) 2012 Annual Meeting. in which 169 patients were randomized 1:1 to receive pazopanib 800 mg for 10 weeks. “While the evaluation of drug tolerability is not easy. France. CT scans were performed before the start of the trial. ASCO GU 2010. The PISCES (Patient Preference Study of Pazopanib vs Sunitinib in Advanced or Metastatic Kidney Cancer) was thus designed to assess the impact of tol- PISCES: Are differences in drug tolerability clinically meaningful for patients? PISCES was a double-blind. which in turn determines patient preference for one therapy over another. “Pazopanib and sunitinib are both approved treatments for mRCC. no brain metastases.93). any renal cancer histology. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1. crossover study. abstract 413] Safety and tolerability takes on a special significance in mRCC. [McCann L.

001).001 (n=80) (n=9) (n=25) Patients prefer pazopanib Results showed that patients had a strong preference in favor of pazopanib. Reasons influencing patients’ choice of therapy and the single most important reason forLess soreness Less nausea/vomiting Pazopanib preferred (n=80) Less soreness in hands/feet Primary analysis population their preference.” 70% 40 said Escudier. Other Less soreness in mouth/throat Figure 1. In the primary endpoint analysis. 70 percent of patients said they preferred to continue treatment with pazopanib vs 22 percent for sunitinib. The physician preference analysis was completed while the patients were still blinded.18 Jul-Aug 2012 ASCO 2012 Meeting Highlights 90 80 70 60 50 Primary analysis population Difference (pazopanib vs sunitinib) p value 49.001 70% (n=80) treatment period. These differences were statistically significant (p<0. (Figure 1) “All pre-planned sensitivity analyses were statistically in favor of pazopanib. safety and quality of life. Two adPatients werepreferred able to select >1 reason Pazopanib preferred No preference Pazopanib preferred Sunitinib Sunitinib preferred No preference Better quality of life ditional questions were asked to determine Less fatigue Adapted from Escudier BJ. Better quality of life Less nausea/vomiting Less hair colour change fatigue Pazopanib preferred (n=80) LessLess soreness in hands/feet 0 10 20 30 40 preferred 50 60 70 Sunitinib (n=25) Lesstastes loss of appetite Less changes in food Number of patients Less stomach pain Less soreness in mouth/throat Less diarrhea Less nausea/vomiting Other Less hair colour Pazopanib preferred (n=80) Less soreness in hands/feet change 0 10 20 30 40 50 60 preferred 70 (n=25) Sunitinib Less loss of appetite Number of patients Less stomach pain Adapted from Escudier BJ.3% tionnaire at the end of the study. ASCO 2012. (Figure 2) Patients also preferred pazopanib because they experienced less soreness in the mouth/throat. abstract CRA4502.3% < 0. Results indicated that 61 percent of . physician preference was 0 Pazopanib preferred Sunitinib preferred No preference quite comparable to patient preference. loss of appetite. nausea/vomiting. Patients were able to select >1 reason Sunitinib preferred (n=25) Less loss of appetite Other endpoints included physician prefBetter quality of life Less stomach pain Primary analysis population Less fatigue Less diarrhea Patients were able to select >1 reason Less changes in food tastes erence. PISCES primary endpoint: Patient preference 40 Percent of patients 90 80 70 60 50 40 30 20 10 0 Percent of patients Difference (pazopanib vs sunitinib) p value 49.”said Escudier. where the 20 (n=9) 22% subjects indicated which drug they pre10 22% Primary analysis population (n=25) 8% 8% 0 ferred to continue treatment with. diarrhea and hair color change during the treatment period. Less diarrhea Other Less hair colour 3. 40 30 61% Physician preference reflects patient choice 20 22% 10 17% “Interestingly. 30 “Patients who had received ≥1 dose in 20 Primary analysis population 90 both treatment periods completed a ques(n=9) 22% 10 80 Difference (pazopanib vs (n=25) 8%49. change Figure Physician preference in PISCES 0 10 Number of patients Primary analysis population Primary analysis population 20 30 40 50 60 70 90 Percent of physicians 80 Percent of physicians 90 80 70 60 50 40 30 20 10 0 61% 70 60 50 40 30 20 10 Pazopanib preferred Sunitinib preferred Sunitinib preferred NoNo Preference Preference Pazopanib preferred 61% 22% 17% 17% Pazopanib preferred Sunitinib preferred No preference Primary analysis population 22% 0 90 Percent of physicians No preference 80 Pazopanib preferred Sunitinib preferred Pazopanib preferred 70 Sunitinib preferred 60 No Preference 50 Adapted from Escudier BJ. ASCO 2012. the reasons that influenced their choice.001 they were still blinded and before end60 70% (n=80) 50 of-study imaging results were disclosed. et al. Less changes in food tastes in mouth/throat Figure 2. et al. abstract CRA4502. ASCO 2012.” Escudier noted. while 0 70 Pazopanib preferred sunitinib) Sunitinib preferred No preference Primary analysis population p value < 0. soreness in the hands/ feet.3% Percent of patients < 0. Better quality of life. abstract CRA4502. stomach pain. said Escudier. The primary endpoint of the 30 study was patient preference. et al. less fatigue and fewer changes in food taste were most commonly cited by patients as the reasons that influenced their preference for pazopanib. Only 8 percent of patients did not have any preference.

p=0. leading to higher rates of anemia. 13 percent of patients required a dose reduction – a lower incidence compared with sunitinib (20 percent). mucositis. neutropenia. In the pazopanib group. compared with 22 percent who preferred sunitinib. pazopanib was more likely to cause an increase in the levels of alanine aminotransferase (ALT) and total bilirubin. it appeared that diarrhea was more common with pazo- Conclusions The PISCES study demonstrated that mRCC patients preferred pazopanib over sunitinib. “This is an excellent method to report the way patients are feeling about the toxicity of drugs. treatment discontinuation rates for sunitinib and pazopanib were 31 percent and 15 percent. physicians preferred pazopanib. hands and feet also established pazopanib’s superiority over sunitinib (p<0. However.19 Jul-Aug 2012 ASCO 2012 Meeting Highlights panib. will help clinicians decide on the most appropriate treatment option for patients. Seventeen percent of the physicians had no preference at all. In the second treatment period. respectively).” Escudier noted. respectively.002). A supplementary questionnaire that evaluated soreness in the mouth/throat. the PISCES investigators confirmed that patients were significantly less likely to experience fatigue when they received pazopanib (p=0.” he pointed out. 18 percent of patients on sunitinib discontinued therapy compared with 14 percent on pazopanib. Upcoming results of the COMPARZ (Pazopanib vs Sunitinib in the Treatment of Locally Advanced and/or Metastatic Renal Cell Carcinoma) study will provide a headto-head comparison of efficacy and safety in treatment-naïve subjects with mRCC. The preference for pazopanib was reflected among physicians as well. “Fewer dose modifications were required with pazopanib. lymphopenia. as they had better HRQoL and were less fatigued during pazopanib therapy. It’s an important reminder that lowgrade toxicities. In terms of biological and hematological toxicity. In contrast. In the first treatment period. which may not seem bad. (Figure 3) Improved quality of life and drug safety Using the Functional Assessment of Chronic Illness Therapy-Fatigue (FACITF) tool to evaluate fatigue. “These landmark findings.” In a comparison of non-hematologic toxicity between the two drugs. dysgeusia.005. leukopenia and thrombocytopenia.001. he highlighted. “This innovative trial clearly demonstrates the better tolerability of pazopanib over sunitinib.025. together with that of PISCES.” said Escudier. .” said Escudier.” However. myelosuppression was more common with sunitinib. “Adverse events were in line with known profiles for both drugs. stomatitis and hand-foot syndrome occurred more frequently in the sunitinib group. Patients receiving pazopanib were also less likely to discontinue therapy prematurely due to adverse events. have an effect on your quality of life if experienced over a long period of time. said Escudier. “How patients feel when they take a drug over many months isn’t reflected in traditional adverse event reporting. the study design of PISCES does not allow an efficacy comparison. p=0.

[Clin Cancer Res 2011. Latest data from the CLEOPATRA trial which evaluated the addition of pertuzumab to trastuzumab based therapy in HER2+ BC were also presented at the meeting. “Once T-DM1 binds to the extracellular component of the HER2 receptor and is internalized. [Hurvitz S. Professor Kimberly Blackwell Blackwell of Duke University Cancer Institute. “Dose reductions were also less frequent on T-DM1 [16. duration of response. T-DM1 achieved a statistically significant 5-month improvement in median PFS compared with a combination of trastuzumab and docetaxel (14. with a median time to progression of <10 months. 17:6437-6447] In a phase II trial of patients without prior HER2-directed therapy for mBC. US.2 percent] and lapatinib [93. much-anticipated results of the EMILIA study demonstrated that an innovative experimental drug. Roche). and time to symptom progression. Trastuzumab emtansine T-DM1 is a three-part antibody-drug conjugate comprising trastuzumab. trastuzumab emtansine (T-DM1. provided significant improvements Prof.9 percent. “Median dose intensity for T-DM1 was 99. respectively. the emtansine component separates from trastuzumab and delivers microtubule-disrupting cytotoxic activity to antigen-expressing tumor cells. in progression-free survival (PFS) over current treatments. presented the data at the American Society of Clinical Oncology (ASCO) 2012 Annual Meeting.4 months and 12.4 percent] and lapatinib [27. ESMO 2011] EMILIA: A phase III study of T-DM1 EMILIA is the first randomized. Recently. the only approved combination for trastuzumab-refractory HER2+ mBC.” she said. phase III trial to evaluate T-DM1 against capecitabine plus lapatinib. Durham.” explained Blackwell.3 percent]. Targeted therapy options for patients with HER2+ metastatic breast cancer (mBC) have been limited.4 percent].2 vs 9. and a stable linker that binds the antibody and the cytotoxic drug.9 months. the potent cytotoxic agent DM-1. The T-DM1 and control arms had a median follow-up of 12.” Blackwell noted. p=0.2 months. ‘Emtansine’ refers to the linker and DM-1 combination. “The study recruited 991 patients with HER2+ locally advanced or mBC whose disease had progressed within 6 months of initial treatment with trastuzumab and a taxane-based chemotherapy.3 percent] than with capecitabine [53. The key secondary endpoints were PFS by investigator review.035). dose intensity was lower for patients on capecitabine [77.20 Jul-Aug 2012 ASCO 2012 Meeting Highlights Trastuzumab emtansine: A new weapon against HER2-positive mBC Approximately 15 to 20 percent of all breast cancers involve human epidermal growth factor receptor 2-positive (HER2+) disease.” . objective response rate (ORR). The study was designed with two co-primary endpoints: PFS by independent review and overall survival (OS).

(Figure 1) PFS results from the investigator assessment were consistent with the independent review. there was an absolute difference in OS of 7.” noted Blackwell.650 8 5 p<0. lap = lapatinib.0001 Superior PFS Figure 1.” Trend towards improved OS 8 129 183 10 73 130 12 53 101 No.650 p<0. Two-year survival was 65.7% p=0.6 0 2 0 0 0 0 0 0 0 0 0 0 0 0 Cap + Lap 30.6 vs 6. at risk by independent review: Cap + Lap 0.2 1.3 months for patients who received capecitabine/lapatinib.2 1.6 Percent 30 20 10 50 0 40 120/389 ORR Difference: 12.8 0.4 Cap + Lap T-DM1 Median. The median PFS for the two treatment arms was 9.6 months vs 6.8% T-DM1 No.7 percent at 1 year and 17.8 percent for those who received capecitabine/lapatinib (p=0. and in clinically relevant subgroups such as estrogen receptor status and exact line of therapy.4 0. et al. there was a 6. abstract LBA1. Objective response rate and duration of response in patients with measurable disease ORR Difference: 12.2 0.0. et al. as well as BC-specific symptoms. Interim analysis indicated that T-DM1 improved OS vs the comparator.1-month absolute improvement in median DOR with T-DM1 [12. which is clinically important.0 0. delivering an absolute improvement of 3. mos 6.0 0. “T-DM1 showed a 2.4 percent vs 47. T-DM1 delivered superior results in ORR and duration of response (DOR) as well.0001 44 30 18 9 1 3 0 1 30 0 0 0. ASCO 2012.8% 43.4 0.0 DOR Cap + Lap T-DM1 Median.6 0.6 percent. ORR in the T-DM1 group was 43.” said Blackwell.66 (p<0.6 ORR = objective response rate.1 months vs 4.8 0 2 4 6 176 236 “EMILIA met its primary endpoint of improving PFS with T-DM1 treatment. 20 10 0 0.2 months in median PFS as compared with capecitabine/lapatinib.6 265 Stratified HR=0. The final analysis is expected in 2014. Cap = capecitabine.6 months on capecitabine/lapatinib (p=0. Better safety profile T-DM1 was associated with fewer grade . DOR = duration of response. at risk by independent review: Cap + Lap 496 404 310 T-DM1 495 419 341 14 16 18 Time (mos) 35 72 25 54 14 44 20 9 30 22 8 18 24 5 9 26 1 3 28 0 1 30 0 0 Unstratified HR=0. One-year survival rate among patients who received T-DM1 was 84.6 265 Time (mos) 35 72 25 54 Stratified 14 9 HR=0.7% p=0. of events Cap 6.” reported Blackwell. patients over 65 years of age had a hazard ratio of 1. “However. treatment line for metastatic disease and the presence of visceral disease. HR = hazard ratio.2 0. (Figure 2) “In patients with an objective response. Median time to progression on T-DM1 was 7. T-DM1 = trastuzumab emtansine Adapted from Blackwell K.6% Proportion progression-free Proportion progression-free DOR Cap + Lap T-DM1 0 2 4 6 Median.4 0. abstract LBA1. As the efficacy boundary has not been crossed and OS has not been reached in T-DM1 patients.0121). including world region.5 12.4 304 9. indicating a less definitive PFS advantage for T-DM1 in this small patient subgroup.5 12. significantly higher than the 30. “Based on the pre-planned analysis.Proportion progression-free Proportion progression-free 21 Jul-Aug 2012 ASCO 2012 Meeting Highlights 1.5-month delay in time to symptom progression from baseline.0001).7 percent vs 77 percent for capecitabine/lapatinib. Cap + Lap T-DM1 No.4 22 24 304 14 + Lap 16 18 20 26 28 T-DM1 9.5 percent.6 496 404 310 T-DM1 495 419 341 Median. lap = lapatinib.06.0002). mos No. at risk Cap + Lap0.0002 50 40 30.4 months (p<0.8 0. mos 6. mos No.6% 1. but had not been reached for the T-DM1 group.0 0.” commented Blackwell.0 0. EMILIA: PFS by independent review 0. at risk Cap + Lap T-DM1 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 0 2 0 0 0 0 0 0 0 0 0 0 0 0 120 105 77 48 32 14 9 8 3 3 1 1 173 159 126 84 65 47 42 33 27 19 12 8 Delay in symptom progression Time to symptom progression was measured by evaluating the patients’ physical and functional well-being. T-DM1 = trastuzumab emtansine Adapted from Blackwell K.5 months]. the OS analysis has not achieved statistical significance. of events 6. PFS = progression-free survival. ASCO 2012.0001). Figure 2.0002 173/397 43.0 0 2 4 6 176 236 8 129 183 10 73 130 12 53 101 No.0 Higher objective response rate 120/389 173/397 Median OS was 23.6 0.8 120 105 77 48 32 14 9 8 3 3 1 1 T-DM1 173 159 126 84 65 47 42 33 27 19 12 8 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 Percent 30 Cap = capecitabine.” said Blackwell. “The treatment effect was shown to consistently favor T-DM1 in most subgroup analyses.0 0.9 percent at 2 years in favor of T-DM1.

” Blackwell concluded. Among patients receiving T-DM1. T-DM1-treated subjects also had increased alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels.8 percent).7 vs 5.7 vs 1. The addition of pertuzumab did not limit the dose or dose intensity of docetaxel that could be delivered. but a higher rate of febrile neutropenia occurred in patients from Asia. Most adverse events occurred when pertuzumab was administered concomitantly with docetaxel. Grade ≥3 adverse events were infrequent. Spain evaluated health-related quality of life (HRQoL) data from CLEOPATRA. ≥3 adverse events than capecitabine/lapatinib (57 vs 40. a novel anti-HER2 monoclonal antibody. despite adverse events associated with the pertuzumab-containing regimen. [Poster 598] . double-blind clinical trial evaluating the efficacy and safety of pertuzumab. Professor Javier Cortes.22 Jul-Aug 2012 ASCO 2012 Meeting Highlights dose. Massachusetts General Hospital. CLEOPATRA study updates CLEOPATRA is a phase III randomized. “Targeted cancer therapy has progressed another step forward with the EMILIA study. Based on these findings. Only one toxicity-related death occurred in the T-DM1 group vs five in the comparator group. An index score assessing physical. trastuzumab and docetaxel. T-DM1 will be submitted to the EMA and the US FDA for approval as therapy for HER2+ mBC. In 2011. the study had demonstrated that adding pertuzumab to trastuzumab and docetaxel improved PFS over placebo. and T-DM1 should offer an important therapeutic option in the treatment of HER2+ mBC.6 percent). Cardiac toxicity was rare in both groups. Nonetheless. Patients who received pertuzumab had similar HRQoL scores as those who received placebo. [Poster 597] In another poster. combined with trastuzumab plus docetaxel as first-line therapy for HER2+ mBC. functional and breast well-being could have improved with discontinuation of docetaxel as well. US suggested that pertuzumab combined with trastuzumab and docetaxel may also be well-tolerated in patients with HER2+ early BC. the most common grade ≥3 adverse events were thrombocytopenia (12. Barcelona. the occurrence of febrile neutropenia – and most adverse events – stopped with the discontinuation of docetaxel. Vall d’Hebron University Hospital. thus delaying the development of resistance.9 vs 0. A higher proportion of patients who received capecitabine/ lapatinib discontinued their treatment due to adverse events (10. Boston. The rationale for adding pertuzumab to trastuzumab-based therapy is to achieve a more comprehensive shutdown of the HER2 pathway.2 percent) and anemia (2. A poster presentation by Professor Jose Baselga. but in most cases they were normalized by the time of the next T-DM1 Conclusions The first phase III study of T-DM1 demonstrated that its efficacy and safety profile is superior to the established capecitabine/ lapatinib regimen. This may be attributed to the fact that the addition of pertuzumab substantially delayed the time to onset of specific BC symptoms.9 percent).

and PLD (40 mg/m2 day 1 q4w). or bevacizumab (15 mg/kg q3w) in combination with chemotherapy (n=179). our objective was to evaluate the efficacy and safety of adding bevacizumab to chemotherapy in this setting. Treatment in both arms was continued until progression or unacceptable toxicity. At first relapse. international trial in 361 patients with epithelial ovarian. when added to standard chemotherapy. However. “Median overall survival [OS] is typically less than 12 months. pegylated liposomal doxorubicin (PLD) or topotecan is the current standard of care. “Ovarian cancer is a highly VEGF-driven disease. topotecan (4 mg/m2 days 1. Study patients had received ≤2 prior anticancer regimens. treatment options for platinum-resistant ovarian cancer are limited. and had no history of bowel obstruction or abdominal fistula.26:1773] AURELIA: Bevacizumab in platinumresistant recurrent disease AURELIA is a multicenter. [Abstract LBA5002] The patients were randomized 1:1 to receive chemotherapy based on investigator choice (n=182). 8. and almost all patients with recurrent ovarian cancer will ultimately develop platinum resistance. This may change. 8 and 15 q4w or 1. As bevacizumab has demonstrated single-agent activity in platinum-resistant ovarian cancer.25:51805186. While single-agent weekly paclitaxel. Results were presented recently at the American Society of Clinical Oncology (ASCO) 2012 Annual Meeting by Professor Eric Pujade-Lauraine of the Group d’Investigateurs Nationaux pour l’Etude des Cancers Ovariens (GINECO) and Université Paris Descartes in France. PujadeLauraine Unmet need in difficult-to-treat disease “Most patients with advanced ovarian cancer will relapse. or clinical or radiological evidence of recto-sigmoid involvement. as the phase III AURELIA trial demonstrated that bevacizumab (Avastin Roche®.” he pointed out. At disease progression. Prof. J Clin Oncol 2008. Roche). patients . Chemotherapy options in the trial were paclitaxel (80 mg/m2 days 1.23 Jul-Aug 2012 ASCO 2012 Meeting Highlights Bevacizumab shows benefit in platinum-resistant ovarian cancer Platinum-resistant ovarian cancer is notoriously difficult to treat as therapeutic options are limited in number and efficacy.25 mg/m2 days 1-5 q3w). 15 and 22 q4w). primary peritoneal or fallopian tube cancer whose disease progressed within 6 months after ≥4 cycles of platinum-based therapy. 25 percent of patients have platinum-resistant disease.” he said. [J Clin Oncol 2007.” said PujadeLauraine. combination regimens have failed to improve efficacy vs monotherapy. significantly improves progressionfree survival (PFS) in patients with platinum-resistant recurrent disease.

40.8 p=0.8 12. Summary of best overall response rates 5050 50 BEV + CTCT CT BEV + CTCT 4545 45 BEV + CT p<0.3 3.5 5.50 Yes (≥5) 161 3. vomiting and dyspnea were less common with bevacizumab/chemotherapy vs chemotherapy alone. presence of ascites.3 6.7 0.5 7.01. fatigue.4 0.32 0.46 0. PFS: Overall population 1.7 7.46 3–6 3–6 257 257 3. 166 (91%) 135 (75%) Median PFS.5 5.5 7. PFS = progression-free survival.3 0.6 0.8 15 15 12.” Significant improvements in PFS and response The trial met its primary endpoint of PFS.7 Median PFS.7 6.46 Measurable No (<1) disease.3 0.40. ASCO 2012.60.0 0.0 0. ASCO 2012.32 Topotecan Topotecan 120 120 2.4 0.5 7. including bleeding.50 0.7 6.49 Age.0 6.001 Log-rank p-value <0. Investigators selected the chemotherapy based on each patient’s previous experience with the drugs. wound-healing complication.4 6. at risk: CT No.4 3. monthsb <3 <3 3–6 257 3. months Median PFS.48 No No 248 248 3.6 11.001 p<0.” In the trial.6 11. CT = chemotherapy.50 disease. reversible posterior leukoencephalopathy syndrome and cardiac disorders. months Median PFS.9 31.001 31.4 0.001 4040 40 p<0. n (%) n (%) 166 (91%) 135 (75%) Events. “The PFS benefit was consistent in all patient subgroups regardless of age. Although peripheral sensory neuropathy and hand-foot syndrome were increased Figure 3.5 5.40 0.4 5.4 0. Safety and tolerability in the chemotherapy-alone arm were allowed to cross over to bevacizumab monotherapy. The difference was highly significant.6 7. differing only in their toxicities.6 11.9 10. .5 3.” noted Pujade-Lauraine. years <65 <65 ≥65 133 3.48 6.6 0. hematologic toxicity.001 31.57 0.3 3. Estimated probability Estimated probability Estimated probability 0. abstract LBA5002.47 0.32 0.9 30.8 0.48 0.46 Measurable No (<1) 74 3.2 0.48 0.4 5.5 0.” (Figures 1 and 2) Overall response rates (ORR) were also significantly higher with bevacizumab/chemotherapy vs chemotherapy alone.57 Topotecan 120 2. unadjusted) (2-sided. while those in the bevacizumab/ chemotherapy arm continued with their chemotherapy without bevacizumab. gastrointestinal perforation (1. abdominal pain.6 0.7 (unadjusted) HR HR (unadjusted) 0.” PujadeLauraine reported.48 Chemotherapy Paclitaxel 115 3.1 5. “Baseline characteristics were well balanced between the two treatment arms.0 0. RECIST = Response Evaluation Criteria in Solid Tumors Adapted from Pujade-Lauraine E.001 Log-rank p-value <0.8 p=0.80.01. HR = hazard ratio Adapted from Pujade-Lauraine E. bmissing n=8. cm Yes (1–<5) Yes (1–<5) 126 126 3. Subgroup analysis of PFS Median PFS.1 5. “Excluding patients at high risk of gastrointestinal perforation helped limit the incidence of these adverse events. months PFI.40 Ascites No 248 3.3 vs 1.8 7.5 0. months Median PFS.4 0.4 0.9 p=0. of No.8 30.3 7.57 PLD PLD 126 126 3.1 vs 0 percent).7 7.4 6.001 27.4 3.5 3.4 3.6 0.40 Ascites Yes Yes 113 113 2.46 0.6 5. were not significantly different between the two arms.5 0.6 7. “The chemotherapy drugs used in the trial are equally effective for resistant ovarian cancer.4 6.001 3535 35 30. platinum-free interval. et al.4 6. HR = hazard ratio.48 HR (unadjusted) Log-rank p-value <0. years 228 228 3.1 2. with bevacizumab/chemotherapy reducing the risk of progression by 52 percent vs chemotherapy alone.5 5.7 3.49 0.7 3.47 b <3 96 2.7 0.7 6. months b 96 96 2.9 3.6 10 10 10 5 5 5 0 0 0 Responders RECIST CA-125 Responders RECIST CA-125 Responders RECIST CA-125 (RECIST and/or responders responders (RECIST and/or responders (RECIST responders responders responders CA-125)and/or (n=287) (n=297) CA-125) (n=287) (n=297) CA-125) (n=287) (n=297) (n=350) (n=350) (n=350) Figure 2.4 6.” he noted.5 1 3 4 253 4 5 a unadjusted. Figure 1. abstract LBA5002.5 7. Patients (%) Patients (%) Patients (%) BEV = bevacizumab. months 3.1 vs 6.8 7.8 5.1 5.20. “The rates of gastrointestinal perforation.60.40.8 0. and fistula or abscess (1.8 0.3 27.6 3.7 0 0 0 0 0 0 6 6 6 TimeTime (months) No.2 0.5 2. tumor size.1 percent with chemotherapy alone). CT = chemotherapy.8 0. cm disease.5 1 2 3 45 0.80. BEV = bevacizumab.3 6.47 0. thromboembolic event. unadjusted) (2-sided.8 0. at risk: (months) No. et al.5 3.” said PujadeLauraine. (Figure 3) “The responses in the chemotherapy arm are in line with what’s expected in platinumresistant patients.48 All patients Age.47 Yes (≥5) Ascites Yes 113 2.1 2.3 7. at risk: 93 1 0 182 37 8 1 0 20 CT 93 1 0 182 182 37 8 1 0 20 CT 140 93 88 37 49 20 18 8 4 1 1 0 1 1 0 0 BEV + CT 179 140 4 179 88 18 49 BEV + CT 140 4 1 1 0 88 18 11 0 49 BEV + CT 179 12 12 12 Time (months) 18 18 18 24 24 24 30 30 30 PFS = progression-free survival. years <65 228 3.46 Chemotherapy Paclitaxel PLD 126 3. BEV + CT a ofCT CT BEV better+ CT better patients Subgroup HRa + BEV CT patients Subgroup CT + HR CT HRa better better better better patients Subgroup All patients 361 3.49 Age.5 0.47 ≥65 ≥65 133 133 3.5 7. n (%) 166 (91%) 135 (75%) Events.6 11.6 11. “PFS nearly doubled. proteinuria (20. PFI = platinum-free interval.5 7.7 vs 0 percent).8 11.9 10.3 25 25 25 20 20 20 15 12.8 0.0 6. BEV = bevacizumab.1 5.4 6.48 0.5 1 2 0.24 Jul-Aug 2012 ASCO 2012 Meeting Highlights OS data were not yet mature and will be released in 2013. Other grade ≥3 adverse events.4 10.4 6. PLD = pegylated liposomal doxorubucin Adapted from Pujade-Lauraine E.No.8 0.4 3.53 PFI.2 3.001 (2-sided.20. ASCO 2012.53 0. CT = chemotherapy.3 0.0 0. or assigned chemotherapy.6 0.4 0. unadjusted) The safety profile of bevacizumab was consistent with findings of pivotal trials of bevacizumab across various tumor types. cm Yes (1–<5) 126 3.001 p<0. Grade ≥3 adverse events that were higher in the bevacizumab/chemotherapy arm included hypertension (7. fistula or abscess were very low with bevacizumab/chemotherapy in the AURELIA trial. months BEV + CT of BEV +BEV CT CT CT CT No.0 BEV + CT CT CT CT BEV +BEV CT + CT (n=182) (n=179) (n=179) (n=182) (n=182) (n=179) Events.46 0.46 Measurable No (<1) 74 74 3. months 3.6 percent).001 p<0.001 p<0.6 7.47 Yes (≥5) 161 161 3.2 0. abstract LBA5002.46 Chemotherapy Paclitaxel 115 115 3. et al.3 3030 30 27.48 All patients 361 361 3.53 PFI.

365:2484-2496] These results formed the basis of the approval of bevacizumab for treatment of ovarian cancer in Europe in December 2011. In the OCEANS trial of patients with platinum-sensitive disease.” with bevacizumab/chemotherapy.1 months with carboplatin/paclitaxel plus concurrent and maintenance bevacizumab. and a significant benefit with a combination regimen vs mono-th-erapy. [N Engl J Med 2011. recurrent disease Phase III trials on bevacizumab in ovarian cancer Bevacizumab-based therapy has demonstrated significant improvements in PFS in four phase III trials totaling nearly 4. 70 percent). [J Clin Oncol 2011. because the time courses of cumulative hand-foot syndrome and cumulative neuropathy were similar Conclusions “AURELIA is the first randomized phase III trial in platinum-resistant ovarian cancer to demonstrate a significant benefit with biologic therapy.4 months with carboplatin/paclitaxel alone.29(June 20 suppl): abstract LBA5007] Results of AURELIA offer hope for patients with platinum-resistant disease. PujadeLauraine pointed out that patients treated with bevacizumab/chemotherapy had higher exposure to chemotherapy than those treated with chemotherapy alone. bevacizumab in combination with chemotherapy should be considered a new standard option in platinum-resistant ovarian cancer. median PFS was 14. “The other hypothesis that bevacizumab could potentiate the toxicity of chemotherapy was unproven. allowing patients to be treated for a longer period of time.2 months with carboplatin/paclitaxel plus concurrent bevacizumab and 10. Adverse events related to bevacizumab were as expected. .25 Jul-Aug 2012 ASCO 2012 Meeting Highlights between bevacizumab/chemotherapy and chemotherapy alone. [N Engl J Med 2011. vs 17. recurrent ovarian cancer. with no new safety signals identified. vs 11. bevacizumab plus carboplatin/gemcitabine followed by single-agent bevacizumab significantly increased PFS by 21 percent vs carboplatin/gemcitabine alone. which led to increased cumulative toxicities of chemotherapy. First-line therapy in advanced disease In the GOG-0218 (Gynecologic Oncology Group-0218) trial of patients with newly-diagnosed stage III (incompletely resectable) or IV disease who had undergone debulking surgery. with bevacizumab/chemotherapy significantly extending PFS vs chemotherapy alone. Previously-treated.000 patients with newly-diagnosed or recurrent ovarian cancer.” commented Pujade-Lauraine.8 months with carbopl- The OCEANS and AURELIA trials demonstrated significant PFS improvements with bevacizumab-based therapies in patients with previously-treated.” he explained.” atin/pacltaxel plus concurrent and maintenance bevacizumab. “Bevacizumab delayed disease progression.365:2473-2483] In the ICON-7 (International Collaboration on Ovarian Neoplasms-7) trial (stage IIIC or IV disease. “In view of these significant benefits.3 months with carboplatin/paclitaxel plus placebo. median PFS was 19.

and those receiving <3 consecutive months of first- .5 mg/kg/week) until further disease progression. patients had to be ≥18 years old with histologically confirmed mCRC. in BEV-naïve patients. To be eligible for participation. more patients were enrolled. [J Clin Oncol 2008. Roche) beyond first progression significantly extends survival in patients with metastatic colorectal cancer (mCRC) previously treated with BEV plus chemotherapy.26 Jul-Aug 2012 ASCO 2012 Meeting Highlights Bevacizumab beyond progression extends survival in mCRC Results from a large phase III study confirm that continuing bevacizumab (BEV) (Avastin Roche®. Subsequently.” said Arnold. and vice versa. The findings were presented recently at the American Society of Clinical Oncology (ASCO) 2012 Annual Meeting by Professor Dirk Arnold of the University Cancer Center Hamburg. Arnold ML18147 study “BEV in combination with fluoropyrimidine-based chemotherapy is a standard of care for mCRC in first-line and. with disease progression ≤4 weeks prior to starting the study treatment. second-line settings. first-line PFS <3 months. Patients who received oxaliplatin-based chemotherapy in the first-line setting were switched to irinotecan-based chemotherapy. The study included 820 patients who were randomized 1:1 to receive oxaliplatin. the efficacy and safety of continuing BEV after first progression had not been investigated in a randomized clinical trial. J Clin Oncol 2010.28(15 suppl): abstract 3596] “However.” said Arnold.26:53265334.or irinotecan-based at physician’s discretion). continuing BEV plus chemotherapy beyond first progression was associated with prolonged survival vs stopping BEV. and the primary endpoint was changed to overall survival [OS]. Those with progressive disease diagnosed >3 months after the last BEV administration.or irinotecan-based chemotherapy with or without BEV (2. Germany. with growing interest throughout Europe. [Abstract CRA3503] “The study started as a national academic trial from the AIO Group [Working Group for Medical Oncology of the German Cancer Society] in Germany with progression-free survival [PFS] as primary endpoint.” Design The ML18147 study is the first randomized phase III trial that prospectively investigated the impact of continued VEGF inhibition with BEV in mCRC patients who progressed after first-line BEV plus standard chemotherapy (oxaliplatin. In nonrandomized observational studies of mCRC patients. Prof.

6 months for the chemotherapy-alone arm. ITT = intention-to-treat. et al.4 percent]. OS = overall survival. Baseline characteristics CT (n=410) CT (n=410) BEV + CT (n=409) BEV + CT (n=409) Unstratifieda HR: 0.77 0. “The balance in further lines of treatment indicates the robustness of the OS effect seen with continuing BEV into the second-line setting after first progression.” suggested Arnold. PFS in first-line setting [≤9 or >9 months].83 0.86 0.7 mo 0 4.8 0.6 0.6 0.4 Adapted from Arnold D.0 0.78 0. anti-EGFR therapy [39.1 months for the BEV/ chemotherapy arm and 9.87 0. median OS was 11.83 0.77 2 2 Baseline characteristics were well balanced between the BEV/chemotherapy (n=409) and chemotherapy-alone (n=411) arms.8 mo 11.81 Unstratifieda HR: 0.79 0.73 0.27 Jul-Aug 2012 ASCO 2012 Meeting Highlights Figure 1.79 0.83 0.2 vs 41.7 percent in the chemotherapy-alone arm received ≥1 line of subsequent therapy. and other therapies [54. PFS = progression-free survival a 1.82 0. (Figure 1) “The OS benefit was consistent in all prespecified subgroups. PFS estimate PFS estimate Unstratifieda HR: 0. In the first-line setting.73 0.81 0.0001 0. vs 43 and 57 percent in the chemotherapy-alone arm. CT = chemotherapy. 68.4 0. The proportions of patients receiving irinotecan. at risk BEV + CT CT BEV + CT p<0. in the BEV/chemotherapy arm.2 0.4 0. at risk 410 293 162 51 24 7 3 2 0 CT 410 328 293 162 BEV + CT 409 188 64 51 29 24 13 7 4 3 1 2 0 0 BEV + CT 409 328 188 64 29 13 4 1 0 a Primary analysis method.76 0. ASCO 2012.” (Figure 2) In the study.86 0.83 p=0.67 0.0062 p=0.82 0.0211 p=0.81 0. ASCO 2012. Use of second-line chemotherapy was well balanced during the study.68 p<0.9 vs 50. Continuing BEV into second-line increases OS 1 1 Patient population refers to sequential enrolment of patients in original AIO and subsequent enrolment in ML18147 when study was transferred to Roche.79 0.8 line BEV were excluded.3 percent]. OS = overall survival Adapted from Arnold D.2 mo 6 12 18 6 12 18 Figure 2. all patients listed under AIO were included in primary analysis.0 1. b stratified by first-line CT. OS: ITT population 1. et al.2 p<0. “While there appeared to be a difference in treatment effect according to gender.0062 0. of organs No. more than half of the patients in each arm had a PFS of ≤9 months (54 vs 56 percent) and received irinotecan-based chemotherapy (59 vs 58 percent).6 0.1 mo 5. ITT = intention-to-treat.and oxaliplatin-based chemotherapy were 42 and 58 percent.6 0. AIO = Working Group for Medical Oncology of the German Cancer Society. After a median follow-up of 11. CT = chemotherapy. first-line PFS.81 0.8 0.73 0.79 0. The trial met its primary endpoint.73 0.2 vs 9. with OS significantly increased in patients who continued BEV beyond progression after first-line BEV/chemotherapy.87 0.8 months.79 0.99 0.0 0.6 percent of patients in the BEV/chemotherapy arm and 67.74 0.68 p<0.78 0. ECOG = Eastern Cooperative Oncology Group.7 mo 0 6 12 18 24 30 0 0 6 12 Time 18 24 30 (months) 410 409 410 409 119 189 119 189 20 45 20 45 6 12 6 12 36 42 CT (n=410) CT BEV +(n=410) CT (n=409) BEV + CT (n=409) 36 42 Time (months) 4 5 4 5 0 2 0 2 0 2 0 2 0 0 0 0 .83 Stratifiedb HR: b Stratified HR: 0.89 0. The duration between the last BEV dose and randomization was ≤42 days for 77 percent of patients in each arm.” added Arnold. 0 0 0 9. of organs with metastasis with metastasis Subgroup Subgroup All AIOAll AIO ML18147 ML18147 Female Female Male Male <65 years <65 years ≥65 years ≥65 0 years 0 ≥1 ≥1 ≤9 months 9 months >9 ≤ months >9 months Oxaliplatin-based Oxaliplatin-based Irinotecan-based Irinotecan-based ≤42 days ≤42 days >42 days >42 No days No Yes 1 Yes >1 1 >1 n 819 n 819 260 260 559 559 294 294 525 525 458 458 361 361 357 357 458 458 449 449 369 369 343 343 476 476 630 630 189 189 592 592 226 226 307 307 511 511 HR 0 HR 0 HR HR 0.8 0.99 0.2 0 24 30 36 42 48 24 30 36 42 48 Time (months) No.67 Stratified No. BEV = bevacizumab.0001 Unstratifieda HR: 0. ECOG performance status at baseline. time from last BEV dose [≤42 or >42 days]. abstract CRA3503.0001 Stratifiedb HR: 0.74 0.2 percent].89 0. time from last dose of BEV.0001 b HR: 0.79 0. BEV = bevacizumab.0 1. “Patients were stratified by first-line chemotherapy.81 p=0. and ECOG [Eastern Cooperative Oncology Group] performance status at baseline [0/1 or 2].1 mo 5.8 mo 11.” said Arnold.76 0.0211 OS estimate OS estimate 0. at risk CTNo. we found no real interaction between BEV benefit and gender as the treatment-gender interaction test was not statistically significant.2 mo 9.82 0. which included BEV [11. at risk Time (months) CTNo.81 0.82 0. abstract CRA3503.4 0.2 4.5 vs 12.83 0. Subgroup analysis of OS: ITT population Category AllCategory All populationa Patient Patient populationa Gender Gender Age Age ECOG performance status ECOG performance status First-line PFS First-line PFS First-line CT First-line CT Time from last BEV Time from last BEV Liver metastasis only Liver metastasis only No. respectively. HR = hazard ratio.

first-line PFS.” The findings also provide an important new insight about the biology of advanced CRC. CT = chemotherapy.0001 Stratifiedb HR: 0. it does not necessarily mean that tumors become resistant to antiangiogenic therapy. abstract CRA3503. he added.6 0. we can make second-line treatment even more powerful. The rates were generally low and similar in the two arms.” As a result of the extended PFS. “Although bleeding/ hemorrhage of all grades was slightly increased with BEV/chemotherapy [26 vs 9 percent]. grade 3-5 adverse events were not significantly different between the two regimens (64 vs 58 percent).83 0.9 percent for chemotherapy alone).79 0. “This represents a new second-line treatment option for patients previously treated with BEV in combination with standard chemotherapy in a first-line setting. PFS: ITT population 1. and this is currently being investigated in other tumor types. “Compared with historical data on firstand second-line use of BEV in mCRC. p<0.0001 No.82 0. BEV = bevacizumab.8 PFS was significantly prolonged with BEV/ chemotherapy vs chemotherapy alone (5.81 0.79 0.77 Secondary endpoints Figure 3. “In these patients.4 percent for BEV/chemotherapy vs 3.1 months).68 p<0.” he added. of organs with metastasis HR 0 1 2 ≤9 months >9 months Oxaliplatin-based Irinotecan-based ≤42 days >42 days No Yes 1 >1 449 369 343 476 630 189 592 226 307 511 0. However. Conclusions The ML18147 study confirms that continuing BEV beyond first progression while modifying chemotherapy provides significant OS and PFS benefits for mCRC patients.89 0. By simply switching chemotherapy drugs when the cancer progresses and continuing with BEV. b stratified by first-line CT. However.7 vs 4.0001) as a result of a higher number of patients who achieved stable disease (63 vs 50 percent).2 vs 3. HR = hazard ratio. time from last dose of BEV.2 0 4. et al. at risk CT BEV + CT a Time (months) 410 409 Primary analysis method. treatment duration was longer in the BEV/ chemotherapy arm than in the chemotherapy-alone arm (4.” he said.82 0.4 0.7 mo 6 119 189 12 20 45 18 6 12 24 4 5 30 0 2 36 0 2 42 0 0 Unstratifieda HR: 0. ECOG = Eastern Cooperative Oncology Group.1 mo 0 5. there was no real difference if you look at grade 3-5 only [2 vs <1 percent]. ITT = intention-to-treat. “There was no sign that continuing BEV beyond first progression had any impact on the rate of grade 3-5 adverse events from chemotherapy. disease control rate was significantly higher with BEV/chemotherapy (68 vs 54 percent.2 months). ECOG performance status at baseline.” suggested Arnold.First-line PFS First-line CT Time from last BEV 28 Jul-Aug 2012 ASCO 2012 Meeting Highlights Liver metastasis only No. BEVrelated adverse events were not increased when the agent was continued beyond first progression.73 0. “Findings of ML18147 indicate a potential new model for treatment approaches through multiple lines. Safety CT (n=410) BEV + CT (n=409) PFS estimate 0. extended BEVbased therapy provides meaningful benefits while maintaining an acceptable safety profile. PFS = progression-free survival Adapted from Arnold D. “If the disease develops resistance to chemotherapy. (Figure 3) Overall response rates were similar in both arms (5. ASCO 2012.0 0.76 0.67 p<0.” .” pointed out Arnold.

A few months later. followed by locoregional radiotherapy (RT). Foon-Yiu Cheung Clinical Oncologist Presentation and treatment A 47-year-old Chinese woman presented in 2002 with a mass in her right breast. She underwent ovarian ablation with irradiation in October 2009 and was started on letrozole in March 2010. while HER2 and thyroid transcription factor-1 (TTF-1) were negative. methotrexate and 5-fluorouracil [5-FU]). Treatment was well tolerated. Resected margin was clear (5 mm). Metastatic workup was negative. CXR showed partial response.29 Jul-Aug 2012 Case Stud y Use of capecitabine in advanced metastatic breast cancer Dr. The left parieto-occipital brain metastasis remained hypermetabolic. multiple hypermetabolic mediastinal lymph nodes and bilateral lung metastases. In June 2009. A PET-CT in March 2012 revealed bilobar liver metastases. PET-CT scans before (top) and after (bottom) capecitabine treatment (A) Brain metastasis (B) Liver metastasis (C) Right hilar metastasis parieto-occipital region by CT scan while on investigation for dizziness. The patient received adjuvant chemotherapy with the Milan scheme (four cycles of 3-weekly adriamycin and eight cycles of cyclophosphamide. she presented with an incidental finding of lung masses on chest X-ray (CXR). Pathology revealed a 1. the patient was found to have a secondary brain tumor at the left Figure. Nine out of 23 resected axillary lymph nodes were involved by tumor. Transbronchial biopsy confirmed metastatic carcinoma. ER and PR were strongly positive. She received tamoxifen from June 2003 until June 2008. Repeat PET-CT in May 2012 after the third cycle revealed: • Metabolic remission of bilobar liver metastases • Significant metabolic improvement of hypermetabolic media-stinal lymph nodes • Significant metabolic improvement of hypermetabolic intrapulmonary and left . Palliative whole-brain irradiation was given in June 2010 with 30 Gy in 10 fractions. Palliative capecitabine (2500 mg/m2 daily for 2 weeks in each 3-weekly cycle) was started in March 2012. She underwent modified radical mastectomy in August 2002. Follow-up CXR in November 2011 revealed interval increase in size of the secondary lung tumor. Estrogen receptor (ER) and progesterone receptor (PR) were positive while human epidermal growth factor receptor 2 (HER2) was negative. completed in October 2009.7-cm invasive ductal carcinoma with grade 3 disease. Paclitaxel and carboplatin were given for six cycles.

which concurs with current published evidence. The treatment is well tolerated and.12:30-39.org. The subsequent use of capecitabine after progression is also in line with international recommendations. chemotherapy and biological therapy. Combination with IV or oral vinorelbine is common. Discussion Breast cancer is the most common cancer among females in Hong Kong.org. she received subsequent systemic therapy in line with the consensus. in 2009. Top 10 cancers in 2009. such as the NICE guideline. Evidence Review.2 Single-agent capecitabine has a response rate of 14-28 percent in pretreated metastatic References: 1.hk/cancereg. 4. http://www. demonstrated activity against brain metastasis as well. Adjuvant chemotherapy using the Milan scheme was the most potent option we could offer at that time. NICE 2009. in this case.ha. NICE pathways: Advanced breast cancer. it was the third cause of cancer mortality. . National Collaborating Center for Cancer. 2. Although there is no phase III randomized trial for this scheme. using a taxane first. xml&content=close. as paclitaxel is free. diarrhea (3-10 percent) and nausea (3-8 percent). 3. Clinical Breast Cancer 2012. http://pathways. The choice of paclitaxel rather than docetaxel was solely a financial consideration.nice. and the median duration of response is about 4.3 Whether it should be used in combination with other agents or as monotherapy after anthracyclin and taxane failure remains inconclusive. the response rate reported in a phase II trial was 33-70 percent. After relapse.4 This case illustrates that capcitabine is an effective agent for advanced breast cancer patients after anthracycline and taxane failure.30 Jul-Aug 2012 Case Stud y breast cancer.1 This patient first presented at a time when third-generation adjuvant chemotherapy with taxanes was either unavailable or very expensive. The patient plans to continue the present treatment. Advanced Breast Cancer: Diagnosis and treatment. The most commonly reported side effects are hand-foot syndrome (2-21 percent).uk/pathways/advancedbreast-cancer#path=view%3A/pathways/advanced-breast-cancer/ advanced-breast-cancer-chemotherapy-and-biological-therapy. parieto-occipital brain metastases • No new hypermetabolic meta-static lesions These findings suggest a partial treatment response.5-9 months.

Hong Kong. impaired renal function was noted due to the use of cisplatin. which was compatible with a liver metastasis. there was a significant improvement in symptoms and the patient could resume normal solid diet. However. and multiple slightly enlarged lymph nodes over the gastroesophageal. Wai-Tong Ng Department of Clinical Oncology Pamela Youde Nethersole Eastern Hospital Hong Kong Presentation A 58-year-old Chinese man presented to Pamela Youde Nethersole Eastern hospital. he could only tolerate fluid diet. Investigations and diagnosis Esophago-gastroduodenoscopy showed a circumferential tumor growth at the lower esophagus with extension to the gastric cardia. (Figure A) The arrow indicates the site of liver metastasis. HER2 immunohistochemistry (IHC) 3+. gastric cardia and proximal lesser curvature. Upon admission. gastro-hepatic and upper para-aortic regions. (B) Before chemotherapy Treatment The patient was given palliative chemotherapy using cisplatin. Computed tomography (CT) showed an irregular growth at the cardia extending to the gastroesophageal junction. Biopsy revealed adenocarcinoma. and a hypermetabolic focus in the liver. Positron emission tomography (PET) scan revealed a primary tumor involving the distal esophagus. PET scan (A) Before chemotherapy Capecitabine in advanced gastric cancer Dr. He was thus switched to oxaliplatin.31 Jul-Aug 2012 Case Stud y Figure. 5-fluorouracil (5-FU) and trastuzumab. After 2 cycles of treatment. in February 2011 with a 2-month history of dysphagia. capecitabine .

Another important advance in the management of mGC is the integration of targeted agents into the chemotherapy backbone. with an unadjusted hazard ratio (HR) of 0. In early February 2012.8 months in the chemotherapy-alone arm. median OS was 14 months among patients assigned to trastuzumab plus chemotherapy vs 11 months for those assigned to chemotherapy alone (p=0.002) and ML17032 (n=316) were included.4 A subgroup analysis indicated that trastuzumab was most effective in prolonging survival in patients with HER2 IHC 3+ or IHC 2+ and FISH (fluorescence in situ hybridization)-positive tumors (HR=0.1. and transtuzumab.3 In this meta-analysis. . In addition. N Engl J Med 2008. but also far more convenient as patients can avoid unnecessary hospitalization or central line insertion for the 5-FU infusion. Trastuzumab is currently the most widely used targeted therapy for patients with HER2-positive tumors. The median OS was 285 days for patients treated with 5-FU and 322 days for patients who received capecitabine. approximately 20 percent of mGC patients are HER2-positive. 4. 3. Overall survival (OS) Discussion References 1. Two important studies – ML17032 and REAL-2 – have evaluated the replacement of these agents by capecitabine (an oral fluoropyrimidine) and oxaliplatin (a platinum analogue with less renal toxicity). Ann Oncol 2009. (Figure B) Total radical gastrectomy and distal esophagectomy were performed in November 2011 with clear margins. Ann Oncol 2009. The combination of 5-FU and cisplatin is a widely accepted standard regimen for metastatic gastric cancer (mGC). This meta-analysis is practice changing as capecitabine is not only better than 5-FU in terms of survival.20:1529-1534. a more interesting observation was noted in a recent combined analysis of these two studies. 8 cycles of treatment were given in total.87 in favor of capecitabine (p=0. However.32 Jul-Aug 2012 Case Stud y was compared for the 664 patients treated with 5-FU combinations vs the 654 patients treated with capecitabine combinations. Lancet 2010.358:36-46. In the ToGA trial. Currently.20:666-673. 2. with no deterioration in cardiac function. Trastuzumab was continued for up to 1 year and treatment was completed in April 2012. and trastuzumab plus chemotherapy represent the standard of care for this group of patients.0 months in the trastuzumab arm. the median OS was 16. The liver lesion was not identifiable during the operation. a total of 1.65).027).2 Similar antitumor activity has been confirmed in these studies. A follow-up PET scan showed good response and the liver metastasis became hypometabolic. He was stable and doing well at the time of last follow-up.318 patients who were randomized within REAL-2 (n=1.0046). In these HER2-positive patients.376:687-697. Repeat PET scan after the operation showed no gross FDG-avid lesion. the need for several days of hospital stay with 5-FU infusion and the potential renal toxicity associated with cisplatin have prompted the evaluation of alternative treatment regimens. he was given stereotactic body irradiation (55 Gy over 10 fractions) to the liver lesion (tumor location based on the pre-treatment PET scan). compared with 11.

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Age. “The prevalence of H. H. USA has shown an increased risk of colon neoplasms in patients with H. pylori infection with increasing number and size of adenomatous polyps. 11 percent in patients with hyperplastic polyps. The results of both recent studies are in contrast with previously published data. pylori being a risk factor for CRC development. had H. Serum antibodies to H. 16. respectively). pylori confers an increased risk for all types of colonic neoplasms.3 and 1. Another report published earlier this year suggested that H.4:1-10] . [Am J Epidemiol 2012. For example.” the authors concluded. a large epidemiological study reported at the 2012 Digestive Disease Week in San Diego. Stratified analyses showed that the risk elevation was essentially confined to left-sided CRC. “H. anatomic subsites. adenoma with high-grade dysplasia and adenocarcinoma. Recently. Amnon Sonnenberg of Oregon Health and Science University and the Portland VA Medical Center. pylori infection may be associated with a small yet relevant risk increase in the left colorectum. The prevalence was similar regardless of the site of the colonic lesion. pylori infection may be associated with an increased risk of CRC in specific colorectal sites. a nested case-control study of men in the ATBC (Alpha-Tocopherol. from hyperplastic and adenomatous polyps to tubulovil- lous adenoma. “Overall. pylori seroprevalence with risk of CRC in a large population-based case-control study conducted in Germany between 2003 and 2007. “H. Dr. CagA-positive strains of H. US. The investigators reviewed the records of nearly 157. and cancer stage.759 patients.669 controls. The association between H. pylori infection confirmed by immunohistochemistry. which analyzed data from nearly 30. and the risk appears to increase with advancing stage of the neoplasm. Beta-Carotene) cancer prevention clinical trial in Finland. there was a trend of increased prevalence of H.000 subjects. with an OR of 1.34 Jul-Aug 2012 News New evidence linking H.and genderadjusted odds ratios (OR) were 1. gender.” he concluded. or 11 percent.14. pylori seroprevalence was higher in CRC patients than in controls (46.1093/aje/kwr331] The authors assessed the association of H. pylori are considered more toxic or carcinogenic.22. pylori prevalence and CRC risk was adjusted for potential confounders and stratified by age group. found no evidence of H. pylori infection. DOI: 10.1 percent. pylori with colon cancer Naomi Rodrig W hile the association between Helicobacter pylori (H.” Furthermore. evidence regarding its role in the development of colorectal cancer (CRC) remains controversial. The data suggest a link between the prevalence of infection and lesion severity.” reported lead author. pylori gastritis was 9 percent among patients without colonic polyps.000 patients who had undergone both colonoscopy and esophago-gastroduodenoscopy between 2008 and 2011. pylori) infection and an increased risk of gastric adenocarcinoma has been well established. respectively. pylori in general and the cytotoxin-associated gene A protein (CagA) were measured in 1.712 incident CRC patients and 1. 14 percent in patients with advanced adenoma and 18 percent in those with adenocarcinoma.1 vs 40. Overall. 12 percent in those with adenoma. [Ann Epidemiol 1994.

Do not administer as an IV push or bolus. Monitor cardiac function during treatment. lacrimation increased. Dosage & administration: Please refer to Herceptin PI for full guidance. vomiting nausea. pyrexia. CT (neo/adjuvant) and radiotherapy (if applicable). Warnings & Precautions: Discontinue Herceptin infusion in case of serious adverse reactions. Nervous system disorders (including dizziness. conjunctivitis. Avoid breast-feeding during therapy. anaemia. Date of preparation: December 2011 Full prescribing information should be viewed prior to prescribing. or in combination with docetaxel for patients who have not received CT. or following adjuvant chemotherapy with doxorubicin and cyclophosphamide.Minimum Product Information Herceptin (trastuzumab) Powder for Concentrate for infusion 150 mg single dose vial & 440 mg multidose vial (with solvent) Indications: HER2 positive patients with: (i) metastatic breast cancer (MBC). HER2 testing is mandatory prior initiation of therapy. . Caution for use in pregnancy as oligohydramnios have been reported. General disorders and administration site conditions (including asthenia. Safety of continuation or resumption in patients experiencing cardiotoxicity has not been studied. Interstitial lung disease may occur as part of an infusion-related reaction or with a delayed onset especially in patients with prior or concomitant therapy with other anti-neoplastic therapies. subsequent doses: 2mg/kg weekly. Not recommended for children < 18 years old. dyspepsia. Contraindications: Known hypersensitivity to trastuzumab or any product excipients. thoracic and mediastinal disorders (including dyspnoea. alopesia. Administer as IV infusions over approx. history of hypertension or documented coronary artery disease and in EBC. Observe for infusion-related symptoms. Consider discontinuing treatment in patients whose LVEF has not improved. BC weekly: loading dose . thrombocytopenia. treat until disease progression. EBC/MBC/MGC 3-weekly: loading dose . Patients with EBC should be treated for 1 year or until disease recurrence. 90 min. pain. or in combination with paclitaxel for patients who have not received CT. in those patients with an LVEF <55%. stomatitis). Respiratory. influenza-like symptoms. Infusion time reduced to 30 min for subsequent doses if initial loading dose was well tolerated. rhinorrhoea). cough. constipation. or (ii) early breast cancer (EBC) following surgery. erythema. Benzyl alcohol contained in the solvent for 440mg vial. Patients experiencing dyspnoea at rest may be at risk of fatal infusion reactions or severe pulmonary reactions.8mg/kg. Very common adverse reactions (>10%): nasopharyngitis. myalgia. fatigue.4mg/kg. or in patients who develop clinically significant heart failure unless benefits outweigh risks. mucosal inflammation) & nail toxicity. weight changes. or in combination with adjuvant chemotherapy consisting of docetaxel and carboplatin. hypoaesthesia). these patient should not be treated with Herceptin. headache. Heart failure has been observed. or in combination with an aromatase inhibitor for the treatment of postmenopausal patients with hormone-receptor positive MBC. abdominal pain. Undesirable effects: For full listings please refer to the Herceptin PI. In MBC or MGC. lymphoedema. infusion related reaction. chills. or (iii) metastatic gastric cancer (MGC) in combination with capecitabine or 5-FU and cisplatin. oropharyngeal pain. chest pain. in combination with paclitaxel or docetaxel. Post Marketing – refer to package insert. paraesthesia. Gastrointestinal disorders (including diarrhoea. decreased appetite. either as monotherapy following at least 2 chemotherapy (CT) regimens. Candidate patients should undergo baseline cardiac assessment and risk-benefit assessment. arthralgia. subsequent doses – 6mg/kg repeated at 3-weekly intervals. or declined further. rash. Caution in patients with symptomatic heart failure. peripheral oedema. epistaxis. insomnia.

“In addition. Hedgehog levels are increased in pancreatic cancer stem cells.” said Dr. The weak point Awasthi and colleagues identified is the RLIP76 protein. which drive tumor growth by generating bulk tumor cells and are particularly resistant to chemotherapy and radiation. our data show that this seemingly unconquerable disease has an Achilles heel – its toxin exhaust system. added Awasthi. which pumps out toxic chemicals accumulating in pancreatic cancer cells as a result of chemotherapy or radiotherapy before they can cause cell death.” he reported. represent progress in a disease that is notoriously difficult to treat.” The Hedgehog pathway is normally silent in the adult pancreas but activated in patients with pancreatic cancer. blocking or depleting levels of this protein dramatically enhanced the ability of radiation and doxorubicin to destroy human pancreatic cancer cells in culture. Progression-free survival at 3 months was 50 percent. contributing to the desmoplastic stroma that is characteristic of the disease. USA. an oral agent approved for use in basal cell carcinoma.” said Kim. Edward Kim of the University of Michigan Comprehensive Cancer Center in Ann Arbor. “Another approach already being tested in the clinic is inhibition of the Hedgehog signaling pathway. “Pancreatic cancer cells are largely resistant to cell death induced by chemotherapy and radiation. cholesterol and triglycerides.” Kim and colleagues have achieved some success in a small number of patients with the Hedgehog pathway inhibitor GDC-0449 (vismodegib). “We found a higher level of RLIP76 in human pancreatic cancer cells than in normal human pancreatic cells. In 20 treatment-naïve patients with advanced pancreatic cancer.36 Jul-Aug 2012 News Overcoming treatment resistance in pancreatic cancer Christina Lau R esearchers in the US have discovered how pancreatic cancer becomes resistant to chemotherapy and identified ways to improve treatment based on their findings. who is founder of a company that makes recombinant RLIP76 protein for treatment of radiation poisoning.” said Professor Sanjay Awasthi of the City of Hope Comprehensive Cancer Center in Duarte. USA. presented recently at the American Association for Cancer Research’s (AACR) first-ever conference on pancreatic cancer. The studies.” An added benefit to depleting RLIP76 levels in mice with established tumors was a decrease in blood glucose. use of GDC-0449 (as monotherapy for 3 weeks and then in combination with gemcitabine) led to a partial response in five patients and stable disease in five patients. Fortunately. . with 90 percent of patients likely to die within 1 year from diagnosis. “Moreover. Depletion of RLIP76 levels killed human pancreatic cancer cells in culture and shrank established human pancreatic tumors in mice. “Early results look promising. “This dense stroma is believed to contribute to resistance to chemotherapy by presenting a physical barrier to chemotherapy delivery.

” he continued. “Also.” Kim explained. “Data from biopsy specimens will help identify predictive markers to determine which patients would benefit from combination treatment with GDC-0449 and gemcitabine. www. suppressing Hedgehog activity within The Complete Solution Innovations in workflow tools for smarter prescribing.37 Jul-Aug 2012 News the cancer stem cells might lead to improved outcomes.com Log on today! CLINICAL PAPERS PRESCRIPTION INFORMATION PILL IDENTIFIER PATIENT EDUCATION DRUG INTERACTION CHECKER MEDICAL NEWS 100% pure knowledge MEDICAL EVENTS PUBMED CME .” “We believe that GDC-0449 has the potential to change the approach to treatment of pancreatic cancer. as pancreatic cancer stem cells have higher Hedgehog levels than bulk cancer cells.mims.” “Treating pancreatic cancer patients with GDC-0449 first as monotherapy and then in combination with the standard chemotherapeutic drug gemcitabine might disrupt the desmoplastic stroma and improve the efficacy of the chemotherapy.

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along with reduced cell viability. suggesting that JAK3 may be a good drug target. 23 of 65 cases (35. especially in China and Korea. In total. “Although relatively rare in the USA. the prognosis of patients with NK/T-cell lymphoma is extremely poor. use of CP-690550 in the JAK3-mutant NK/T-cell lymphoma cell lines led to inhibition of STAT5 [signal transducer and activator of transcription-5] phosphorylation. Further validation was conducted in another 61 patients with Sanger sequencing and high-resolution melt (HRM) analysis. “There is a JAK3 inhibitor [CP-690550 (tofacitinib)] currently in phase III trials for treatment of rheumatoid arthritis. In our study. This means that JAK3 mutations cause dysregulated activation of JAK3.4 percent) harbored JAK3 mutations. “NK/T-cell lymphoma is particularly prevalent in Asia.” . this form of lymphoma is responsible for the deaths of a large number of people in Asia.39 Jul-Aug 2012 News Arthritis drug to be tested in lymphoma Christina Lau S ingaporean researchers are planning to test a Janus kinase 3 (JAK3) inhibitor in patients with natural killer (NK)/Tcell lymphoma – a very aggressive form of lymphoma frequently found to harbor JAK3 mutations. interleukin-2 (IL-2).” said Professor Bin-Tean Teh of the National Cancer Center Singapore–Van Andel Research Institute Translational Research Laboratory and Duke–National University of Singapore Graduate Medical School.” he continued. accounting for almost half of all T-cell lymphomas in some parts of the region. Teh and colleagues conducted whole-exome sequencing of NK/Tcell lymphoma cells from four patients.” reported Teh. “Very little was known about the genetic and molecular defects causing the aggressive disease before we started our study. [Cancer Discov 2012. “With no effective treatment.” In their study. and identified JAK3 somatic-activating mutations in two of them. e-pub 15 Jun] The mutations enabled NK/T-cell lymphoma cell lines to grow in culture without the normally essential growth factor.” “It is tremendously rewarding to have identified genetic mutations that appear to have an important role in driving NK/T-cell lymphoma in a considerable proportion of cases. “We are in the process of planning a clinical trial to test the agent as a treatment for NK/T-cell lymphoma with JAK3 mutations.” he continued.

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For sorafenib. “There is still an unmet medical need in mRCC. apart from other side effects. the adverse event profiles of these drugs varied considerably. Since 2005. “The drugs that we have today are not curing our patients. This has resulted in improved clinical outcomes for patients with mRCC.or second-line. et al. the more difficult and complicated it becomes to make treatment decisions.” said Schöffski. In particular. he highlighted the latest data focusing on the angiogenesis inhibitor pazopanib.41 Jul-Aug 2012 Meeting Highlights Everolimus plus exemestane improves PFS in advanced breast cancer At a sponsored satellite symposium in conjunction with the Asian Oncology Summit held recently in Singapore. which may be partly attributed to improved diagnosis. Head of the Department of General Medical Oncology and the Laboratory of Experimental Oncology at the University Hospitals Leuven. Many patients suffer from adverse events associated with some tyrosine kinase inhibitors (TKIs). either as first. Catholic University Leuven.152] “For sunitinib. and I’m seeing it daily in my own patients as well. The incidence of RCC worldwide continues to increase by 1 to 2 percent per year. the main problem that we all encounter. European Multidisciplinary Cancer Congress 2011. We are delaying tumor growth and shrinking metastasis in a large proportion of patients. Other challenges in targeted therapy for mRCC include identification of the most effective sequence or combination of available targeted agents to reduce adverse events and prevent or overcome the development of drug resistance. is fatigue/asthenia. seven targeted agents have been approved for use in the treatment of mRCC. [Levy A. Belgium. a variety of adverse events were reported with the targeted agents sunitinib. the dominant problem from my personal experience is hand-foot .” Refractoriness to treatment develops in the majority of cases.” Schöffski said. hand-foot syndrome and gastrointestinal complaints such as diarrhea all require adequate assessment and prompt management. In general. Prof. Professor Patrick Schöffski. Mucositis. Abstract 7. In a retrospective study involving approximately 700 patients with mRCC. “However. sorafenib or bevacizumab. fatigue. Schöffski Unmet needs in mRCC The treatment options for mRCC have been revolutionized over a short period of time. reviewed the current treatment options for metastatic renal cell carcinoma (mRCC). but complete responses are rare. the more treatment options we have.

” said Schöffski. In vitro studies demonstrated that pazopanib has >6 times greater affinity for VEGFR-2 and is overall more selective than sunitinib. the rate of fatigue/ asthenia has reached 44. (Figure 3) In cytokine-pretreated patients.2 months vs 4. (Figure 2) The benefits of pazopanib were even more pronounced in treatment-naïve patients. but many patients do not tolerate full doses. Increases in alanine aminotransferase [ALT] and bilirubin levels are also associated with other anti-VEGF agents. hypertension. and the actual dosing and scheduling of drugs. The study allowed for early cross-over from placebo to active treatment with pazopanib. The most common adverse events reported were diarrhea. which is usually combined with interferon-alfa. A 54 percent reduction in the risk of progression or death was also observed with pazopanib. Fatigue/asthenia is a repeating theme among patients treated with these targeted agents.” he reported.” Schöffski warned. “I see a major advantage here for pazopanib. the primary mediator of angiogenesis – is a welcome addition to the mRCC treatment portfolio. with varying in- syndrome and also fatigue/asthenia. respectively. treatmentrelated adverse events have a negative impact on the well-being of patients. The drug has a favorable overall risk:benefit profile and works by inhibiting the intracellular tyrosine kinase of vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR). For bevacizumab.4 months and 29 percent. without any impact on PFS. p<0. Median duration of response was more than 1 year. patients were randomized to either pazopanib (n=290) or matching placebo (n=145). hair color changes and elevation of liver enzymes. PFS was significantly longer with pazopanib than with placebo (9.2 months. Between 12 to 25 percent of patients had to discontinue treatment due to adverse events. [J Clin Oncol 2010. (Figure 1) A phase III trial has demonstrated that pazopanib improves progression-free survival (PFS) and response rates in both treatment-naïve and cytokine-pretreated patients. Unlike sunitinib.42 Jul-Aug 2012 Meeting Highlights causes less inhibition of Fit-3.1 months and a response rate of 32 percent. the PFS and response rates were 7. In this study. pazopanib also . with PFS reaching 11. In the study. In general. Pazopanib in mRCC: Efficacy and safety The treatment strategy for mRCC continues to evolve. “Of note.001).28:1061-1068] These data have established pazopanib’s role as a new option in the treatment of advanced or metastatic RCC. treatment modifications occurred quite often. a mediator of hematopoiesis.4 percent and this has led to treatment discontinuation in a considerable number of patients. “Any variation to the prescribed regimens has an effect on treatment outcomes. Drugs are used according to labeled instructions. this drug has less hematologic toxicity compared with other targeted therapies. In the overall study population. Pazopanib – a potent inhibitor of VEGFR-2.

8 60% 0.8 1.8 months p<0. How to manage hypertension in patients taking pazopanib Monitor blood pressure Monitor regularly (at least during every visit at outpatient clinic) Hypertension Persistent hypertension Continue pazopanib treatment and intensify existing antihypertensive drug therapy Continue pazopanib treatment and initiate antihypertensive drug therapy Reduce pazopanib dose and continue antihypersensitive drug Discontinue pazopanib if arterial hypertension is severe and persists despite antihypersensitive therapy and pazopanib dose reduction .5 0 2009.2 5 5 8484 2222 5 84 22 1010 1515 Median PFS p<0. Pazopanib vs placebo: PFS in the treatment-naïve Pazopanib (n=155): 11.101:1717-1723. Pazopanib is a potent inhibitor of VEGFR-2: Preclincal studies of pazopanib and sunitinib 229 229 230 230 Proportion progression-free progression-free Proportion Proportion progression-free cidence and severity. Pazopanib vs placebo: PFS in the overall population 1. Guidelines are available to help physicians make sound therapeutic deci- PFS = progression-free survival Adapted from J Clin Oncol 2010.1 months population Pazopanib (n=155): 11.0 Median PFS Median PFS Conclusions 0 0 0.2 5 5 159 159 3838 5 159 38 1010 1515 2929 2 2 15 29 2 Median PFS Median PFS Pazopanib (n=290): 9.4 0.358:2039-2049.6 0.0 0. 20 6 290 145 1.2 months Pazopanib (n=290): 9.0 1.4 40 0. is expected to provide more data to facilitate treatment selection for individual patients.5 00 229 15 229 30 1 -1 2 -2 3 -3 β it β α α Kit KR R R R R R R R RFR F FG15 FGF FGF F FG15 FG C-C G G G 20 G G E E E E E E D D VV V V 15 V V 15 PD PP PD 10 229 2.1 months 0.4 229 2.2 0.2 Number at at risk Pazopanib 290 290 Pazopanib Placebo 145 Placebo 0 145 0 Number at risk Pazopanib Placebo Time (months) Time (months) 7676 1414 10 2020 6 6 reduction reduction in in risk risk of of progression progression death with oror death with 54% pazopanib pazopanib vsvs reduction in placebo placebo risk of progression or death with pazopanib vs placebo 54% 54% Time (months) 76 14 Adapted from J Clin Oncol 2010.2 months p<0.28:1061-1068. Figure 1.6 0.0001 Median PFS Pazopanib (n=290): 9.8 0.001 p<0.2 months Placebo (n=145): 4.8 0.1 months Placebo (n=78): 2. liver enzyme elevation and diarrhea.2 months p<0.2 months Placebo (n=145): 4.001 Proportion progression-free progression-free Proportion Proportion progression-free ‘‘ This drug has PFS = progression-free survival 0 0 0.0001 p<0.0 0. 100 Pazopanib 100 Pazopanib Sunitinib 9090 Sunitinib 8080 229 7070 100 Pazopanib 6060 229 229 90 Sunitinib 5050 80 4040 70 229 1515 229 229 229 3030 60 229 2020 1515 1515 50 1515 1515 1010 229 2. Comorbidities. but there are clear guidelines on how to deal with it.4 0.2 months Placebo (n=145): 4.” (Figure 4) “Fatigue is also less prominent with pazopanib than with other drugs I’ve prescribed before for my patients.001 Pazopanib (n=155): 11. Schöffski noted that the ongoing COMPARZ (Pazopanib Versus Sunitinib in the Treatment of Locally Advanced and/or Metastatic Renal Cell Carcinoma) trial. Arterial hypertension is an uncommon event. 2) N Engl J Med 2008.6 0.6 0.4 0 0 Number risk 0.8 0. Its safety profile is different from other agents. which involves a head-to-head comparison of the two TKIs. The drug is clearly manageable.4 0.8 months Placebo (n=78): 2.0001 less hematologic toxicity compared with other targeted therapies Figure 3. but it is important to assess and manage relevant adverse events such as hypertension. Fatigue can be bothersome for patients and translates into poorer outcomes. Adapted from 1) Br J Cancer it -1 -2 -3 -β -α R R R R R F F F F F C-K G G VEG VEG VEG PD PD Kiapp (nM) Kiapp (nM) Kiapp (nM) 230 229 229 3t-3 -i FitF 229 Fit- 3 Figure 2.0 0.6 0.4 0.0 1.2 Number at at risk Pazopanib 155 155 Pazopanib Placebo 78 Placebo 0 78 0 Number at risk Pazopanib Placebo 155 78 Time (months) Time (months) 3939 7 7 10 39 7 2020 1 1 20 1 reduction reduction in in risk risk of of progression progression death with oror death with 60% pazopanib pazopanib vsvs reduction in placebo placebo risk of progression or death with pazopanib vs placebo Time (months) 1111 2 2 15 11 2 Pazopanib is the third TKI and the sixth targeted therapy approved for the treatment of advanced or metastatic RCC. lifestyle and individual patient expectations should be carefully considered when making treatment decisions.6 0.8 months 1.2 0.” he remarked.28:1061-1068.4 0 0 Number risk 0.5 0.43 Jul-Aug 2012 Meeting Highlights sions.8 60% Placebo (n=78): 2.4 0. Figure 4.

patients who have a chance to receive all five drugs live longer than those who use fewer drugs. Hui Pun. Therefore. “Some patients may deteriorate fast unless they receive powerful firstline therapy. The standard treatment regimen of cetuximab plus FOLFOX or FOLFIRI consists of 12 biweekly cycles for a total of 6 . Dr. Edwin. Hui Treatment of mCRC “The currently available options in mCRC include three cytotoxic chemotherapy drugs – 5-flurouracil [5-FU]. A recent phase II trial demonstrated that rechallenge with cetuximab-based therapy may provide clinical benefit for patients who responded to previous treatment with the same regimen. Chinese University of Hong Kong. for thirdline treatment. “For first-line therapy we usually select two cytotoxic drugs and one targeted agent.” he said. At present. subsequent lines of treatment are eventually required following disease progression. it is recommended to use cetuximab in first-line therapy rather than reserving it for subsequent treatment lines. Conversely. it is not covered by the public healthcare system.” According to Hui. For second line. However. In our experience. “KRAS mutation testing is reimbursed. as KRAS WT tumors are likely to respond to anti-epidermal growth factor receptor (EGFR) therapy such as cetuximab. Specialist in Medical Oncology and Director of the Comprehensive Cancer Trials Unit. “Although the benefit of cetuximab in KRAS WT tumors is significant. we tend to prescribe a targeted therapy upfront with the first chemotherapy course.” he explained. Dr. so they may not get another chance to use the targeted therapy later. options are limited since we had probably used all the available choices and nothing is left. oxaliplatin and irinotecan. Merck Serono) in patients with KRAS wild-type (WT) metastatic colorectal cancer (mCRC) are well established. so we test everybody in case they can get funding later. and two targeted agents – cetuximab and bevacizumab. “ said Hui. patients with KRAS mutations would benefit from chemotherapy alone or non-EGFR targeted therapies. we would start treatment with chemotherapy. the Community Care Fund covers cetuximab only for mCRC patients with liver-limited metastases. reviewed the therapeutic options for mCRC and discussed the practical implications of the study. adding cetuximab for KRAS WT patients who can afford it or get funding from other sources. Hence.” For selecting first-line treatment.44 Jul-Aug 2012 Expert Opinion Cetuximab rechallenge: Extending clinical benefits in mCRC While the benefits of first-line chemotherapy plus cetuximab (Erbitux®. we would try the ones we haven’t used before. KRAS mutation status is determined before initiating therapy.

6 months.1093/annonc/mdr623] The study was based on the hypothesis that KRAS status remains the same despite the treatments received. The primary endpoint was overall response rate (ORR). In addition. and we have occasionally used this approach for select- . after another progression. PD = progressive disease Adapted from Ann Oncol 2012. [Oncologist 2008.” the authors noted. they were retreated with the initial cetuximab plus irinotecan-based therapy. this is the first published report that clearly demonstrates the clinical benefit of rechallenge with the initial cetuximab-based therapy after progression on several treatment lines. ORR = overall response rate. Tumor response was evaluated every 8 weeks according to Response Evaluation Criteria in Solid Tumors (RECIST).7 53. Patients were treated until disease progression or unacceptable toxic effects. The ORR was 53. (Table) Table. for which they received a new line of chemotherapy with or without bevacizumab.17:1429-1434] The investigators enrolled 39 KRAS WT mCRC patients who had had a clinical benefit after cetuximab plus irinotecan-based therapy and then a progression of disease during therapy. “While longer treatment might further arrest disease progression. after a new line of therapy. SD = stable disease. [Ann Oncol 2012. DOI:10. PR = partial response. CCR = clinical control rate. a significant correlation between skin toxicity during the first cetuximabbased therapy and during rechallenge was observed. “Although there have been case reports. Median progression-free survival was 6.13:1270-1275.9 98. DOI:10. including 19 partial responses and 2 complete re- CR = complete response.2 months.8 35. Ann Surg Oncol 2010. Cetuximab rechallenge study The phase II study investigated whether patients with KRAS WT mCRC who responded and then progressed during cetuximab-based therapy would gain a clinical benefit.1 48. Clinical implications According to Hui.9 10.8 percent.1093/annonc/ mdr623.” Hui remarked. Previous responses during the first cetuximab-based therapy (stable disease lasting >6 months or partrial response) were found to predict clinical benefit after cetuximab-based retreatment. Finally. Tumor response rates Response CR PR ORR (CR+PR) SD CCR (CR+PR+SD) PD Number of patients 2 19 21 14 35 4 % 5. from retreatment with the same cetuximab-based regimen. it’s at the cost of cumulative toxicities from chemotherapy. “KRAS mutation is an early pathogenic step in CRC development and it seems to remain the same during tumor progression.45 Jul-Aug 2012 Expert Opinion sponses. Disease stabilization was reported in 14 patients and 4 patients had progressive disease.

1/2011 . with disease progression 9 months after therapy end.8/2011: Irinotecan + cetuximab x 12 cycles (3rd course. the progression-free intervals after successful response become successively shorter. 1/2010 . The primary tumor was asymptomatic and was not resected. “Patient selection is crucial. However. which may have practice-changing implications.46 Jul-Aug 2012 Expert Opinion Therefore. Cetuximab was started from the second cycle after confirmation of KRAS WT status. 4/2010 .2/2008: FOLFOX/XELOX. the residual liver metastases were not amenable to resection or radiofrequency ablation. rechallenge #1). as many patients cannot tolerate several lines of chemotherapy. Conclusions The study is the first demonstration that rechallenge with the same cetuximab-based therapy may achieve a new important clinical benefit in mCRC.” he said. rechallenge #2).” he commented. However. “As seen in this case. Case report: Repeat rechallenge with cetuximab-based therapy A 67-year-old man was diagnosed with adenocarcinoma of the rectum with multiple liver metastases in 6/2007. and achieved good radiological response and symptom control. Reduction of liver metastases was documented after 5 months (Figure a). The patient tolerated three courses of 12-cycle cetuximab-based treatment well. it is important to identify those who might benefit from this strategy with minimal toxicity.” commented Hui. repeat rechallenge with cetuximab-based therapy can be successfully applied to achieve tumor response and prolong survival. 6/2007 . and passed away a few months later following disease progression. 12 cycles with good response. 10/2008 .3/2010: Bevacizumab + oxaliplatin x 4 cycles with poor response. this is the first prospective trial to provide solid evidence.” ed patients. further delaying disease progression and improving the therapeutic options. Hui noted that the multicenter design of the study further confirms the validity and applicability of the results. however. Based on these data. . this approach may be more widely applied in clinical practice. I’m now much more confident to recommend retreatment with the same therapy to patients who responded previously to cetuximabbased therapy. with fewer therapeutic options remaining after each treatment course. “Based on these findings. Reduction of liver metastases was documented after 3 months (Figure b). he decided to take a treatment break after the last course. Nevertheless.3/2009: Irinotecan + cetuximab x 12 cycles (1st course).11/2010: Irinotecan + cetuximab x 12 cycles (2nd course. Reduction of liver metastases was documented after 4 months (Figure c). with disease progression 3 months after therapy end.

47 Jul-Aug 2012 Expert Opinion Figure. CT scans: Liver metastases (a) First course of cetuximab + irinotecan Before After 5 months (b) Second course of cetuximab + irinotecan (rechallenge #1) Before After 3 months (c) Third course of cetuximab + irinotecan (rechallenge #2) Before After 4 months .

multicenter.23:832-841] “Patients with clear cell histology are mostly treated upfront with multi-targeted receptor tyrosine kinase inhibitors (TKIs) such as sunitinib or pazopanib.” he said. patients with non-clear cell histology.” said Yau.” “The treatment for patients with advanced or metastatic RCC – when the diseased tissue cannot be completely eradicated with surgery alone – is not as straightforward. Thomas Yau. “Patients enrolled in this study had poor-prognosis. “Usually. However. Temsirolimus in poor-prognosis mRCC patients The phase III.” Study subjects had at least three of the following disease parameters.” explained Yau. randomized. interferon alfa (IFNα) and a combination of both.8 4 0 Jul-Aug 2012 Industr y Upda te 48 First-line temsirolimus improves survival in poor-prognosis mRCC patients In a randomized phase III study. Karnofsky performance score of 60 or 70. “Early-stage RCC patients are routinely referred for surgical tumour excision to reduce disease burden and preserve renal function. time from initial diagnosis of RCC to randomization <1 year. Clinical Assistant Professor. Department of Medicine. Pfizer) monotherapy demonstrated significant improvements over interferon alfa (IFNα) as firstline treatment for metastatic renal cell carcinoma (mRCC) patients with poor prognosis. and multiple organ metastases. temsirolimus (Torisel®. corrected serum calcium level >10 mg/dL. those patients only survive for about 3 to 6 months. University of Hong Kong discussed the management options for RCC and the findings of the pivotal trial that compared temsirolimus. . based on the Memorial Sloan-Kettering Cancer Center risk stratification system. RCC is treated in accordance with the US National Comprehensive Cancer Network (NCCN) guidelines. Yau Management of mRCC “In Hong Kong. or those with poor prognosis [regardless of histology]. Dr. which predicts short survival: serum lactate dehydrogenase >1. [J Clin Oncol 2005. Dr. open-label study evaluated the efficacy and safety of temsirolimus against IFNα or combined temsirolimus/IFNα therapy in 626 treatment-naïve patients. hemoglobin below normal levels.” said Yau. are treated with temsirolimus – a mammalian target of rapamycin (mTOR) kinase inhibitor.5 × upper limit of normal. The choice of first-line treatment for mRCC is largely dependent on the patient’s histological finding and prognosis.

5 months 0. Conclusion Temsirolimus monotherapy is an effective therapeutic option for managing mRCC in patients with poor prognosis.9 A vs 7. patients in the combined therapy arm received temsirolimus 15 mg IV weekly plus IFNα 3-6 million IU SC 3 times weekly.356:2271-2281.00 0 Number at risk Interferon alfa Temsirolimus Combination (B) Temsirolimus Combination Interferon alfa 5 10 15 20 25 30 Months 207 209 210 55 91 89 24 38 32 10 14 16 5 7 4 1 1 1 0 0 1 Adapted from N Engl J Med 2007.25 0. (Figure) 0 Months Objective response rate was nearly doubled in the temsirolimus monotherapy arm vs the IFNα monotherapy arm (8.75 0.50 0. Kaplan-Meier estimates of overall survival (A) and progressionfree survival (B) A (A) Probability of survival 1. good response to temsirolimus monotherapy. Temsirolimus-related adverse events included mild-to-moderate rash.25 those on IFNα (p=0. stomatitis.8 percent). patients in the IFNα-only arm received 3-18 million IU subcutaneously (SC) 3 times weekly. “Compared with IFNα-based therapy.00 5 10 15 20 25 30 PFS.00 0.75 0. it has a significantly improved efficacy and an acceptable toxicity profile.25 0. translating into a 77 percent increase in 0.3 months. peripheral edema.1 months for 0. Adverse events such as mucositis and hyperglycemia were easily managed. [N Engl J Med 2007.00 0 Number at risk Interferon alfa Temsirolimus Combination B Temsirolimus Combination Interferon alfa Compared with IFNα monotherapy.00 the primary endpoint – (10. four had Probability of survival Number at risk Interferon alfa Temsirolimus Combination 207 209 210 126 159 135 80 110 93 42 56 50 15 19 17 3 3 7 0 0 2 5 10 15 20 25 30 Months 207 209 210 126 159 135 80 110 93 42 56 50 15 19 17 3 3 7 0 0 2 Num Inter Tems Comb B Probability of progressionfree survival 1.” remarked Yau. “In my experience with six poor-prognosis patients at our hospital. resulting in fewer dose delays. p=0. “Interestingly. hypercholesterolemia and hyperlipidemia.0001).0078).” said Yau.50 for patients receiving temsirolimus vs 3.6 vs 4. patients receiving combination therapy did not achieve improved outcomes vs temsirolimus monotherapy.75 Interferon alfa sion-free survival (PFS) was 5.50 0.9 4 0 Jul-Aug 2012 Industr y Upda te 49 Patients in the temsirolimus-only arm received a dose of 25 mg IV weekly.00 0. Median Temsirolimus progresCombination 0. hyperglycemia. . Severe adverse events were less common in patients receiving temsirolimus monotherapy.” concluded Yau.356:2271-2281] Efficacy and safety Figure. patients on temsirolimus monotherapy had a 49 percent increase in median overall survival – 1. dose reductions and treatment discontinuation vs IFNα monotherapy.

poorly differentiated carcinoma. possibly of papillary type. as well as multiple hepatic nodules. but most became necrotic. Liver biopsy confirmed mRCC. Apart from her uncle. showing shrinkage of retrocaval lymph node CT at the 61st course of temsirolimus and 12th course of bevacizumab showed stable disease. as indicated by a slight increase in size of the segment II and segment VI hepatic lesions and the right retrocaval lymph node. open radiofrequency ablation of rightlobe tumors and resection of inferior vena cava lymph node. not further classifiable. The patient was treated with sunitinib 50 mg daily since August. CT abdomen after 20 cycles of temsirolimus. CT examination after 6 cycles showed worsening of all lesions. 69 U/L and 54 U/L. Subsequent MRI showed further shrinkage of the liver metastases. CT examination after 6 cycles showed shrinkage of the liver metastases and retrocaval lymph node. malaise associated with temsirolimus. IV bevacizumab 10 mg/kg every 2 weeks was added to maximize treatment efficacy. (Figure 1) Weekly intravenous temsirolimus (25 mg) was started in April. (Figure 2) Reassessment CT at the 38th course showed a mixed response in terms of sizes of the hepatic metastases. p-4EBP1. The histological diagnosis was RCC. except for transient Grade 3 ALT elevation and Grade 2 hypertension requiring amlodipine.6-cm × 8. with clear margins. p-Akt. 12. Treatment was changed to intravenous bevacizumab (10 mg/kg) every 2 weeks and subcutaneous interferon (9 mIU) three times weekly. No adjuvant treatment was indicated. . she was incidentally found to have a right kidney mass on a routine check-up. her family history was unremarkable.1-cm RCC. 145 U/L (normal). calcium. Baseline blood tests results were: hemoglobin. Her past health had been good except for a cholecystectomy in 1996. The patient also complained of mild stomatitis. computer tomography (CT) reassessment after 2 months showed enlarged retrocaval and hepatic metastases. There were no retroperitoneal lesions or lymph node involvement. lactate dehydrogenase (LDH).0 5 0 Jul-Aug 2012 Industr y Upda te 50 Case report A 39-year-old Han Chinese woman was referred for management of mRCC in 2008. The pathology of the resected specimen showed metastatic. and mild headache and proteinuria associated with bevacizumab. 2. In 2007. as well as a new caudate nodule. CT examinations at the 20th and 28th cycles both showed stable liver metastases.5 g/dL (normal). The treatment was discontinued after 6 weeks due to progressive disease. After liver metastasectomy the patient continued on temsirolimus plus bevacizumab. Her Karnosfsky performance status was 100 percent. p-S6. dry skin. Figure 1. A subsequent CT scan showed an 8. However. The patient was then enrolled in a clinical trial and randomized to receive sorafenib 400 mg bid. The patient eventually proceeded to left lateral segmentectomy of the liver. The immunohistochemical staining was positive for phosphorylated (p)-mTOR. The patient was therefore classified as ‘good risk’ according to the Memorial Sloan-Kettering Cancer Center risk stratification system. respectively. Right radical nephrectomy was performed in October 2007. who had liver cancer and colorectal cancer. CT abdomen after 6 cycles of IV bevacizumab and interferon Figure 2. indicating progressive disease.35 mmol/L (normal). Her disease remained stable for 9 months. slightly raised alanine transaminase (ALT) and aspartate transaminase (AST). However. PET-CT after 9 months showed a mildly enlarged retrocaval lymph node medial to the second portion of the duodenum. There were no major side effects. 2008. 2009.

org http://www.org/Home.eu http://www.org http://www.com http://www.aspx 2012 American Association for Cancer Research (AACR)/ASCO Workshop: Methods in Clinical Cancer Research 28/7/2012 to 3/8/2012 Vail. USA Info: AACR Tel: +215 440 9300 Fax: +215 599 0111 E-mail: programs@aacr. Austria Tel: +41 (0)91 973 19 39 Fax: +41 (0)91 973 19 18 E-mail: registration@esmo.vailworkshop.org/index.com/index.aspx 3rd Oncology Forum of Hong Kong 21/7/2012 Hong Kong Info: PC Tours and Travel Tel: +852 2734 3312 / +852 2734 3315 Fax: +852 2367 3375 E-mail: veronica@pctourshk.org/events/vienna-2012-congress.php?id_page=1 ASCO 2012 Multidisciplinary Symposium in Thoracic Oncology 6/9/2012 to 8/9/2012 Chicago.org http://www.hkcr.thoracicsymposium.worldcancercongress.esmo.org/index.jp/en/ 32nd Congress of the European Society of Surgical Oncology (ESSO) 19/9/2012 to 21/9/2012 Valencia.org/ 10th Annual Meeting of the Japanese Society of Medical Oncology 26/7/2012 to 28/7/2012 Osaka. Canada Info: International Union for Cancer Control Tel: +41 22 809 1811 E-mail: congress@uicc. Germany Tel: +32 (0) 789 2345 Fax: +32 (0) 743 1550 E-mail: info@ilca-online. Spain Info: European Cancer Organization Tel: +32 2 775 02 01 Fax: +32 2 775 02 00 E-mail: esso32@ecco-org.html International Liver Cancer Association 6th Annual Conference 14/9/2012 to 16/9/2012 Berlin.ilca2012. Italy Tel: +39 02 36753900 Fax: +39 02 43911650 / +39 02 49542900 E-mail: congress@cq-travel. (ICS) – Grit Schoenherr Tel: +1 604 681 2153 Fax: +1 604 481 1049 E-mail: lalca2012@icsevents.org http://breastcasymposium.com http://jsmo2012.eu 2012 World Cancer Congress 27/8/2012 to 30/8/2012 Montreal.ecco-org.51 Jul-Aug 2012 Calendar ASCO 2012 Breast Cancer Symposium 13/9/2012 to 15/9/2012 San Francisco.ecco-org.lalca2012. USA Tel: +888 282 2552 Fax: +571 483 1300 E-mail: membermail@asco.eu http://www.cq-travel. USA Tel: +706 502 1550 Fax: +703 502 7852 http://www. Hungary Info: European Cancer Organization Tel: +32 2 775 02 01 Fax: +32 2 775 02 00 E-mail: ecop2012@ecco-org.eu/Conferences/Conferences/ ESSO-32.html .org/ 37th ESMO Congress 28/9/2012 to 2/10/2012 Vienna.html European Conference of Oncology Pharmacy (ECOP) 27/9/2012 to 29/9/2012 Budapest.org http://www.com http://www.umin.org International CardiOncology Society Annual Meeting 28/9/2012 to 29/9/2012 Milan. Japan Tel: +81 3 6809 1250 Fax: +81 3 6809 1138 E-mail: jsmo2012@sunpla-mcv.com http://www. Brazil Info: International Conference Services Ltd.org/ 5th Latin American Conference on Lung Cancer 25/7/2012 to 27/7/2012 Rio De Janeiro.

eu/Conferences/Conferences/ EORTC_NCI_AACR-2012.org Markers in Cancer – Joint Meeting by ASCO.org/Home. USA Tel: +888 282 2552 Fax: +571 483 1300 E-mail: membermail@asco. and NCI 11/10/2012 to 13/10/2012 Hollywood.52 Jul-Aug 2012 Calendar 44th Congress of the International Society of Pediatric Oncology 5/10/2012 to 8/10/2012 London. Florida.org http://molecularcameeting. UK Info: European Cancer Organization Tel: +32 (0) 2 775 02 01 Fax: +32 (0) 2 775 02 00 E-mail: info@siop2012.asco.org/ASCOv2/Meetings/ ASCO%27s+Quality+Care+Symposium .org http://www. Ireland Info: European Cancer Organization Tel: +32 (0) 2 775 02 01 Fax: +32 (0) 2 775 02 00 E-mail: ena2012@ecco-org.aspx 24th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics 6/11/2012 to 9/11/2012 Dublin.eu http://www. USA Tel: +888 282 2552 Fax: +571 483 1300 E-mail: qualitysymposium@asco.aspx ASCO’s Quality Care Symposium 30/11/2012 to 1/12/2012 San Diego.org http://www. EORTC.siop2012.ecco-org.

Hong Kong Fax: (852) 2559 6910 Tel: (852) 2559 5888 Email: info@oncologytribune. omissions or inaccuracies in this publication whether arising from negligence or otherwise howsoever. Daniel Chua Tsin-Tien (Hong Kong Sanatorium & Hospital) Dr. Agnes Chieng. 3rd Floor. Permission to reprint must be obtained from the publisher. Hextan Ngan (University of Hong Kong) Dr. Oncology Tribune is a controlled circulation publication to medical practitioners in Asia. Poon (University of Hong Kong) Dr. Chung On Industrial Building. Hong Kong. No part of this publication may be reproduced in any language. The inclusion or exclusion of any product does not mean that the publisher advocates or rejects its use either generally or in any particular field or fields. the authors.com Advertising Enquiries : Jacqueline Cheung.com Oncology Tribune is published 6 times a year by UBM Medica. photocopying. Ronnie T. Editorial matter published herein has been prepared by professional editorial staff. The price per annum is US$48 (surface mail) and US$60 (overseas airmail). ISSN: 2078-2535 Oncology Tribune contains articles from Cancer Network. a division of United Business Media. All rights reserved. Advertisements are subject to editorial acceptance and have no influence on editorial content or presentation. in any form or by any means (electronic. Copyright © 2012 UBM Medica LLC. Sigourney Liu. Chai Wan. Roberta Pang (University of Hong Kong) Prof. Marisa Lam. Although great effort has been made in compiling and checking the information given in this publication to ensure that it is accurate. The information contained within should not be relied upon solely for final treatment decisions. without the written consent of the copyright owner.Publisher : Ben Yeo Naomi Rodrig Christina Lau Marisa Lam Charity Chan. the publisher and their servants or agents shall not be responsible or in any way liable for the continued currency of the information or for any errors. or transmitted. stored in or introduced into a retrieval system. Ava Kwong (University of Hong Kong) Dr. 28 Lee Chung Street. or for any consequences arising therefrom. OTB Building 160 Gloucester Road. Sam Shum Edwin Yu. Editorial Advisory Board – Hong Kong Dr. Printed by Fortune Printing International Ltd. directly or indirectly. Wai-Man Sze (Cancer Care Center) . Ho Wai Hung Louella Ng Deputy Managing Editor : Editor Publication Manager Designer : : : Production Circulation Executive Accounting Manager Publication Manager Published by : : : Minty Kwan : Jose Tin : UBM Medica Pacific Limited 27th Floor. Wan Chai. back issues at US$5 per copy. the quality or efficacy of any product or service described in the advertisements or other material which is commercial in nature. Kristina Lo-Kurtz. recording or otherwise). mechanical.hk@ubmmedica. Miranda Wong Tel: (852) 2559 5888 Email: enquiry. P. Carol Kwok (Princess Margaret Hospital) Dr. It is also available on subscription to members of allied professions. William Foo (Hong Kong Baptist Hospital) Dr. Kwok-Chi Lam (Chinese University of Hong Kong) Prof. © 2012 UBM Medica. Michael Cheung Ming-Chee (Asia Cancer & Hematology Centre) Dr. Philip Kwok (Queen Elizabeth Hospital) Dr. under license from UBM Medica LLC. Raymond Liang (Hong Kong Sanatorium & Hospital) Prof. Views expressed are not necessarily those of UBM Medica. UBM Medica does not guarantee.

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