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    14 views9 pages

    Pembro Liz Um Ab Informacion

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    Alejandra Rodríguez

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    ‘OPINION Expert Opinion on Biological Therapy ISSN: 1471-2598 Prin) 1744-7682 (Online) Journal homepage: httns/émw/tanefonline.com/lofieht20 Pembrolizumab for the treatment of diffuse large B-cell lymphoma Semira Sheikh & John Kuruvilla To cite this article: Semira Sheikh & John Kuruvilla (2019): Pembrolizumab for the treatment of difuse large B-cell lymphoma, Expert Opinion on Biological Therapy, DO! 10.1080/14712598,2019.1659777 To link to this article: https://dol,org/10.1080/14712598,2019,1659777 PB) Pubisned onine 28 ago, CF suomicyourartce to this journal By vewewesonces@ ©& views crossmark data Full Terms & Conditions of access and use can be found at hteps://waw tandfonline.com/actionyjournalinformation?journalCode=iebt20 [EAPERTOPHON ON BIOLOGICAL THERAPY tesa oarerasa 2019689777 DRUG EVALUATION, brolizumab for the treatment of diffuse large B-cell lymphoma Semira Sheikh and John Kuruvilla Taylor & Francis, itetantce Dhision of Medical Oncology and Hematology, Princess Margaret Cancer Centre, Department of Medicine, Univesity of Toronto, Toronto, Canada Introduction: Pembrolizumab Is a novel monoclonal antlbady that targets the interaction between programmed cell death protein 1 (PD-1) and its ligand (PD-L1). Pembrolizumab has shown significant linical efficacy in Hodgkin Lymphoma (HL), but results in non Hodgkin Lymphoma (NHL) are mixed, Some NHL subtypes, which share certain genetic features with HL, such as alterations in chromosome 9p24.1 and expression of PD-L1, have shown promising responses in early phase Was. ‘Areas covered: In this review, ve provide an overview of pembrolzumab as a compound, and present the available clinical efficacy and safety data in the treatment of diffuse large 8 call lymphomas. Expert opinion: Current early phase data suggest that single agent pembrolizumab in NHL demon strates both efficacy and a favorable safety profile. However, itis anticipated that future treatment strategies will be blomarker-criven and incorporate pembrolzumab into combination therapies with Received 3 Api 2019, Decepted 21 August 208 Pembolzumabs difuse lage cel mphoma: chedpoit han chemotherapy and/or Immunotherapy agents. troduction 'Nor-Hodgkin Lymphoma (NHL) is the fifth most common cancer, In North America, with approximately 75,000 new cases diag- nosed in the US each year (1) Diffuse large 8 cell lymphoma (DLBCL Is the most common NHL subtype, and frontline treatment with a standard immuno- ‘chemotherapy regimen consisting ofthe antibody rituximab in combination with cyclophosphamide, hydroxydaunorubicin, vincristine, and. prednisone (R-CHOP) is curative in approxi mately 60% of patients. However, an estimated 30-40% of patients with DLBCL relapse after treatment, and an additional 10% of patients have refractory disease (2). Recent advances in molecular biology and genetics, including gene expression profling, have led to a significantly improved Understanding of the molecular heterogeneity underlying the biology of DLBCL. What are now understood to be distinct blolo- {ical OLBCL subtypes, such as primary mediastinal 8 cell Iym- phoma (PMBCL), aggressive 8 cell transformation of indolent ymphomas (TRI), and EBV positive DLBCL, have previously all ‘been grouped under the broad umbrella diagnosis of DLBCL despite differing clinical presentations and disease course, Despite these biologic differences, curative treatment regimens ‘employed for frontline and second line treatment of these lym= pphomas are similar. In addition, certain aggressive lymphomas ‘occurring In so-called sanctuary sites, such as testicular or central nervous system (CNS) lymphomas, are often grouped as DLBCL subtypes (3-51 Relapsed or refractory (R/R) DLBCL carties a poor prognosis. ‘The current standard of care (SOC) in R/R DLBCL for patients eligible for curative therapy Is a nor-ctoss resistant salvage chemotherapy regimen, followed by an autologous stem cell transplant (ASCT). Two recent prospective studies, the Canadian- led LY.12 study, and the European Collaborative tal In Relapsed ‘Aggressive Lymphoma (CORAL) demonstrated that about half of Patients treated with this approach will prove resistant to salvage chemotherapy, and half of patients will relapse after ASCT [3,5], Allogeneic transplantation (allo-SCT) may offer the advantage of a graft-versus-lymphoma effect that can control the disease and lead to reduced relapse rates, but allo-SCT in DLBCL is considered controversial. Mature data report relatively modest success rates, with a non-relapse mortality of up to 3096 in the frst year, and increased rates of post-transplant morbidity due to chronic graft- vversus-host disease [7-9] For those R/R DLBCL patients who are unfit or unwilling to undergo a stem cell transplant, and those who relapse post- transplant, treatment options are more limited, and the out- come is poor, especially for those who have higher risk features such as a secondary IPI score 22 or relapse <12 months post- [ASCT. Treatment strategies in this scenario are considered pal- lative and include radiation, oral chemotherapy, or participation In clinical trials, with a median overall survival (05) between 5-10 months (10,11]. The SCHOLAR-1 study collected extensive patient-level data for patients with refractory DLBCL from four diferent sources, including follow-up from the LY.12 and CORAL studies, as well as observational cohorts from the MD Anderson Cancer Center (MDACC) and the Molecular Epidemiology Resource of the University of lowa/Mayo Clinic Lymphoma Specialized Program of Research Excellence (IMC). The pooled objective response rate to the next line of therapy in this com- prehensive study cohort was 26%, with only 7% of patients achieving complete remission (CR). The median OS was short (10 months) across all subgroups, regardless of prognostic factors and refractory status (12) ACT John Kuruaa @) john kurvllaaubnonca G) Divison of Medal Oncology and Hematology, Princess Margaret Cancer Cente, Depart of Medicina, Univesity of Toronto, Toronto, Canad (©2019 ors Uc Utd tang alr & Francs Grup 2 © s steno ano 1 KURA + Pembroiaumab is novel ant-PD-1 monodonal antibody wth ro- ‘mang aca) in non oda mph + ata fom ear phase cll wile with pembrokauna has ient> fied cerain DLACL subypes, such 25 PMBCL, 35 belng patetly sensi 0 checkpoint nhibiion | + For DUBCL as a whole, chaacterzation of molecu subtypes wil be cal ta dec the most efficacious use of hecpat into with parbiotumab inca tal combining pembrokmumsb with targeted agents in DUBCL ate ongoing This box surwmarzes key points contained inthe article rg Summa rug Name Pembrloumab Phase n nication Die Large Beall lymehoms Pharmacology despionmechanim of ants®D1 manacona ‘ctor soy Aswan references, 2-45) ‘The development of novel strategies for treating FVR DLBCL is therefore urgently needed. Clinical trials evaluating both non- immunological as well as immunotherapy-based approaches are ‘ongoing, and include agents such as the immunomodulatory agent lenaidomide, the BTK inhibitor Ibrutinib, the nuclear export inhibitor selinexor, or antibodies, either monoclonal or bispecific, ‘that target tumor cell surface markers (Including the bispecific {anti-CD19/CD3 antibody blinaturmomab, the ant-CD79b antibody rug conjugate polatuzumab vedotin, or the ant-CD19 MOR208, antibody), oF various immune effector mechanisms [13-18] Using checkpoint inhibitor therapy and/or chimeric antigen receptor T cells (CART cells) to hamess the immune system in ‘order to target tumor cells has shown encouraging results in, terms of achieving sustained remissions in patients with R/R DLBCL [19-23]. immune blockade of the PD-1/PO-L1 pathway by monoclonal antibodies directed against either PO-1 or PD- LL alms to restore disabled immune checkpoints and thereby the anti-tumor activity of cytotoxic T cells The PD-1 antibody pembrolizumab (Box 1) has been shown to have significant activity in R/R classical Hodgkin Lymphoma (HL), 2 lymphoma derived from germinal center 8 cells with a high frequency of PD-L1 expression which Is driven by chromosome 9p24.1 alterations in the majority of cases. Given its efficacy In the F/R setting, pembrolizumab is now algo being incorporated into frontline and salvage regimens in patients with HL (20,24). In addition, pembrolizumab was ‘granted accelerated FDA approval in June 2018 for patients with R/R primary mediastinal B cell lymphoma (PMBCL) a subtype of NHL which shares some genetic features with classical HL such as increased levels of PD-L1 expression [25] By contrast, PD-L1 expression Is variable In mast other types of B-cell NHL, but clinical activity of PD-1 blockade has never- theless also been demonstrated in some cases. The reasons for, this differential efficacy in lymphoma patients are not well under- stood. To date further clinical trials evaluating the use of check- point inhibition in general, and pembrolizumab in particular, in other DLBCL entities, are ongoing (24,26,271 2. Overview of the market ‘The consistently poor outcomes for patients with ®/R DLBCL Indicate a significant unmet need for effective salvage thera- pies in this group of patients. A key component of any such ‘therapy would be a response rate that is both high and also durable, with a favorable toxicity and economic profile, The approach to second-ine therapy in /RDLBCL has thus far bbeen defined by the eligibility of patient for aggressive therapy; patients with acceptable comorbicity will be considered for sal ‘vage chemotherapy and ASCT, based on the randomized Parma tral [28], Reports of salvage chemotherapy regimens have gen- erally incorporated all subsets of DLBCL when reporting out- ‘comes in this patient group, but retrospective analyses highlight the potential for differential outcomes in DLBCL subsets such as PMBCL or TRIL, given the different tumor biology asso- ciated with these entities. Considering treatment approaches based on these unique features would consequently present 2 logical treatment rationale. In addition, teeatment options in the non-aggressive setting, n patients limited by functional sta- tus or comorbidities, are often restricted to conventional che- ‘motherapy or palliative radiation, and only a few agents have so far received FDA and/or EMA approval with outcomes generally considered poor {29-31 ‘Therapeutic T cell engineering has made It possible to gen- erate chimeric antigen receptors (CARS), which can redirect the speeifcty of T cells and reprogram thelr function, thereby del: vering activated T cells with potent cytotoxicity against tumor- specific antigens. Anti-CD19 CAR T cells have been shown to hhave significant clinical efficacy, but are also associated with ‘unique toxicities, such as cytokine release syndrome or neurolo- gical events [21-23]. in addition, the financial impact of CAR T cells is substantial, given the logistical challenges including collection and manufacturing ofthe product. By contrast, checkpoint inhibitors are known to be well tolerated based on extensive experience in patients with Iym- phoma and solid cancers. Two checkpoint inhibitors, nivolu- mab and pembrolizumab, are approved for use in HL, and are considered comparable in terms of tolerability, efficacy and ‘cost. While both agents require intravenous administration, infusion times are short and schedules range from 2 to @4 ‘weekly dosing which is not inconvenient. Given their favorable administration and toxicity profiles, these agents represent excellent candidates for potential combination strategies in patients with R/R DLBCL. 3. Introduction to the compound 3.1. Mechanistic considerations Immunotherapy aims to activate and enable to hosts own Immune system to seek out and destroy malignant cell Immune checkpoints are molecules that allow modulation of immune signaling, and can be either stimulatory ie. supporting ‘activation, maturation and proliferation of T cells or inhibitory, Le. having the converse effect, leading to eventual apoptosis of Tells (32) The PD-1/PD:L1 pathway has been shown to play a critical role inthe antitumor response and immune evasion, Exploting the susceptibility of this pathway to antibody-mediated block- ‘ade therefore constitutes an attractive target for therapeutic intervention, Alterations in chromosome 9p24.1 which are com- monly found in HL and lead to over-expression of programmed ypadi geuouneuyg eunmpqug (Gre a10Wan qeunmorqued ym uoneaquos u qeuoumenG Jo UD pue Kayes an SuneBpsen4 fps Bae LS ipoaave ora ive) ‘ew uous ep 8 #5 amy 10 wows seraoy etree 20 perdi anad Bunmen &GeunnoLquE pee GeuPM -suned ewoyéurt > 257 asia 4 geuaorqud kay UoReUgUED UL oRBPERD6es J Kons (eyay a) ewoyduky 435-9 2:61 asyig KooDeyes 1m pasts Jy qeunajoqwed aH Dana w aeuenGu 6 © s sven ano» uRUVILA transplant during the post-pembrolizumab follow up period). "No patients discontinued treatment due to adverse events, and no patients died due to TRAEs. No new safety signals were ‘generated dluring the extension period of the study (19,42), In the KEYNOTE 170 study, 57% of patients experienced TRAES, with neutropenia (199%), hypothyroidism (88), fatigue (856), and_pyrexia (6%) being most commonly reported, ‘Twelve patients experienced Grade 3-4 TRAES, Including neu- tropenia and one case of Grade 4 pneumonitis, No treatment- related deaths were reported (43) Furthermore, safety data published by Ding et al which Included 9 patients with RT, showed that TRAEs occurred in all patients included In the study, with Grade 3 or above ‘events experienced in 609 of the trial population, The most frequently reported Grade 3-4 events were anemia, thrombo- ‘ytopenia, neutropenia, dyspnea or hypoxia [44], Taking into consideration tral data with nivolumab, another fully human anti-PD-1 monoclonal antibody, PD1 blockade in NHL appears to be safe, with severe immune-related adverse ‘events having been rarely observed to date (24,4748) slatory affairs To date, pembrolizumab Is only FDA-approved for use in R/R PMBCL as the only NHL subtype [25]. It is currently not approved for use in any NHL subtype by the EMA. Checkpoint inhibition has been transformative in the treat- ment of R/R HL. In the setting of F/R NHL, however, results (of PD-1 inhibition have so far been mixed. Pembrolizumab has shown promising results in early phase trials of R/R NHL with chromosome 9p24.1 alterations and PO-L1 over-expression, No Phase 3 data is available at the time of writing, The role of PO-I/PD-L1 checkpoints and the degree of PO-LT expression in NHL remains relatively poorly understood, Improved Immunohistochemical and molecular techniques may lead to a better and more reproducible characterization of PO-LI expres- sion on tumor cells and within the tumor microenvironment as ‘well asa better understanding of the complex dynamics involved, In NAL tumor biology. Moreover, the design of biomarker-driven ‘alsin this eld may help to evaluate the role of pembrolizumab ‘urther and provide a scientific rationale for more efficiently direct- ing targeted therapy inthis setting. pert opinion To date, the available data from early phase clinical vals demon- strate that single agent pembrolizumab shows encouraging eff- ‘acy and is well tolerated in patients with DLBCL subtypes with ‘chromosome 9p24.1 amplification and PD-Lt over-expression. The toxicity profile of pembrolizumab in general appears favorable, and is no diferent from that reported in the treatment of solid ‘malignancies, where the experience with these agents has been ‘more long-standing. However, the majority of DLECL appears to be only mod- estly sensitive to pembrolizumab monotherapy and it there- fore seems less advisable to pursue testing this agent in lunselected patient populations. Thus far, there remains a lack of other predictive biomarkers that could indicate whether, and which, other DLBCL subtypes may also benefit from treatment with pembrolizumab, There may be specific entities (e.g. EBV-associated DLBCL) and specific disease pre- sentations (eg. testicular or CNS involvement) in which the immunologic characteristics of the disease provide the poten- tial to enrich for responders to checkpoint inhibitors, For example, Chapuy et al were able to identify deregulated PO- L1 and PD-L2 expression in patients with primary testicular lymphoma and primary CNS lymphoma, and a pllat study in patients with relapsed primary CNS lymphoma showed responses to checkpoint inhibition with nivolumab [33,49] ln addition, it remains unclear whether long-term durable responses can be achieved with pembrolizumab, and what the risks of treatment discontinuation and long-term side effects may be, It is anticipated that approaches that combine pembrolizu- ‘mab with elther conventional chemotherapy or other targeted agents, such as for example other checkpoint inhibitors or in the context of CAR T cell therapy (see Table 2 for examples), may demonstrate a greater magnitude of effect and more durable responses in this setting. The positioning of pembro- lzumab in the timing and sequencing of NHL therapy, there- fore, remains an important issue to be resolved. These outstanding questions should be addressed in the context of translational clinical tials. Declaration of interest 4 Kuril as received honoraria fom and const for Merce The authors Ihave mo other relevant aflations or fan iwolvernent with any gan= zation or ent wth franca interest in or nancial confit wth the subject ‘matty or mates dscused inthe manuscript apar rom those core Reviewer Disclosures Peer reviewers on this manuscript have ne relevant hand tlatonships or otherwise to dle. References Papers of spcil note have been highlighted as ether of interest) or of considerable interest () to readers. 1. NCL ted 2019 Mar 20. Avasble fom: heee/ecercancergovsat facta 3013 2 Giselovecht , Van Oen Neste € How | manage patient with relopsed/tetractory fuse large 8 cll ymphoma. Br J Hoematl 2018 Sept8215)633-663 3. Gump M Kurla J, Couban 5, etal Randomized comparon of gemcitabine, dexamethasone, sd csplatn versus dexamethscone, jarabine, and cplatin cheratherapy before autologous seme ‘tansplanation for relapsed and rerectory aggresive bps: OCCT LY.12. JC Oncol. 2014 Nov 13201) 3480-3496. 4. Kuruvi Petite M, Tsang Ret al Sahage chemotherapy and ato: Iogous stem coll vasplantation ae Ineo for elapsed or reeatoy 20. 2 2 primary mesastiallage

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