Alectinib

https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/2
08434s003lbl.pdf

(1)
On November 6, 2017, the Food and Drug Administration granted regular approval to
alectinib (ALECENSA, Hoffmann-La Roche, Inc./Genentech, Inc.) for treatment of patients
with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer
(NSCLC), as detected by an FDA-approved test.

In December 2015, alectinib received accelerated approval for treatment of patients with
ALK-positive metastatic NSCLC whose disease progressed on or who were intolerant of
crizotinib based on an independent review committee (IRC)-assessed overall response rate
(ORR) of 38% and 44% among 87 and 138 patients, respectively, in two single arm trials.

This current approval is based on data from ALEX (NCT02075840), a randomized, multi-
center, open-label, active-controlled trial conducted in 303 patients with ALK-positive
NSCLC who had not received prior systemic therapy for metastatic disease. All patients were
required to have evidence of ALK-rearrangement identified by the VENTANA ALK (D5F3)
CDx Assay performed through central laboratory testing. Patients were randomized 1:1 to
receive alectinib 600 mg orally twice daily (n=152) or crizotinib 250 mg orally twice daily
(n=151).

ALEX demonstrated an improvement in progression-free survival (PFS) as assessed by

blinded IRC (BIRC), with a hazard ratio (HR) of 0.53 (95% CI: 0.38, 0.73; p<0.0001). The
estimated median PFS for patients randomized to alectinib was 25.7 months (95% CI: 19.9,
not estimable [NE]) compared with 10.4 months (95% CI: 7.7, 14.6) for those randomized to
crizotinib. The time to cause-specific central nervous system (CNS) progression as assessed
by IRC was also significantly improved; there was a lower incidence of progression in the
CNS as first site of disease progression, alone or concurrent with systemic progression, in the
alectinib arm (12%) compared to the crizotinib arm (45%). Confirmed ORR was 79% (95%
CI: 72, 85) and 72% (95% CI: 64, 79) in the alectinib and crizotinib arms, respectively.
Among the 120 responders in the alectinib arm and the 109 responders in the crizotinib arm,
the proportion of patients with response duration of ≥12 months was 64% and 36%,
respectively.

CNS involvement was assessed in all patients. Among the 43 patients with measurable CNS
lesions on baseline brain scans, the CNS ORR, assessed by BIRC neuro-radiologist, was 81%
(95% CI: 58, 95) in the alectinib arm and 50% (95% CI: 28, 72) in the crizotinib arm. Among
patients with measurable CNS lesions and a CNS response, the proportion of patients with a
CNS response duration of ≥12 months was 59% in the alectinib arm and 36% in the crizotinib
arm.

The most common adverse reactions (occurring in ≥20% of patients taking alectinib in
ALEX) were fatigue, constipation, edema, myalgia, and anemia. Serious adverse reactions
occurred in 28% of patients treated with alectinib. Adverse reactions leading to alectinib
discontinuation occurred in 11%. Adverse reactions that led to alectinib discontinuation in 1%
or more of patients were renal impairment, hyperbilirubinemia, increased alanine
aminotransferase, and increased aspartate aminotransferase. Dose interruption due to adverse
reactions occurred in 19% of alectinib-treated patients, while dose reductions were required in
16%.

The recommended dose of alectinib is 600 mg orally twice daily with food.

(2)

What is the drug for?

ALECENSA is a drug used to treat a type of lung cancer called non-small cell lung cancer
(NSCLC) that is advanced (metastatic). It is to be used in patients who have a specific gene
rearrangement in what is called the anaplastic lymphoma kinase (ALK) gene. It should be
used only in patients whose cancer has worsened after, or who could not tolerate treatment
with, another drug called Xalkori (crizotinib).

How is this drug used?

ALECENSA is a capsule that is taken two times a day with food.

What are the benefits of this drug?

In one trial, 38% of patients taking ALECENSA had a partial shrinkage of their cancer, which
lasted an average of 7.5 months. In a second trial, 44% of patients had a partial shrinkage of
their tumor, which lasted an average of 11.2 months.

For the two trials combined, 61% of patients who had measurable cancer lesions in the brain
prior to taking ALECENSA had a complete or partial reduction of the lesions in the brain
which lasted an average of 9.1 months.

Were there any differences in how well the drug worked in clinical trials among sex, race
and age?
 Sex: ALECENSA worked similarly in men and women.
 Race: The majority of patients in the clinical trial were white. Differences in response
to ALECENSA among races could not be determined.
 Age: The majority of patients in the clinical trial were younger than 65 years of age.
Differences in response to ALECENSA between patients below and above 65 years of age
could not be determined.
What are the possible side effects?
The most common side effects of ALCENSA are tiredness, constipation, swelling in hands,
feet, ankles, and eyelids and muscle pain. Treatment with ALECENSA may cause sunburn
when patients are exposed to sunlight.

ALECENSA may cause serious side effects, including liver problems, life-threatening
swelling (inflammation) of the lungs, slow heartbeat, and severe muscle problems.

ALECENSA can harm an unborn baby.

Were there any differences in side effects among sex, race and age?
 Sex: The risk of side effects was similar in men and women
 Race: The majority patients in the clinical trial were white. Differences in side effects
among races could not be determined.
 Age: The majority of patients in the clinical trial were younger than 65 years of age.
Differences in side effects between patients below and above 65 years of age could not be
determined.

WHO WAS IN THE CLINICAL TRIALS?

Who participated in the clinical trials?

The FDA approved ALECENSA based on the evidence from two clinical trials of 253 patients
with NSCLC with the ALK mutation. The trials were conducted in the USA, Canada, Europe,
Asia, and Australia.

The figure below summarizes how many men and women were in the clinical trials.

Figure 1. Baseline Demographics by Sex

Figure 2 and Table 1 below summarize the percentage of patients by race enrolled in the
clinical trials.

Figure 2. Baseline Demographics by Race

Table 1. Demographics of Efficacy Trials by Race

Race Number of Patients Percentage

White 186 73.5%

Asian 46 18.2%

Other 11 4.3%

Black or African American 4 1.6%

Unknown 4 1.6%

American Indian or Alaska Native 1 0.4%

 Multiple 1 0.4%

Figure 3 summarizes the percentage of patients by age enrolled in the clinical trials.

Figure 3. Baseline Demographics by Age

How were the trials designed?

The benefit and side effects of ALECENSA were evaluated in two clinical trials of patients
with NSCLC with the ALK mutation. All patients received ALECENSA. The benefit of
ALECENSA was evaluated by measuring if and how much the tumor size changed during
treatment and how long that response lasted.

GLOSSARY
CLINICAL TRIAL: Voluntary research studies conducted in people and designed to answer
specific questions about the safety or effectiveness of drugs, vaccines, other therapies, or new
ways of using existing treatments.
COMPARATOR: A previously available treatment or placebo used in clinical trials that is
compared to the actual drug being tested.
EFFICACY: How well the drug achieves the desired response when it is taken as described
in a controlled clinical setting, such as during a clinical trial.
PLACEBO: An inactive substance or “sugar pill” that looks the same as, and is given the
same way as, an active drug or treatment being tested. The effects of the active drug or
treatment are compared to the effects of the placebo.
SUBGROUP: A subset of the population studied in a clinical trial. Demographic subsets
include sex, race, and age groups.
(3)

Introduction

A 2007 report first described the finding that tumors in a small number of patients with non–
small cell lung cancer (NSCLC) harbored a rearrangement in the anaplastic lymphoma
receptor tyrosine kinase (ALK) gene and the echinoderm microtubule–associated protein-like
4 (EML4) gene (referred to hereafter as “ALK rearrangement;”), resulting in an EML4–ALK
fusion protein that in preclinical studies demonstrated the potential to result in malignant
transformation. Based on this observation, clinical development of ALK inhibitors was
pursued in hopes of developing more effective treatments for the estimated 2% to 7% of
NSCLC patients with tumors harboring ALKrearrangements. Some patient and tumor risk
factors that appear to be associated with the presence of ALK rearrangement are younger age,
light- or never-smoking status, adenocarcinoma histology, and stage IV disease. ALK testing
is recommended for adenocarcinomas and mixed lung cancers with an adenocarcinoma
component.
Crizotinib, a multitargeted tyrosine kinase inhibitor that targets ALK, was the first kinase
inhibitor approved for the treatment of ALK-positive, metastatic NSCLC. The FDA granted
accelerated approval of crizotinib in 2011 and traditional approval of crizotinib in 2013.
Acquired resistance to crizotinib develops in the majority of tumors during treatment with
crizotinib. Mechanisms of resistance include mutations in the ALK tyrosine kinase domain
and activation of alternative signaling pathways. In addition to resistance, another mechanism
of treatment failure is the development of brain metastases. A retrospective analysis of two
studies assessing crizotinib for the treatment of patients with advanced ALK-positive NSCLC
reported that, among patients without brain metastases at the time of enrollment who
developed progressive disease, 20% developed brain metastases.
In April 2014, the FDA granted accelerated approval to ceritinib, an ALK inhibitor, for the
treatment of patients with ALK-positive, metastatic NSCLC who have progressed on or are
intolerant to crizotinib. In the single-arm trial providing the primary data that led to the
approval of ceritinib, the objective response rate (ORR) was 44%, with a median duration of
response of 7.4 months. Approximately 60% of patients required at least one dose reduction,
and dose modification related to gastrointestinal (GI) toxicities of diarrhea, nausea, vomiting,
or abdominal pain occurred in 38% of patients.
Alectinib is a tyrosine kinase inhibitor that targets ALK and ret proto-oncogene (RET) kinase.
In June 2013, the FDA granted alectinib breakthrough therapy designation based on the
preliminary evidence of clinical activity in patients with metastatic, ALK-positive NSCLC
previously treated with crizotinib, including activity in patients with central nervous system
(CNS) metastases. The FDA review of the new drug application (NDA) for alectinib for this
indication is summarized in this article.

Chemistry, Manufacturing, and Control

Alectinib is a low solubility drug. Alecensa (Genentech) 150-mg oral capsules do not exhibit
rapid dissolution across the physiologic pH range. The capsule formulation containing sodium
lauryl sulfate (SLS; as solubilizing agent) was administered in the two efficacy clinical trials
[studies NP28761 (NCT01871805) and NP28673 (NCT01801111)]. SLS is a surfactant and a
known GI mucosal irritant that may be associated with GI adverse effects, including nausea,
vomiting, diarrhea, and abdominal pain. The recommended dose of alectinib (600 mg twice
daily) results in oral ingestion of an amount of SLS daily that is higher than the amount of
SLS previously approved by the FDA in other oral products. Therefore, the concentration of
SLS posed a regulatory challenge. To support the necessity of this concentration of SLS,
Roche/Genentech conducted additional studies demonstrating that the bioavailability of
alectinib was decreased below a minimal concentration of SLS. Roche/Genentech will
continue to closely monitor the incidence of GI disorders in clinical studies and postmarketing
settings.

Nonclinical Pharmacology and Toxicology

Pharmacology studies demonstrated that alectinib is a reversible kinase inhibitor that targets
ALK and RET. In an in vitro screening assay, alectinib did not result in inhibition of other
kinases, including ROS1, at clinically significant concentrations. Alectinib suppressed
activation of ALK and was able to inhibit mutated versions of ALK that have been identified
in patients whose disease has progressed following treatment with crizotinib. In addition, the
major metabolite of alectinib, M4, identified at high levels in both humans and animals,
showed comparable inhibitory activity against ALK and RET.
Alectinib administration resulted in inhibition of tumor growth in mice implanted
intracranially with the NCI-H2228 tumor cell line carrying an EML4–ALK fusion protein,
suggesting that alectinib can cross the blood–brain barrier and may have activity against brain
metastases. Alectinib had broad tissue distribution, including the brain; levels of radioactivity
in brain tissues were similar to those in the plasma of animals administered radiolabeled
alectinib, further supporting penetration of alectinib across the blood–brain barrier.

The predominant target organs of alectinib toxicity in the rat and monkey were the GI tract,
adrenal gland, liver, and respiratory system. Alectinib was phototoxic, aneugenic in in
vivo micronucleus assays, and embryotoxic at maternally toxic doses. Cardiovascular
assessments in monkeys suggested a potential for bradycardia and hypotension.

Clinical Pharmacology

In patients with ALK-positive NSCLC, alectinib exposure increased in a dose-proportional

manner at doses ranging from 460 mg to 900 mg under fed conditions after a single dose and
after repeated doses. Its exposure accumulated about 6-fold at steady state with twice-daily
dosing. The administration of a single 600-mg dose with an FDA-specified high-fat, high-
calorie meal resulted in a 3.1-fold increase in the combined exposure of alectinib and its
major similarly active metabolite, M4. The approved product labeling recommends that
alectinib be taken with food to improve bioavailability and GI tolerability. The elimination
half-life is 33 hours for alectinib and 31 hours for M4. No clinically meaningful effect on the
combined exposure of alectinib plus M4 was observed in clinical studies following
coadministration of alectinib with a strong CYP3A inhibitor (posaconazole), a strong CYP3A
inducer (rifampin), or an acid-reducing agent (esomeprazole). No dose adjustment is
recommended for patients with mild hepatic impairment or mild-to-moderate renal
impairment. A study (NCT02621047) is ongoing to determine an appropriate dose for patients
with moderate to severe hepatic impairment.

Clinical Trial Design

Two multicenter, single-arm trials (studies NP28761 and NP28673) provided the primary
clinical data for the review of the alectinib NDA. Both were designed to include dose-
escalation and dose-expansion parts; however, the recommended phase II dose for alectinib
was determined in NP28761 prior to dose escalation in NP28673. Inclusion criteria for both
studies included age ≥18 years, metastatic or stage IIIB NSCLC not amenable to curative
therapy, documented ALKrearrangement based on an FDA-approved test, progression of
disease on crizotinib, Eastern Cooperative Oncology Group (ECOG) performance status (PS)
≤2, and adequate organ function. At the time these studies were conducted, FDA-approved
testing for ALK rearrangement involved fluorescence in situ hybridization performed on
formalin-fixed, paraffin-embedded tissue specimens. Information on FDA-approved tests for
the detection of ALK rearrangements in NSCLC is available on the FDA website (17).
The primary endpoint for both studies was ORR as determined by central independent review
committee (IRC) per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1
(v1.1). In addition to duration of response (DOR), secondary endpoints included CNS
objective response rate (CORR) and CNS duration of response (CDOR) in patients with
measurable disease in the CNS at baseline assessed by IRC neurological specialized
radiologists using both RECIST v1.1 and Response Assessment in Neuro-Oncology (RANO)
criteria. Safety evaluations included physical examinations, laboratory evaluations,
electrocardiograms, and assessment of adverse events. During the course of the studies, the
primary analysis population for response endpoints was modified to the Response Evaluable
(RE) population, defined as patients with measurable disease at baseline by IRC assessment
who received at least one dose of alectinib.

Efficacy

There were 87 patients enrolled in the expansion portion of NP28761 and 138 patients in
NP28673 who received alectinib 600 mg twice daily; this “As Treated” population comprises
the primary efficacy population evaluated by the FDA. Demographic and disease
characteristics are presented in Table 1. The RE population proposed by Roche/Genentech as
the primary analysis population excluded 18 patients (21%) in NP28761 and 16 patients
(12%) in NP28673 who did not have measurable disease at baseline per IRC assessment. By
RECIST criteria, patients without measurable disease at baseline whose disease has not
progressed can be qualified as having either complete response or stable disease; an
assessment of partial response is not possible in the setting of no baseline measurable disease.
With this knowledge, the decision was made to include ORR in the “As Treated” population
per both IRC and investigator assessment in product labeling. ORR and DOR results are
presented in Table 2.
Table 1.
Demographic and baseline disease characteristics of patients in the “As Treated” populations
for studies NP28761 and NP28673

Characteristic NP28761 (N = 87) NP28673 (N = 138)

Median age, years (range) 54 (29–79) 52 (22–79)

Age ≥65 years 18% 10%

Race

 Caucasian 84% 67%

 Asian 8% 26%

Gender

 Female 55% 56%

 Male 45% 44%

ECOG PS 0 or 1 90% 91%

Never or former smokers 100% 98%

Adenocarcinoma histology 94% 96%

Prior chemotherapy 74% 80%

Stage IV disease 99% 99%

Brain metastases 60% 60%

Measurablea brain metastases 18% 25%

 Table 2.
Efficacy results in studies NP28761 and NP28673

NP28761 (N = 87) NP28673 (N = 138)

Efficacy IRC Investigator IRC Investigator

parameter assessmenta assessment assessmenta assessment

ORR (95% CI) 38% (28–49) 46% (35–57) 44% (36–53) 48% (39–57)

Number of
responders 33 40 61 66

Median DOR,
months (95% 11.2 (9.6–
CI) 7.5 (4.9–NE) NE (4.9–NE) NE) 7.8 (7.4–9.2)

Median duration
of follow-up,
months 4.8 4.8 10.9 7.0
 Abbreviations: CI, confidence interval; NE, not estimable.
 ↵aEighteen patients in NP28761 and 16 patients in NP28673 did not have measurable
disease at baseline as per IRC assessment and were classified as nonresponders in the IRC
analysis.
Results of pooled analyses of CNS-related secondary endpoints in patients with measurable
disease in the CNS at baseline are presented in Table 3. An exploratory analysis of CORR and
CDOR in patients with and without a history of prior CNS radiation was conducted by the
FDA. CNS responses were observed in both patients who had (n = 35) and had not (n = 16)
received prior CNS radiation (CORR 57% and 69%, respectively), and CDOR was similar
across these subgroups.

Table 3.
CNS efficacy endpoints' pooled analyses (NP28761 and NP28673)

Patients with measurable CNS disease at baseline

(n = 51)

Efficacy parameter RECIST v1.1 criteria RANO criteria

CORR (95% CI) 61% (46–74) 51% (35–67)

 Patients with measurable CNS disease at baseline
(n = 51)

Efficacy parameter RECIST v1.1 criteria RANO criteria

Median CDOR, months

(95% CI) 9.1 (5.8–NE) 9.1 (7.4–NE)
 Abbreviations: CI, confidence interval; NE, not estimable.

Safety

The primary safety analysis population included 253 patients from NP28761 and NP28673
exposed to alectinib at a dose of 600 mg twice daily. The median age was 53 years, 14% of
patients were ≥65 years old, 74% were Caucasian, and 18% were Asian. Baseline
characteristics were otherwise similar to those of the efficacy populations. Median duration of
exposure was 9.3 months. Common adverse reactions and laboratory abnormalities are
presented in Table 4. Grades 3 to 4 adverse reactions and laboratory abnormalities occurring
in ≥2% of patients are presented in Table 5. Other adverse reactions of interest based on
reported adverse reaction profiles for agents of the same class include vision disorder (10%),
bradycardia (7.5%), interstitial lung disease/pneumonitis (0.4%), and prolonged QT interval
(0.4%).

Table 4.
Common adverse reactions (incidence ≥20%) and laboratory abnormalities (incidence ≥30%)
in NP28761 and NP28673

Alectinib 600 mg b.i.d. (n = 253)

Adverse reaction All grades

 Fatigue 41%

 Constipation 34%

 Edema 30%

 Myalgia 29%

Laboratory abnormality

 Anemia 56%

 Increased aspartate aminotransferase 51%

 Increased alkaline phosphatase 47%

 Increased creatine phosphokinasea 43%

 Alectinib 600 mg b.i.d. (n = 253)

 Hyperbilirubinemia 39%

 Hyperglycemiab 36%

 Increased alanine aminotransferase 34%

 Hypocalcemia 32%
 Abbreviation: b.i.d., twice daily.
 ↵an = 218 for creatine phosphokinase (with baseline values missing for 91 of these
patients).
 ↵bn = 152 for fasting blood glucose (with baseline values missing for 5 of these
patients).

Table 5.
Most common grades 3–4 adverse reactions and laboratory abnormalities (incidence ≥2%) in
NP28761 and NP28673

Alectinib 600 mg b.i.d. (n = 253)

Adverse reaction Grades 3–4

 Dyspneaa 3.6%

Laboratory abnormality

 Increased alanine aminotransferase 4.8%

 Increased creatine phosphokinaseb 4.6%

 Lymphopeniac 4.6%

 Hypokalemia 4.0%

 Increased aspartate aminotransferase 3.6%

 Hypophosphatemia 2.8%

 Hyperbilirubinemia 2.4%

 Hyperglycemiad 2.0%

 Hyponatremia 2.0%

 Anemia 2.0%
 Abbreviation: b.i.d., twice daily.
 ↵aIncludes one grade 5 event.
 ↵bn = 218 for creatine phosphokinase (with baseline values missing for 91 of these
patients).
 ↵cn = 217 for lymphocytes (with baseline values missing for 5 of these patients).
 ↵dn = 152 for fasting blood glucose (with baseline values missing for 5 of these
patients).

Serious adverse reactions occurred in 19% of patients; the most frequently reported were
pulmonary embolism, dyspnea, and hyperbilirubinemia, each occurring in 3 patients (1.2%).
The incidence of fatal adverse reactions was 2.8%; death was attributed to hemorrhage in 2
patients and to intestinal perforation, dyspnea, pulmonary embolism, and endocarditis in 1
patient each. Dose reductions due to adverse reactions occurred in 12% of patients, whereas
27% of patients had alectinib dosing interrupted due to adverse reactions. Grades 3 to 4 AST
and/or ALT elevations led to discontinuation of alectinib in 4 patients (1.6%), and grade 3
bilirubin elevations led to discontinuation in 3 patients (1.2%). While no Hy's law cases were
identified among patients with elevated liver function tests, 2 patients (0.8%) with grades 3 to
4 AST/ALT elevations had documented drug-induced liver injury based on liver biopsy. The
U.S. Prescribing Information (USPI) for alectinib recommends monitoring liver laboratory
tests every 2 weeks during the first 2 months of treatment, and then periodically during
treatment.

Grade 3 myalgia, defined as a composite term incorporating the preferred terms myalgia and
musculoskeletal pain, occurred in 3 patients (1.2%). Of these, only one had creatine
phosphokinase (CPK) measured close to the time of the event; this patient had grade 3 CPK
elevation. Based on laboratory shift data, CPK elevations occurred in 43% of 218 patients
with CPK laboratory data available. Ten patients (4.6%) experienced grade 3 CPK elevation;
among these patients, concomitant myalgia was reported in 3 (one grade 3, two grade 1),
whereas the remaining patients were asymptomatic. There were no cases of grade 4 myalgia
or CPK elevation, and there were no cases meeting the criteria for rhabdomyolysis as defined
by the National Cholesterol Education Program Advisory Panel (CPK >10 times the upper
limit of normal, with renal compromise). These events were adequately managed with
interruption and/or dose reduction of alectinib, and no patient discontinued alectinib due to
myalgia or CPK elevation. The USPI for alectinib recommends measurement of CPK every 2
weeks during the first month of treatment and in patients reporting unexplained muscle pain,
tenderness, or weakness.

Discussion

Alectinib received accelerated approval based on determination of a favorable benefit–risk

profile considering the surrogate endpoint of ORR along with duration of response and the
safety profile of alectinib as determined in two single-arm trials. Limitations of single-arm
trials include the potential for known and unknown patient selection bias and the lack of
controlled safety data. Continued approval for this indication requires verification of clinical
benefit in a confirmatory trial. The confirmatory trial (the ALEX study, NCT02075840),
assessing alectinib versus crizotinib in treatment-naïve patients with ALK-positive, advanced
NSCLC, is currently ongoing. The results of a randomized trial conducted in Japan, J-ALEX,
that assessed alectinib 300 mg twice daily versus crizotinib in 207 ALK inhibitor–naïve
patients with ALK-positive NSCLC were recently reported to show a progression-free
survival advantage for alectinib over crizotinib. The ALEX study will determine whether
similar findings are observed in a global population treated with alectinib 600 mg twice daily.
For NSCLC, ORR may be considered a surrogate endpoint reasonably likely to predict
clinical benefit when the treatment effect size is large and the responses are durable. The
observed ORRs of 38% and 44% by IRC-based assessment in NP28761 and NP28673,
respectively, are clinically meaningful when considering the intended patient population:
patients with ALK-positive NSCLC who have progressed following therapy with crizotinib.
The DOR data bolster the assessment of a clinically meaningful benefit. Demonstration of
significant clinical benefit compared with ceritinib was not required for alectinib, as ceritinib
was approved under accelerated approval.
In addition to ORR and durability, the effects on CNS metastases were strongly supportive.
The incidence of brain metastases in NSCLC patients has been reported as 16% to 36% in
various population-based and cohort studies. In a randomized trial of crizotinib for the first-
line treatment of ALK-positive NSCLC, 27% of patients had brain metastases at the time of
enrollment. In addition, a retrospective analysis of two studies assessing crizotinib for the
treatment of patients with advanced, ALK-positive NSCLC reported that among patients
without brain metastases at the time of enrollment who developed progressive disease, 20%
were diagnosed with brain metastases. In NP28761 and NP28673, 60% of patients had CNS
metastases at baseline; this high proportion is not surprising in a population of patients with
metastatic, ALK-positive NSCLC previously treated with crizotinib. It is also possible that
patients with brain metastases were preferentially referred to these studies based on
preclinical and early clinical evidence of possible antitumor activity in the CNS with
alectinib. Assessment of the treatment effect of alectinib in the CNS was prospectively
undertaken in NP28761 and NP28673. The assessment of CNS disease by an IRC composed
of neuroradiologists increased confidence in the validity of these assessments, as did the
consistency of the observed treatment effect using RECIST v1.1 and RANO criteria.
Despite a high concentration of SLS, a known GI mucosal irritant, in the studied formulation
of alectinib, the GI adverse event profile did not negatively affect the tolerance of alectinib.
Based on the review of the safety data for alectinib, dose-modification recommendations for
grades 3 and 4 CPK elevations were included in product labeling, as were recommendations
for assessment of CPK during treatment with alectinib. The high incidence of CPK elevation
observed with alectinib was not expected based on preclinical toxicology data and the
reported safety profiles of the approved ALK inhibitors, crizotinib and ceritinib. It should be
noted that CPK is not routinely included in the serum chemistry tests done during clinical
trials of oncology drugs. CPK was included as part of routine laboratory testing in NP28761
from the beginning, but was not added in NP28673 until partway through the study. The
ongoing ALEX study includes CPK as part of the serum chemistry panel obtained throughout
treatment on study. This will help to more accurately define the incidence of CPK elevation
for both alectinib and crizotinib, and allow for a direct comparison.

Whether treatment of patients with ALK-positive NSCLC with alectinib in the first-line
setting can delay occurrence or progression of disease in the CNS compared with first-line
treatment with crizotinib is not currently known. Time to CNS progression is a secondary
endpoint in the ALEX study, which may provide an answer to this question. Studies are still
needed to address optimal sequencing of ALK inhibitors in the treatment of patients with
metastatic, ALK-positive NSCLC.
(4)
Introduction
Fusion kinases resulting from chromosomal rearrangements have emerged as important
oncogenic drivers in NSCLC. Anaplastic lymphoma kinase gene (ALK)
and ROS1 rearrangements are identified in 3% to 5% and 1% to 2% of patients with NSCLC,
respectively, and confer sensitivity to treatment with targeted tyrosine kinase inhibitors
(TKIs), such as crizotinib. These findings have spurred ongoing efforts to uncover novel
recurrent fusions in lung cancer.

Rearranged during transfection gene (RET) rearrangements were first identified in NSCLC in
2011 and have since been found in 1% to 2% of patients with NSCLC. As
with ALK- and ROS1-rearranged NSCLC, RET-rearranged NSCLC has been associated with
characteristic features such as younger age, history of never smoking, and adenocarcinoma
histologic type. RET fusions are transforming in vitro and in vivo, and inhibition of RET
in RET-rearranged lung cancer cells leads to suppressed viability. Importantly, responses to
multitargeted TKIs with anti-RET activity, such as cabozantinib and vandetanib, have been
described in patients with RET-rearranged lung cancer, suggesting that RET rearrangements
define a new targetable subset of NSCLC.

Despite the preliminary antitumor activity reported with the aforementioned multitargeted
TKIs, the toxicities observed with these agents and the likelihood of acquired resistance
emerging on the basis of experiences with other oncogene-driven lung cancers collectively
underscore the need to develop more potent and selective RET inhibitors. Alectinib is an
orally active TKI originally developed to target anaplastic lymphoma kinase (ALK). In phase
I and II studies, alectinib demonstrated high response rates in patients with advanced ALK-
rearranged NSCLC, including those with central nervous system (CNS) disease, leading to
accelerated approval by the U.S. Food and Drug Administration (FDA). Recent work has
shown that alectinib also inhibits RET with a half maximal inhibitory concentration of 4.8
nM. Furthermore, alectinib demonstrates significant in vitro and in vivo antitumor activity
in RET-rearranged models. These findings, together with alectinib’s favorable toxicity profile,
provide a strong rationale for investigating the efficacy of alectinib in patients with RET-
rearranged NSCLC. Here, we present a clinical series of four patients with RET-rearranged
metastatic NSCLC treated with alectinib.
Methods

Identification of RET Rearrangements

RET rearrangement testing was performed by fluorescence in situ hybridization (FISH) or
targeted next-generation sequencing (NGS) using anchored multiplex polymerase chain
reaction. RET FISH was performed on formalin-fixed paraffin-embedded tissue using break-
apart probes (Kreatech RET (10q11) Dual Color, Break Apart Rearrangement Probe [Leica
Biosystems, Nussloch, Germany]). Samples with more than 15% of cells showing split signals
were defined as RET rearranged. The rearrangement NGS panel targets validated oncogenes,
including ALK exons 19 to 22, ROS1 exons 31 to 37, and RET exons 8 to 13.

Treatment with Alectinib

All patients were treated at Massachusetts General Hospital. Patients 1 and 2 were treated
with alectinib as part of single-patient compassionate use protocols. Patients 3 and 4 received
commercial alectinib off label.

Results

Case 1
Case 1 involves a 50-year-old male former light smoker with stage IIIB lung adenocarcinoma
who was treated with definitive chemoradiation (Table 1). He experienced a relapse with lung
and brain metastases 11 months later and underwent a craniotomy with tumor resection
followed by stereotactic radiosurgery. The results of EGFR, ALK, and ROS1 testing were
negative; RET FISH identified a RET fusion. He therefore began receiving an experimental
RET inhibitor. After an initial improvement in systemic disease, he was found to have
worsening symptomatic brain metastases. He underwent whole brain radiotherapy followed
by resumption of the drug, but continued CNS progression prompted a change in therapy. He
began receiving alectinib, 600 mg twice daily, 2 months after completing whole brain
radiotherapy. The dose was increased to 900 mg twice daily to augment CNS penetration on
the basis of pharmacokinetic and safety data from a phase I dose-finding study of alectinib.
Patient 1 had no reported toxicities while receiving alectinib. Repeat imaging 6 weeks later
showed improvement in both intracranial and extracranial disease, including decreased
bilateral septal thickening, nodularity, and pleural effusion. According to the Response
Evaluation Criteria in Solid Tumors (RECIST), version (v) 1.1, patient 1 achieved a
confirmed partial response (PR) (–38.9%). After 3.5 months, an enlarging right frontal brain
lesion developed and required resection 3 months later followed by fractionated radiation to
the surgical resection cavity. Ultimately, alectinib was discontinued after a total of 8 months
of therapy for both intracranial and extracranial disease progression. He has since been treated
with stereotactic radiosurgery for a progressive CNS metastasis, followed by platinum-based
doublet chemotherapy (duration of therapy 1 month) and subsequently paclitaxel and
bevacizumab (duration of therapy more than 5 months).

Table 1Baseline Characteristics of RET-Positive Patients Treated with Alectinib

Smoking Prior RET

Patient Age Sex History RET Fusion Inhibitors Alectinib Dose

1 50 M <10 pack- FISH positive; PCR Experimental 600 mg twice

years not performed TKIa daily increased
to 900 mg twice
daily

2 62 F Never- KIF5B (exon 15)- Cabozantinib, 600 mg twice

smoker RET (exon 12) experimental daily
TKIa

3 48 M <10 pack- CCDC6 (exon1)- Cabozantinib 600 mg twice

years RET (exon 12) daily

4 58 F Never- KIF5B (exon 15)- None 600 mg twice

smoker RET (exon 12) daily

RET, rearranged during transfection gene; M, male; F, female; RET, rearranged during
transfection; PCR, polymerase chain reaction; TKI, tyrosine kinase inhibitor; KIF5B, kinesin
family member 5B gene; CCDC6, coiled coil domain containing 6 gene.

Patients 1 and 2 were treated with experimental TKIs with anti-RET activity as part of
ongoing clinical trials.

Responses to alectinib. (A) Axial, T1 post–gadolinium magnetic resonance images before

alectinib (A1) and after 6 weeks of therapy (A2) in patient 1 with rearranged during
transfection gene (RET)-rearranged NSCLC, demonstrating a decrease in size of the
intracranial metastases. (B) Axial chest computed tomography (CT) images at baseline (B1)
and after 8 weeks of therapy (B2) in patient 2 with kinesin family member 5B gene (KIF5B)-
RET, showing a decrease in the number and size of liver lesions. Her hepatic disease had
progressed while she was receiving cabozantinib followed by an experimental rearranged
during transfection (RET) inhibitor in the context of dose reductions on account of toxicities.
(C) Axial chest CT images at baseline (C1) and after 6 weeks of therapy (C2) in patient 3 with
coiled coil domain containing 6 gene (CCDC6)-RET, which reveals a decrease in size of the
dominant right upper lobe lung mass and an adjacent small peripheral right upper lobe nodule.
Postradiation changes are seen. (D) Axial chest CT images at baseline (D1) and after 6 weeks
of therapy (D2) in patient 4 with KIF5B-RET, demonstrating disease progression with an
increase in bilateral nodularity, septal thickening, and mediastinal mass/lymphadenopathy.
The post alectinib scans (D2) were performed without contrast because of the patient’s renal
dysfunction.

Case 2
Case 2 involves a 62-year-old female never-smoker with a history of surgically resected lung
adenocarcinoma (see Table 1) in whom liver and lung metastases developed and progressed
despite four lines of chemotherapy. Her original lung resection specimen revealed
a RET rearrangement by FISH. A liver biopsy specimen also tested positive for a kinesin
family member 5B gene (KIF5B)-RET fusion by NGS. Cabozantinib therapy was initiated
with stable disease on the first restaging scans, but it was discontinued within a month on
account of grade 3 hyperbilirubinemia. She then received stereotactic body radiation therapy
to the liver lesions. Given no other evidence of disease, she was monitored closely until
she began receiving an experimental RET inhibitor in December 2014. This was complicated
by toxicities requiring two dose reductions, and the drug was ultimately discontinued for
disease progression. Given fairly indolent growth, the patient then remained off therapy for 3
months. Subsequent imaging revealed new, enlarging lung and liver lesions. With limited
alternative options, she began receiving alectinib, 600 mg twice daily. A repeat computed
tomography scan 8 weeks later revealed moderate regression (–27.8%) in the number and size
of liver lesions, although this was classified as stable disease by RECIST v1.1. Unfortunately,
she experienced grade 3 toxicities of hyperbilirubinemia and an increase in creatinine kinase
level (Common Terminology Criteria for Adverse Events, v. 4.03), requiring discontinuation
of alectinib after 10 weeks. She went on to receive platinum-doublet chemotherapy (duration
of therapy 2.5 months), followed by nivolumab (initiated in February 2016 and ongoing).

Case 3
Case 3 involves a 48-year-old male former light smoker in whom metastatic NSCLC was
diagnosed in 2013 (see Table 1). Targeted NGS of a supraclavicular lymph node specimen
revealed a coiled coil domain containing 6 gene (CCDC6)-RET fusion confirmed by FISH.
He was treated with carboplatin and pemetrexed followed by cabozantinib, achieving stable
disease. Treatment with cabozantinib (60 mg daily) was complicated by grade 2 hand-foot
syndrome, requiring a dose reduction (40 mg daily) and eventual discontinuation of the drug.
Thereafter, he received pemetrexed (18 months of therapy) followed by nivolumab. After
receiving nivolumab for 2 months, patient 3 experienced hemoptysis and exhibited
radiographic evidence of disease progression. He received a course of palliative chest
radiation. In March 2016, he began receiving alectinib, 600 mg twice daily. Within 3 days, he
reported dramatic improvement in energy and respiratory symptoms. Adverse events were
notable for only grade 1 fatigue and grade 1 rash. Restaging scans 6 weeks later demonstrated
postradiation changes and decreases in the dominant right upper lobe mass and right pleural
effusion, which improved further on repeat imaging after he had been receiving alectinib for
14 weeks. By RECIST v. 1.1, patient 3 achieved an unconfirmed PR (–35.5%). The patient
continues to receive alectinib.

Case 4
Case 4 involves a 58-year-old female never-smoker in whom stage IV lung adenocarcinoma
was diagnosed in April 2014 (see Table 1). She was treated with carboplatin and pemetrexed
followed by pemetrexed maintenance therapy for 18 months. In the interim, targeted NGS of
a malignant gastrohepatic lymph node revealed a KIF5B-RET fusion. In March 2016, her
disease progressed with a worsening right hilar mass, lymphangitic carcinomatosis, and
retroperitoneal lymphadenopathy. She thus began receiving alectinib, 600 mg twice daily.
Clinically, she experienced worsening dyspnea and cough. Repeat computed tomography
scans 6 weeks later showed progressive disease (+30.8% by RECIST v. 1.1), prompting
discontinuation of the drug. She went on to receive nivolumab before transitioning to hospice
care in the setting of rapid clinical deterioration.

Discussion

Genetic alterations in RET have been identified in a number of malignancies and include gain-
of-function point mutations (medullary thyroid cancer) and chromosomal rearrangements
(papillary thyroid carcinomas, chronic myelomonocytic leukemia, and NSCLC). In
NSCLC, RET rearrangements define a distinct molecular subgroup of the disease, and efforts
are now ongoing to target RET therapeutically.

A number of different multitargeted agents have shown activity against RET-rearranged cell
lines and xenografts. Reports have subsequently emerged describing clinical responses among
patients with RET-rearranged NSCLC treated with cabozantinib, vandetanib, sorafenib, and
sunitinib. In addition, more recently, preliminary findings from several prospective clinical
trials focused on RET-rearranged NSCLC have been presented. For example, in a phase II
study of 20 patients with RET-rearranged lung cancer treated with cabozantinib (of whom 18
were evaluable for response), the objective response rate (ORR) was 38%, with stable disease
in 56% of patients. In two independent phase II studies, vandetanib led to an ORR of 53% and
a disease control rate of 88% in 17 evaluable patients, and an ORR of 17% and a disease
control rate of 61% in 18 patients, respectively. A number of other early-phase studies of RET
inhibitors are also under way (Table 2).
Table 2
Currently Available RET Inhibitors in Clinical Trials for Patients with RET-Rearranged
NSCLC

Anti
-
RET

(IC50 Other
Manufactur , Major
Agent er nM) Targets Selected Clinical Study

Cabozantini Exelixis 5–10 VEGFR, Phase II in patients with advanced NSCLC

b MET, harboring RET/NTRK/ROS1fusion
AXL, or MET/AXL alteration (NCT01639508)
FLT3,
KIT,
TIE2

Vandetanib AstraZeneca 100 VEGFR, Phase II in patients with RET-positive

EGFR advanced NSCLC who failed platinum-based
chemotherapy (NCT01823068)

Lenvatinib Eisai 1.5 VEGFR Phase II in patients with RET-positive

1-3, advanced NSCLC (NCT01877083)
FGFR1-
4,
PDGFR,
KIT

Sunitinib Pfizer 220– VEGFR Phase II in never-smokers with lung

1300 1-2, adenocarcinoma, or RET-positive lung
PDGFR adenocarcinoma (NCT01829217)
β, FLT3,
KIT

Ponatinib Ariad 25.8 BCR- Phase II in patients with RET-positive

ABL, advanced NSCLC (NCT01813734)
SRC,
VEGFR,
PDGFR,
FGFR,
FLT3,
KIT

Sitravatinib Mirati 44 VEGFR, Phase I/IB in patients with NSCLC with

Therapeutics PDGFR alterations
α, MET, in MET, AXL, RET, NTRK, DDR2, KDR, PD
AXL, GFRα, or KIT(NCT02219711)
 TRK,
DDR1-2,
FLT3,
KIT,
EPHA2-
4,
EPHB2/
4, MER,
MST1R

Apatinib Jiangsu 13 VEGFR Phase II in patients with RET-positive

Hengrui/LS 2, KIT, advanced NSCLC who failed prior treatment
K SRC (NCT02540824)
BioPharma

Alectinib Roche 4.8 ALK, Phase I/II in patients with advanced, RET-
LTK, rearranged NSCLC (UMIN000020628)
CHEK2,
FLT3,
PHKG2

RET, rearranged during transfection; RET, rearranged during transfection gene; IC50, half
maximal inhibitory concentration; VEGFR, vascular endothelial growth factor receptor; MET,
MET proto-oncogene, receptor tyrosine kinase; AXL, AXL receptor tyrosine kinase; FLT3,
FMS-like tyrosine kinase 3; KIT, KIT proto-oncogene receptor tyrosine kinase; TIE2, tyrosine
kinase with immunoglobulin-like and EGFR-like domains 2; NTRK, neurotrophic tyrosine
kinase gene; MET, MET proto-oncogene receptor tyrosine kinase gene; AXL, AXL receptor
tyrosine kinase gene; FGFR, fibroblast growth factor receptor; PDGFR, platelet-derived
growth factor receptor; BCR-ABL, breakpoint cluster region-Abelson murine leukemia viral
oncogene homolog 1; SRC, SRC proto-oncogene, non-receptor tyrosine kinase; NTRK,
neutrophic tyrosine kinase; DDR, discoidin domain receptor; EPHA, ephrin receptor A;
EPHB, ephrin receptor B; MST1R, macrophage-stimulating protein receptor 1; TRK,
tropomyosin receptor; DDR2, discoidin domain receptor 2 gene; KDR, kinase insert domain
receptor gene; PDGRFα, platelet-derived growth factor receptor alpha gene; KIT, KIT proto-
oncogene receptor tyrosine kinase gene; ALK, anaplastic lymphoma kinase; LTK, leukocyte
receptor tyrosine kinase; CHEK2, checkpoint kinase 2; PHKG2, phosphorylase kinase,
gamma 2.

Alectinib is a U.S. Food and Drug Administration–approved ALK inhibitor that has
demonstrated significant efficacy in patients with ALK-rearranged NSCLC. Recent work has
revealed alectinib to have in vitro activity against RET, but its clinical activity in patients
with RET-rearranged NSCLC has not yet been determined. Here, we have described a series
of four patients with RET-rearranged NSCLC who were treated with alectinib. Importantly,
three of the four patients were previously treated with other RET inhibitors, including
cabozantinib. In total, objective radiographic responses were observed in two of four cases,
with one additional patient achieving a best response of stable disease. Alectinib notably
demonstrated evidence of CNS activity in one patient whose disease progressed during
administration of an experimental RET inhibitor, which is consistent with prior reports of
effective CNS penetration by alectinib. Moreover, as alectinib has little anti–kinase insert
domain receptor effect and rarely causes hypertension and proteinuria (in contrast to the other
available RET inhibitors), it may serve as a valuable alternative option.

Although these data are encouraging, this report has several notable limitations. First, we have
described a single-institution experience with treating a small number of patients with RET-
rearranged NSCLC with alectinib, and follow-up was limited. Larger prospective studies with
longer follow-up are warranted to better evaluate the efficacy of alectinib in this setting.
Indeed, a phase I/II study investigating the activity of alectinib in patients with
advanced RET-rearranged NSCLC (UMIN000020628) is currently enrolling in Japan.
Second, patients in this study received different doses of alectinib (ranging from 600 mg to
900 mg twice daily), and the optimal dose to treat RET-rearranged lung cancers remains to be
established. One of the two patients who achieved a PR and also had improvement in CNS
disease was treated with alectinib 900 mg twice daily—suggesting that perhaps a higher dose
may be more appropriate to inhibit this particular driver fusion gene. Moreover, the patients
presented herein had generally received prior RET TKIs, and therefore, further studies are
needed to assess the potential activity of alectinib in RET TKI-naive patients. In addition,
moving forward it will be critically important to identify molecular mechanisms of resistance
to RET inhibitors by using repeat biopsies and/or cell-free DNA assays. Of note, among the
three patients previously treated with RET inhibitors in this series, post-RET TKI/pre-
alectinib biopsies were not performed, except in patient 2, but this specimen was insufficient
for molecular testing. In general, mechanisms of resistance to RET inhibitors at the time of
progression during administration of these agents, including alectinib, remain
uncharacterized. Alectinib appears to have activity against RET gatekeeper mutations in vitro,
but whether this will be validated clinically is unknown. Ultimately, more potent and selective
RET inhibitors that have activity against both wild-type and mutant RET will need to be
developed, and understanding of resistance mechanisms will be helpful to guide these efforts.

In summary, our series provides the first clinical data demonstrating initial antitumor activity
of alectinib in patients with advanced RET-rearranged NSCLC, including in patients with
CNS disease. Larger prospective studies are needed to evaluate the efficacy of alectinib in
patients with NSCLC and other malignancies driven by recurrent RET fusions. In parallel,
development of more potent and selective RET inhibitors is warranted.