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ALK Inhibitors in Non–Small Cell Lung Cancer: Crizotinib and Beyond

2/3/2015

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Dr. Mark M. Awad, MD, PhD and Dr. Alice T. Shaw, MD, PhD
Abstract

The treatment of patients with advanced non–small cell lung cancer (NSCLC) harboring chromosomal rearrangements of anaplastic lymphoma kinase (ALK) has been revolutionized by the development of crizotinib, a small molecule inhibitor of the tyrosine kinases ALK, ROS1, and MET. Resistance to crizotinib invariably develops, however, through a variety of mechanisms. In the last few years, a flurry of new and more potent ALK inhibitors has emerged for the treatment of ALK-positive NSCLC, including ceritinib (LDK378), alectinib (RO5424802/CH5424802), AP26113, ASP3026, TSR-011, PF-06463922, RXDX-101, X-396, and CEP-37440. Cancers harboring ALK rearrangements may also be susceptible to treatment with heat shock protein 90 inhibitors. This review focuses on the pharmacologic and clinical properties of these compounds, either as monotherapies or in combination with other drugs. With so many ALK inhibitors in development, the challenges of how these agents should be studied and ultimately prescribed are also discussed.

IntroductionNon–small cell lung cancer (NSCLC) is the leading cause of cancer-related deaths, both worldwide and in the United States. Most patients who have NSCLC present with advanced or incurable disease, and cytotoxic chemotherapy generally results in low response rates and only modest improvements in overall survival (OS). Groundbreaking research on the molecular drivers of NSCLC has led to major treatment advances over the past decade, starting with the discovery in 2004 that activating mutations in the epidermal growth factor receptor (EGFR) gene are the basis of dramatic responses to the EGFR tyrosine kinase inhibitors (TKIs) gefitinib (Iressa, AstraZeneca) and erlotinib (Tarceva, Genentech/Astellas).1–3

Just 3 years later, investigators in Japan identified anaplastic lymphoma kinase (ALK) as another potential target in NSCLC. In a small subset of NSCLC tumors, a chromosomal inversion event leads to fusion of a portion of the ALK gene with the echinoderm microtubule–associated protein-like 4 (EML4) gene. The resulting EML4-ALK fusion protein is constitutively activated and transforming, leading to a state of oncogene addiction. 4 EML4-ALK fusion and other ALK rearrangements occur in 3% to 7% of patients with NSCLC (herein referred to as “ALK-positive” lung cancer) and are associated with younger age, never smoking or light smoking history, and adenocarcinoma histology.4,5 Patients who have advanced ALK-positive NSCLC are highly responsive to the ALK inhibitor crizotinib (Xalkori, Pfizer), with an objective response rate (ORR) of approximately 60% and a median progression-free survival (PFS) of 8 to 10 months.6,7

Enthusiasm for crizotinib has been tempered, however, by the emergence of drug resistance. Most patients with ALK-positive lung cancer who respond to crizotinib undergo a relapse within a few years after starting therapy.8,9 In particular, the central nervous system (CNS) is one of the most common sites of relapse in patients with ALK-positive NSCLC, and CNS disease can prove refractory to standard therapies.10 In light of these limitations with crizotinib, many novel ALK inhibitors that have greater potency and different kinase selectivity compared with crizotinib are currently in development (Table 1). Additionally, heat shock protein 90 (Hsp90) inhibitors have emerged as potentially active agents in the treatment of ALK-positive lung cancers, and these are being tested alone and in combination with ALK TKIs. This review provides an update on each of the TKIs and Hsp90 inhibitors in clinical development for ALK-positive NSCLC (Table 2), focusing on drug potency, selectivity, and side effects (Table 3).


AlectinibAlectinib (RO5424802/CH5424802), which is being developed by Roche, was designed to be a more selective and potent ALK inhibitor than crizotinib; in addition to activity against ALK, it has activity against the kinases LTK and GAK, but it is not active against INSR, IGF-1R, MET, or ROS1.53–55 Preclinical studies have demonstrated that alectinib is active against the crizotinib-resistant ALK mutations L1196M, C1156Y, and F1174L,54 suggesting that alectinib may be effective in patients who have become resistant to crizotinib through these mechanisms. The activating mutations F1174L and R1275Q, which are found in neuroblastoma, are susceptible to inhibition by alectinib,54 indicating a potential clinical use for this compound in neuroblastoma.

The activity of alectinib was first studied in a multicenter Japanese phase 1/2 trial of patients with ALK-positive NSCLC who had not previously received crizotinib or other ALK inhibitors. Patients were identified as having ALK-positive NSCLC based on positive immunohistochemical staining for ALK expression, followed by ALK FISH for confirmation. Among 46 patients who were treated with the recommended phase 2 dose of 300 mg twice daily, the ORR was 93.5%. Median PFS has not yet been reached. The most common side effects of alectinib at this dose included predominantly grade 1 or 2 dysgeusia, elevated AST, increased bilirubin, decreased neutrophil count, increased creatinine, increased creatine phosphokinase (CPK), myalgias, gastrointestinal symptoms, and rash. The only grade 3 adverse event that occurred at this dose was decreased neutrophil count, and no grade 4 toxicities were observed.55,56

Like ceritinib, alectinib appears to be active in the majority of patients with crizotinib-resistant ALK-positive NSCLC. A phase 1 study of alectinib has been conducted in the United States, with doses ranging from 300 to 900 mg twice daily. This study enrolled 47 patients who had ALK-positive NSCLC previously treated with crizotinib (but not with other ALK inhibitors). Among 44 evaluable patients, the unconfirmed response rate to alectinib was 54.5%. Preliminary results also suggest that alectinib has antitumor activity in the CNS in patients with disease refractory to crizotinib.57 Common adverse events included fatigue (30%), myalgia, peripheral edema, CPK elevation, nausea, increased ALT, photosensitivity, constipation, and rash. Grade 3 or 4 adverse events were uncommon and included headache, neutropenia, fluid retention/peripheral edema, increased γ-glutamyltransferase, and hypophosphatemia.57 An ongoing phase 2 study of alectinib is open for patients who have ALK-positive NSCLC previously treated with crizotinib (NCT01871805).


AP26113AP26113 is in development by Ariad. In preclinical studies, AP26113 was found to be a potent inhibitor of wild-type ALK (IC50=21 nM in a Ba/F3 model of EML4-ALK) and maintains reasonable activity against several crizotinib-resistant ALK mutants (IC50=26–254 nM). This compound also inhibits ROS1 (IC50=16–41 nM in Ba/F3 models), with a potency similar to that for ALK regardless of the ROS1 upstream fusion partner (including CD74, FIG, SDC4, or EZR).58

In an ongoing phase 1/2 study of AP26113, among 16 patients with ALK-positive NSCLC resistant to crizotinib (but who did not receive any other ALK TKIs), 12 patients (75%) responded at doses of AP26113 between 60 and 240 mg daily, with response durations of up to more than 40 weeks. Of 4 TKI-naive patients with ALK-positive NSCLC, 2 patients responded to AP26113, and the other 2 patients had stable disease. Among 3 patients with NSCLC in the trial who had previously received 2 ALK inhibitors (crizotinib and ceritinib), one remains in the study with stable disease, one developed progressive disease, and the third discontinued treatment before follow-up scans. Additionally, 4 of 5 ALK-positive patients who had CNS lesions showed improvements with AP26113 treatment on follow-up magnetic resonance imaging of the brain. AP26113 has also shown clinical activity in a patient with an ALK-positive IMT. The most common adverse events in this trial (all grades) were fatigue (40%), nausea (36%), diarrhea (33%), and headache (18%).59 In this trial, early-onset pulmonary symptoms (dyspnea, hypoxemia, lung infection) were observed in 9% to 12% of patients, typically on day 1 or 2 after initiation of the medication at a dose of 180 mg daily. Because of this, the recommended phase 2 dosing is 90 mg daily for 1 week, and if no respiratory symptoms arise, the dose is increased to 180 mg daily.60


ASP3026ASP3026, which is being developed by Astellas Pharma, inhibits ALK with an IC50 of 3.5 nM in enzymatic assays and an IC50 of 64.8 nM in H2228 cells. This agent also displays activity against the neuroblastoma-activating ALK mutants F1174L (IC50=10 nM) and R1275Q (IC50=5.4 nM) and against the crizotinib-resistant gatekeeper mutation L1196M. Among a panel of 86 tyrosine kinases, ASP3026 showed the highest selectivity for ROS1 (IC50=8.9 nM) and ACK (IC50=5.8 nM). This compound has antitumor activity in both NCI-H2228 subcutaneous xenograft mouse models and EML4-ALK transgenic mice.61 Preliminary results of a phase 1 trial of patients with advanced solid tumors (ALK positivity not required) showed that ASP3026 has a favorable safety profile, with a maximum tolerated dose of 525 mg daily. Gastrointestinal symptoms were the most common side effects, but grade 3 rash and elevations of AST and ALT were also observed. The clinical activity of ASP3026 has not yet been reported.62


TSR-011TSR-011, which is being developed by Tesaro, is a potent inhibitor of ALK, with an IC50 of approximately 1 nM in various preclinical models.63 In a phase 1 trial, 65% of the 17 evaluable patients with advanced malignancies (including NSCLC, papillary thyroid cancer, pancreatic cancer, and colorectal cancer) achieved stable disease or a partial response at 8 weeks. Of 3 evaluable patients with ALK-positive NSCLC who had relapsed on crizotinib, 1 patient had a partial response and 2 had stable disease. Dose-limiting toxicities included QTc prolongation and dysesthesia.64

Of note, TSR-011 is also a potent inhibitor of TRK-A, TRK-B, and TRK-C (encoded by NTRK1, NTRK2,and NTRK3, respectively).64 Rearrangements in NTRK1 were recently described in a small fraction of patients with lung cancer who did not have other, more commonly found genomic alterations.65 BecauseTRK rearrangements have also been found in other tumor types, including colon cancer66 and papillary thyroid cancer,67 TSR-011 may be a useful targeted agent in a variety of cancer types.


PF-06463922PF-06463922, which is in development by Pfizer, is a novel, highly potent, selective inhibitor of both ALK and ROS1, and it has strong activity against all known ALK and ROS1 mutants identified in patients with crizotinib-resistant disease. This compound was designed to be a low-efflux substrate from cell lines overexpressing P-glycoprotein in order to increase its potential CNS penetration. Preclinical in vivo rodent models have demonstrated that levels of PF-06463922 in the brain are about 20% to 30% of the levels achieved in plasma. Furthermore, in mice harboring EML4-ALK–driven brain tumors, treatment with PF-06463922 caused brain tumor regression and increased OS, indicating that it may be an excellent therapeutic agent for patients with crizotinib-resistant disease and/or patients with CNS disease in either the crizotinib-naive or crizotinib-resistant setting.68–70 A phase 1/2 clinical study of PF-06463922 in ALK-positive and ROS1-positive NSCLC is currently under way.


RXDX-101RXDX-101 (formerly called NMS-E628, Nerviano) is an inhibitor of ALK, ROS1, TRK-A, TRK-B, and TRK-C. This compound, which is being developed by Ignyta, induces tumor regression in mouse models of NPM-ALK–driven lymphoma and EML4-ALK–driven NSCLC; it also has activity against the crizotinib-resistant ALK mutants L1196M and C1156Y. RXDX-101 also crosses the blood-brain barrier, inhibits tumor growth, and prolongs survival in mice with intracranially injected NCI-H2228 EML4-ALK cells.71,72In vitro and in vivo activity against ROS1-driven cancers has also been reported.73 Preliminary results of the RXDX-101 phase 1 trial show that the drug is well tolerated, with early evidence of antitumor activity.74


X-376 and X-396Compared with crizotinib, X-376 and X-396 inhibit ALK with approximately 10-fold greater potency in biochemical assays and 3- to 10-fold greater potency in cell-based assays. By contrast, crizotinib is a slightly more potent MET inhibitor than X-376 and X-396 in biochemical assays (IC50=0.51, 0.69, and 0.74 nM for crizotinib, X-376, and X-396, respectively) as well as in cell-based assays with the MKN-45 MET-driven cell line (IC50=51, 150, and 156 nM for crizotinib, X-376, and X-396, respectively). In Ba/F3 models of crizotinib resistance, X-396 was an approximately 10-fold more potent inhibitor than crizotinib of the ALK mutants L1196M and C1156Y.75 Initial results of a phase 1 study of X-396 showed responses in both crizotinib-naive and crizotinib-reistant ALK-positive NSCLC patients.76 Both X-376 and X-396 are being developed by Xcovery.


CEP-28122 and CEP-37440CEP-28122, which is being developed by Teva, is a potent and selective ALK inhibitor (IC50=1.9 nM in enzymatic assays). Against a panel of 259 protein kinases, CEP-28122 also displayed activity against the serine/threonine kinases RSK2, RSK3, and RSK4 (IC50 range, 7–19 nM); the degree of inhibition for all other kinases was at least 10-fold weaker than that for ALK. CEP-28122 displayed antitumor activity in the ALK-driven mouse xenograft models with the NCI-H2228 and NCI-H3122 cell lines. Complete tumor regression within 1 to 2 days after the initiation of CEP-28122 was observed in human primary NPM-ALK–positive anaplastic large cell lymphoma mouse grafts.77 Another Teva compound, CEP-37440, is an inhibitor of ALK as well as focal adhesion kinase (FAK); this drug is in phase 1 development in patients with advanced solid tumors.


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Heat Shock Protein 90 InhibitorsHsp90 is a protein chaperone involved in regulating the stability of proteins involved in normal cellular functions as well as tumorigenesis.78 Fusion proteins formed as the result of chromosomal rearrangement are thought to be particularly dependent on Hsp90 for protein folding, transport, and stability,79 and at least 3 Hsp90 inhibitors have been tested in patients with ALK rearrangements: retaspimycin hydrochloride (IPI-504), ganetespib (STA-9090), and AUY922.

Preclinical studies have shown that crizotinib-resistant ALK-positive cell lines are highly sensitive to the Hsp90 inhibitor 17-allylamino-17-demthoxygeldanamycin (17-AAG).80,81 Retaspimycin hydrochloride (IPI-504), an analogue of 17-AAG, was tested in a phase 1/2 study of patients with NSCLC. Among 76 patients enrolled in the study, the ORR was 7%, but among the 3 patients in the study with ALK rearrangements, 2 had a partial response and a third had prolonged stable disease. Although the estimated median PFS for all patients in this study was 2.9 months, the 3 patients with ALK-positive NSCLC received IPI-504 for approximately 7 months.82 The most common side effects of IPI-504 were grade 1 or 2 fatigue, nausea, and diarrhea; grade 3 or 4 liver function test abnormalities occurred in 12% of patients.83

Preclinical work has demonstrated that NSCLC cell lines harboring oncogenic rearrangements of ALK,ROS1, or RET are all sensitive to the Hsp90 inhibitor ganetespib. Of the 99 patients enrolled in a phase 2 study of ganetespib, only 4 patients (4%) achieved a partial response, but all 4 of these patients were ALK-positive and crizotinib-naive, with response durations ranging from 7.4 to 21 months. The most common side effects of ganetespib were diarrhea (82%), fatigue (58%), nausea (41%), and anorexia (37%). Treatment-related deaths occurred in 2 patients (2%): one from cardiac arrest and the other from renal failure.84

Preliminary data from a phase 2 study of the Hsp90 inhibitor AUY922 in 121 patients with NSCLC showed partial responses in 6 of 21 patients (29%) with ALK rearrangements. Of these 6 responders who had ALK-positive NSCLC, 4 were crizotinib-naive and 2 had previously been treated with crizotinib. The estimated median PFS rate was 42% at 18 weeks in ALK-positive patients. The most frequent adverse events in this study included eye disorders (77%), diarrhea (74%), and nausea (46%).85

Hsp90 inhibitors may be challenging to develop in ALK-positive NSCLC, given the established efficacy and safety of crizotinib, ceritinib, and other ALK TKIs. Compared with TKIs, Hsp90 inhibitors appear to have lower response rates and side effects that are less tolerable. Their activity appears to be limited in the setting of crizotinib resistance, and they do not have CNS activity. One potential clinical use of Hsp90 inhibitors in ALK-positive NSCLC may be for those patients who cannot tolerate TKIs (eg, because of TKI-associated pneumonitis).

Because of the invariable emergence of resistance in patients who have ALK-positive NSCLC treated with crizotinib monotherapy, a number of trials are under way combining an ALK TKI with an Hsp90 inhibitor (see Table 2) in the hope that therapies with nonoverlapping mechanisms of action may be more effective than monotherapies in delaying or overcoming resistance. This approach is supported by preclinical evidence demonstrating synergistic antitumor effects when TKIs are combined with Hsp90 inhibitors in ALK- or MET-driven cancers.83,86 Crizotinib is being combined with ganetespib in patients who have crizotinib-naive ALK-positive disease (NCT01579994), and 2 clinical trials are open for patients who have crizotinib-resistant NSCLC; in one trial (NCT01712217), the Hsp90 inhibitor AT13387 is being administered alone or in combination with crizotinib, and in another trial (NCT01772797), AUY922 is being combined with ceritinib.


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ConclusionsNew drugs are urgently needed in the treatment of NSCLC, a prevalent disease with a high mortality rate. Crizotinib has quickly become a promising treatment option for patients with ALK-positive NSCLC, IMT, and anaplastic large cell lymphoma, as well as for patients with cancers harboring aberrations in ROS1. However, the efficacy of crizotinib in these cancers is limited by poor activity in the CNS and the frequent emergence of drug resistance in a relatively short time. Several new TKIs are in various stages of clinical development for ALK-positive cancers, and many of these agents have activity both in the CNS and in cancers that have become resistant to crizotinib. Despite the increased potency and specificity of next-generation ALK TKIs, resistance to these compounds has also been described.49

These challenges raise a number of questions for the research community. In what sequence should ALK TKIs be prescribed? Should crizotinib still be prescribed as the first targeted therapy, with next-generation ALK inhibitors reserved for subsequent lines of treatment because they are still able to overcome crizotinib resistance in the majority of cases? On the other hand, would the administration of more potent ALK inhibitors in the first-line setting result in deeper responses and longer response durations, or would the earlier use of more potent ALK TKIs lead to the more rapid development of highly resistant disease? Ongoing clinical trials with ceritinib and alectinib in crizotinib-naive patients may help to address these questions once results are available.

Would the earlier use of brain-penetrable ALK TKIs like PF-06463922 delay or possibly prevent the development of CNS metastases, a common cause of morbidity and mortality in this patient population? Also, if patients become resistant to next-generation ALK TKIs, will they exhibit cross-resistance to all other ALK TKIs? Should patients be switched to a different ALK inhibitor before resistance to their prior treatment emerges? Will combinations of ALK TKIs with other agents (eg, cytotoxic chemotherapy, Hsp90 inhibitors, immunotherapy, other TKIs) be both tolerable and effective in patients with ALK-positive cancers? With so many ALK inhibitors in development, it will be difficult to sort out with randomized clinical trials which drugs should be used and at what times in a patient’s treatment course. Mathematical modeling of the growth kinetics of TKI-sensitive and TKI-resistant cancer cells may help us to determine how kinase inhibitors, cytotoxic agents, and other therapies should be dosed and intercalated.87–89

Despite the challenges that lie ahead in the treatment of ALK-positive cancers, OS for patients who have NSCLC with targetable mutations is increasing. Although it will be impossible to show OS benefits in clinical trials because of crossover effect, data presented at the 15th World Conference on Lung Cancer in October 2013 demonstrated that patients whose cancers had an oncogenic driver that could be treated with a genotype-directed therapy (eg, EGFR, ALK) had a median OS of 3.5 years, whereas patients whose cancers had an oncogenic driver that could not be treated with genotype-directed therapy (eg, KRAS) lived for 2.4 years (P<.0001).90 With many next-generation ALK inhibitors and combination strategies on the horizon, survival rates in patients with ALK-positive lung cancers will likely continue to improve. However, with these breakthroughs come increasing expenses that place significant financial burdens on health care systems.91,92 For example, the National Institute for Health and Care Excellence (NICE) denied approval of crizotinib in the United Kingdom because its use was not deemed cost-effective.93 Improving the efficiency of tumor genotyping and decreasing the costs of drug development and delivery will remain top priorities, so that all patients can have access to these life-prolonging cancer treatments.

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Interstitial lung disease induced by alectinib 

2/3/2015

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A 75-year-old woman with anaplastic lymphoma kinase (ALK)-rearranged Stage IV lung adenocarcinoma was administered the selective anaplastic lymphoma kinase inhibitor, alectinib, as a third-line treatment in a Phase 1-2 study. On the 102nd day, chest computed tomography showed diffuse ground glass opacities. Laboratory data revealed high serum levels of KL-6, SP-D and lactate dehydrogenase without any clinical symptoms. There was no evidence of infection. Marked lymphocytosis was seen in bronchoalveolar lavage fluid analysis, and transbronchial lung biopsy showed mild thickening of alveolar septa and lymphocyte infiltration. Interstitial lung disease was judged to be related to alectinib based on improvements in imaging findings and serum biomarkers after discontinuation of alectinib. To our knowledge, this is the first reported case of alectinib-induced interstitial lung disease. Alectinib is a promising drug for ALK-rearranged non-small cell lung cancer. Clinical trials of this selective anaplastic lymphoma kinase inhibitor will facilitate the meticulous elucidation of its long-term safety profile.

© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

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Rapid response of brain metastases to alectinib in a patient with non-small-cell lung cancer resistant to crizotinib.

2/3/2015

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AbstractCrizotinib is a potent and specific small-molecule inhibitor of both anaplastic lymphoma kinase (ALK) and c-MET tyrosine kinases, and patients with ALK rearrangement tumor benefit from crizotinib treatment; however, its penetration into calculated cerebrospinal fluid (CSF) is considered to be poor. Alectinib is a highly selective, next-generation ALK inhibitor, and both preclinical and clinical studies have indicated that alectinib is also effective in crizotinib-resistant tumors. A recent in vitro study demonstrated significant antitumor activity of alectinib for brain metastases using mouse models of ALK-positive non-small-cell lung cancer. In this paper, we report a first case alectinib was highly effective against brain metastases refractory to crizotinib. Further investigation of alectinib in this setting would be particularly valuabl


Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, 54 Shogoin-Kawaharacho, Sakyo-ku, Kyoto, 606-8507, Japan
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Dr. Govindan on the Potential for Alectinib

2/3/2015

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Phase III Study Comparing Alectinib With Crizotinib Currently In Prgogress

2/3/2015

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This randomized, active controlled, multicenter Phase III open-label study is de signed to evaluate the efficacy and safety of alectinib compared with critozinib treatment in patients with treatment-naive ALK-positive advanced NSCLC. Patient s will be randomized in a 1:1 ratio to receive either alectinib, 600 mg orally t wice daily (BID), or critozinib, 250 mg orally BID. Patients will receive treatm ent until disease progression, unacceptable toxicity, consent withdrawal or deat h occurs. The study is expected to last approximately 42 months.



ConditionInterventionPhaseNon-Small Cell Lung Cancer
Drug: alectinib
Drug: crizotinib
Phase 3


Study Type:InterventionalStudy Design:Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: TreatmentOfficial Title:A RANDOMIZED, MULTICENTER, PHASE III, OPEN-LABEL STUDY OF ALECTINIB VERSUS CRIZOTINIB IN TREATMENT-NAÏVE ANAPLASTIC LYMPHOMA KINASE-POSITIVE ADVANCED NON-SMALL CELL LUNG CANCER
Resource links provided by NLM:

MedlinePlus related topics: Cancer Lung Cancer Lymphoma
Drug Information available for: Crizotinib
Genetic and Rare Diseases Information Center resources: Lymphosarcoma
U.S. FDA Resources 

Further study details as provided by Hoffmann-La Roche:

Primary Outcome Measures:
  • Progression-free survival (PFS) as assessed by investigators according to response evaluation criteria in solid tumors (RECIST) v. 1.1 criteria [ Time Frame: Up to 33 months ] [ Designated as safety issue: No ]


Secondary Outcome Measures:
  • Objective response rate (ORR) as determined by the investigators according to RECIST v. 1.1 criteria [ Time Frame: Up to 33 months ] [ Designated as safety issue: No ]
  • Time to central nervous system (CNS) progression as determined by IRC using RECIST v. 1.1 criteria [ Time Frame: Up to 33 months ] [ Designated as safety issue: No ]
  • PFS as assessed by independent review committee (IRC) according to RECIST v. 1.1 criteria [ Time Frame: Up to 33 months ] [ Designated as safety issue: No ]
  • Duration of response defined as time from when response (complete or partial [CR or PR]) was first documented until first documented disease progression or death, whichever occurs first. [ Time Frame: Up to 33 months ] [ Designated as safety issue: No ]
  • Overall survival, defined as the time from randomization until death from any cause [ Time Frame: Up to 42 months ] [ Designated as safety issue: No ]
  • Incidence of adverse events [ Time Frame: 42 months ] [ Designated as safety issue: No ]
  • Area under the concentration-time curve (AUC) of alectinib [ Time Frame: Up to 33 months ] [ Designated as safety issue: No ]
  • Patient reported time to deterioration (TTD) as measured by the European Organization for the Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire C30/LC13 [ Time Frame: 33 months ] [ Designated as safety issue: No ]
  • Patient reported health-related quality of life (HRQoL) as measured by the European Organization for the Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire C30/LC13 [ Time Frame: 33 months ] [ Designated as safety issue: No ]


Estimated Enrollment:286Study Start Date:August 2014Estimated Study Completion Date:December 2017Estimated Primary Completion Date:December 2017 (Final data collection date for primary outcome measure)ArmsAssigned InterventionsExperimental: alectinibDrug: alectinib600 mg given orally BID. Taken with food
Active Comparator: crizotinibDrug: crizotinib250 mg given orally BID. Taken with or without food.



  Eligibility

Ages Eligible for Study:  18 Years and olderGenders Eligible for Study:  BothAccepts Healthy Volunteers:  NoCriteria
Inclusion Criteria:

  • Histologically or cytologically confirmed diagnosis of advanced or recurrent (Stage IIIB not amenable for multimodality treatment) or metastatic (Stage IV) NSCLC that is ALK-positive as assessed by the Ventana IHC test
  • Age >/= 18 years old
  • Life expectancy of at least 12 weeks
  • ECOG PS of 0-2
  • Patients had no prior systemic treatment for advanced or recurrent (Stage IIIB not amenable for multimodality treatment) or metastatic (Stage IV) NSCLC
  • Adequate renal, hematologic and liver function
  • Patients must have recovered from effects of any major surgery or significant traumatic injury at least 28 days before the first dose of study treatment
  • Measurable disease (by RECIST v1.1) prior to the administration of study treatment
  • Prior brain or leptomeningeal metastases allowed if asymptomatic (e.g., diagnosed incidentally at study baseline). Asymptomatic CNS lesions might be treated at the discretion of the investigator per local clinical practice. If patients have neurological symptoms or signs due to CNS metastasis, patients need to complete whole brain radiation or gamma knife irradiation treatment. In all cases, radiation treatment must be completed at least 14 days before enrollment and patients must be clinically stable
  • Use of highly effective contraception as defined by the study protocol
Exclusion Criteria:

  • Patients with a previous malignancy within the past 3 years are excluded (other than curatively treated basal cell carcinoma of the skin, early gastrointestinal (GI) cancer by endoscopic resection, in situ carcinoma of the cervix, or any cured cancer that is considered to have no impact on PFS and OS for the current NSCLC)
  • National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) (version 4.0) Grade 3 or higher toxicities due to any prior therapy (e.g., radiotherapy) (excluding alopecia), which have not shown improvement and are strictly considered to interfere with current study medication
  • Co-administration of anti-cancer therapies other than those administered in this study.
  • Patients with baseline QTc > 470 ms or symptomatic bradycardia
  • Receipt of strong/potent cytochrome P4503A inhibitors or inducers within 14 days prior to the first dose until the end of study treatment except for oral corticosteroids up to 20 mg of prednisolone equivalent per day
  • Receipt of any drug with potential QT interval prolonging effects within 14 days prior to the first dose until the end of study treatment
  • Pregnant or breast-feeding women
  • Any clinically significant disease or condition (or history of) that could interfere with, or for which the treatment might interfere with, the conduct of the study or the absorption of oral medications or that would, in the opinion of the Principal Investigator, pose an unacceptable risk to the patient in this study

  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies. 

Please refer to this study by its ClinicalTrials.gov identifier: NCT02075840

Contacts
Contact: Reference Study ID Number: BO28984 www.roche.com/about_roche/roche_worldwide.htm888-662-6728 (U.S. Only)global.rochegenentechtrials@roche.com
  Show 174 Study Locations 
Sponsors and Collaborators
Hoffmann-La Roche
Investigators
Study Director:Clinical TrialsHoffmann-La Roche
  More Information
No publications provided 

Responsible Party:Hoffmann-La RocheClinicalTrials.gov Identifier:NCT02075840     History of ChangesOther Study ID Numbers:BO28984, 2013-004133-33Study First Received:February 27, 2014Last Updated:January 19, 2015Health Authority:United States: Food and Drug Administration

Additional relevant MeSH terms:Carcinoma, Non-Small-Cell Lung
Lung Neoplasms
Bronchial Neoplasms
Carcinoma, Bronchogenic
Lung Diseases
Neoplasms
Neoplasms by Site
Respiratory Tract Diseases
Respiratory Tract Neoplasms
Thoracic Neoplasms
Crizotinib
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Protein Kinase Inhibitors


ClinicalTrials.gov processed this record on February 02, 2015

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 Alectinib approved for people with advanced lung cancer

2/3/2015

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Roche made the following announcement via press release:

Data showed that over 90 percent of Japanese people in the study responded to treatment with alectinib

Roche (SIX: RO, ROG; OTCQX: RHHBY) today announced that the Japanese Ministry of Health, Labour and Welfare (MHLW) has approved alectinib for the treatment of people living with non-small cell lung cancer (NSCLC) that is anaplastic lymphoma kinase fusion gene-positive (ALK+). The approval was based on results from a Japanese Phase I/II clinical study (AF-001JP) for people whose tumours were advanced, recurrent or could not be removed completely through surgery (unresectable).

“The approval of alectinib, a treatment specifically targeted to ALK+ lung cancer, in Japan is great news for people living with this difficult to treat disease,” said Sandra Horning MD, Roche’s Chief Medical Officer and Head of Global Product Development. “Another interesting aspect of alectinib is that based on early studies it may also work in people living with tumours that have spread to the brain, a difficult area to reach with current medicines. Our research will continue in this area."

Alectinib is expected to be made available in Japan later this year. Alectinib was also granted Breakthrough Therapy Designation (BTD) by the U.S. Food and Drug Administration (FDA) in June 2013 for patients with ALK+ NSCLC who progressed on crizotinib. BTD is designed to expedite the development and review of medicines intended to treat serious diseases and to help ensure patients have access to them through FDA approval as soon as possible.

Global pivotal studies are currently ongoing which will further inform on the clinical value of alectinib in this disease setting as well as in treatment-naïve patients. The results of these studies will be used in future regulatory submissions in the US and in Europe.

About the Japanese Phase I/II study (AF-001JP)This trial was conducted in 13 medical institutions in ALK fusion gene positive recurrent or advanced non-small cell lung cancer patients with a treatment history of one or more chemotherapy regimens.

The trial consisted of two phases: Phase I that evaluated safety, tolerability, pharmacokinetic parameters and recommended dose (24 patients), and a Phase II part that evaluated the efficacy and safety of the recommended dose (46 patients). The primary endpoint was response rate.

Japanese Phase I/II study (AF-001JP) resultsThe Phase I part of the study determined a recommended dose of 300 mg twice daily. No dose limiting toxicity was observed.

  • The Phase II portion of the study was conducted using the recommended dose, and demonstrated a response rate of 93.5% (43/46 patients; 95%CI: 82.1-98.6%). 
    - 14 patients entered the study with Central Nervous System (CNS) metastases1
    - 9 of the 14 patients remained in the study without CNS or systemic progression for more than 12 months1
  • Progression Free Survival (PFS) at 12 months was measured as 83% (95% CI: 68-92%)1
  • There were no treatment-related deaths and/or grade 4 or higher serious adverse reactions assessed according to CTCAE (Common Terminology Criteria for Adverse Events) defined by the Japan Clinical Oncology Group. The most frequently observed grade 3 or higher adverse reaction was neutropenia, and the incidence of the adverse event was 4 out of 58 patients (6.9%) who were treated with 300 mg twice daily, the approved dose.
About AlectinibAlectinib (RG7853/AF-802/RO5424802/CH5424802) is an investigational oral medicine created at Chugai Kamakura Research Laboratories and is being developed for people with NSCLC whose tumours are identified as ALK+. ALK+ NSCLC is often found in younger people, women and those who have a light or non-smoking history. It is almost always found in people with a specific type of NSCLC, adenocarcinoma.

Early studies with alectinib have shown activity on brain metastases, indicating that the drug may be taken up in the brain. The brain is protected by the blood-brain barrier, a network of tightly joined cells that line the inside of the blood vessels in the brain and spinal cord. One of the ways the blood-brain barrier prevents molecules from affecting the brain is to actively eject them from the barrier through a process known as ‘active efflux.’ The active efflux system does not recognise alectinib, which means that it may travel into and throughout brain tissue.

The Global Phase 3 studies2 of alectinib include a companion test co-developed with Ventana Medical Systems, Inc., a member of the Roche Group. Alectinib will be marketed in Japan by Chugai Pharmaceutical, a member of the Roche Group.

About Roche in lung cancerLung cancer is a major area of focus and investment for Roche, and we are committed to developing new approaches, medicines and tests that can help people with this deadly disease. Our goal is to provide an effective treatment option for every person diagnosed with lung cancer. We currently have two approved medicines to treat certain kinds of lung cancer and more than 10 medicines being developed to target the most common genetic drivers of lung cancer or to boost the immune system to combat the disease.

About RocheHeadquartered in Basel, Switzerland, Roche is a leader in research-focused healthcare with combined strengths in pharmaceuticals and diagnostics. Roche is the world’s largest biotech company, with truly differentiated medicines in oncology, immunology, infectious diseases, ophthalmology and neuroscience. Roche is also the world leader in in vitro diagnostics and tissue-based cancer diagnostics, and a frontrunner in diabetes management. Roche’s personalised healthcare strategy aims at providing medicines and diagnostics that enable tangible improvements in the health, quality of life and survival of patients. Founded in 1896, Roche has been making important contributions to global health for more than a century. Twenty-four medicines developed by Roche are included in the World Health Organisation Model Lists of Essential Medicines, among them life-saving antibiotics, antimalarials and chemotherapy.

In 2013 the Roche Group employed over 85,000 people worldwide, invested 8.7 billion Swiss francs in R&D and posted sales of 46.8 billion Swiss francs. Genentech, in the United States, is a wholly owned member of the Roche Group. Roche is the majority shareholder in Chugai Pharmaceutical, Japan.

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