ALK-positive NSCLC Patients Research Articles

Alectinib provides a new option for ALK-positive NSCLC patients after progression on crizotinib

Alectinib provides a new option for ALK-positive NSCLC patients after progression on crizotinib

SY12-3 - Safety of crizotinib in 892 Japanese ALK-positive advanced NSCLC patients: Interim report of post-marketing surveillance

SY12-3 - Safety of crizotinib in 892 Japanese ALK-positive advanced NSCLC patients: Interim report of post-marketing surveillance

3069 Impact of alectinib on survival after crizotinib failure in ALK-positive NSCLC patients

3069 Impact of alectinib on survival after crizotinib failure in ALK-positive NSCLC patients

3062 Ceritinib following crizotinib in ALK-positive (+) advanced NSCLC patients (pts): Results from the French Temporary Authorization for Use (ATU) experience

3062 Ceritinib following crizotinib in ALK-positive (+) advanced NSCLC patients (pts): Results from the French Temporary Authorization for Use (ATU) experience

Impact of alectinib on survival after crizotinib failure in ALK-positive NSCLC patients.

e19138 Background: The next generation ALK inhibitor, alectinib, reportedly has potent efficacy after crizotinib failure in ALK-positive NSCLC patients. In the present study, we investigated progre...

O3-9-4 - Clinical Benefit of Continued Therapy with Crizotinib Beyond Initial Disease Progression in Advanced Alk Positive Nsclc

Background: ALK-positive advanced NSCLC patients treated with crizotinib typically progress after initial tumor response. However, most patients continue crizotinib beyond RECIST-defined Progressive disease (PD) if they are clinically benefiting from it.Methods: We screened 53 patients whose tumors harbor ALK rearrangement, and identified 32 patients received crizotinib as initial ALK inhibitor between 2010 and 2013. Baseline characteristics, response, sites of initial progression, efficacy of continuation therapy with crizotinib beyond PD, PFS, and OS were analyzed.Results: Among 32 patients who received crizotinib, 14 (43%) were male, median age was 43 (range: 21-66), 15 (47%) were never-smokers, 23 (72%) were stage IV at diagnosis. All patients had ECOG PS of 0/1 before treatment with crizotinib. Four patients without progression have received crizotinib. All 32 patients were radiologically evaluated. 21 patients achieved an objective response (65%): two patients had a complete response and 19 had a partial response. Disease control (ie, complete response, partial response, or stable disease) was achieved by 27 patients. Median PFS and OS were 168 days (range: 28-837) and 525 days (range: 45-1238), respectively. The most common sites of disease progression in these population were brain (n = 10), lung (n = 3), and bone (n = 3). Among 28 patients who had PD, 18 continued crizotinib treatment beyond PD, including ten patients with only isolated CNS metastasis, one with metastases in both the CNS and primary lesion, and seven with metastasis at non-CNS sites only. The patients who continued crizotinib beyond PD tend to be longer survival from the time of PD.Conclusion: Patients who continued treatment with crizotinib beyond PD were more likely to have isolated CNS metastasis. The present study suggested that continuation of treatment with crizotinib after PD may provide survival benefit to ALK positive patients.

Anaplastic Lymphoma Kinase (Alk) Positivity in Non Small Cell Lung Cancer (Nsclc) Has Similar or Worse Prognosis for Clinical Outcome As Alk Wild Type: a Systematic Review of Published Literature

ABSTRACT Aim: Anaplastic lymphoma kinase (ALK) positive NSCLC identifies a unique subset of patients who respond to treatment with crizotinib (Pfizer Inc, NY), an ALK receptor tyrosine kinase inhibitor. However, it is not well established whether ALK status is predictive of a better or a worse outcome for those who do not receive crizotinib. We performed a systematic review of recent literature on ALK positive NSCLC to answer this question. Methods: Ovid Medline and Embase databases were searched for publications on ALK-positive NSCLC until December 2013. Studies were included if outcomes for crizotinib naive patients were presented for either Progression-Free Survival (PFS) or Overall Survival (OS). For each study identified, 2 investigators independently extracted and tabulated relevant findings. Demographics, ALK status, type of diagnostic test, treatment received and response to treatment were noted. To determine if ALK status was prognostic, efficacy outcomes (PFS and / or OS) for ALK-positive patients were compared to ALK wild type (WT) patients. Results: Twenty one studies published between 2009 to 2013, with nearly 8000 screened NSCLC patients and 700 ALK-positive patients, met the selection criteria. All publications were retrospective in nature, majority reported single institution experiences, with a mix of completely resected early stage NSCLC and recurrent or advanced disease. The number of ALK-positive patients in studies determined by Fluorescent In Situ Hybridisation (FISH) ranged from 7 to 121 (mean = 32) and the number of ALK-positive patients in studies determined by non-FISH methods ranged from 3 - 39 (mean = 18). Enrichment strategies were commonly employed with predominantly adenocarcinomas being selected for ALK testing. PFS and / or OS for ALK-positive NSCLC patients did not demonstrate a favourable outcome and was similar or worse compared to EGFR WT/ ALK WT patients. Conclusions: This analysis of published retrospective studies in ALK-positive NSCLC, suggest that ALK-positivity is not a positive prognostic factor and does not confer a favourable outcome in absence of crizotinib therapy. Disclosure: J. Binko: Employee of Pfizer Oncology and holder of Pfizer stock; P. Delahoy: Employee of Pfizer Oncology and holder of Pfizer stock. M. Alam: Employee of Pfizer Oncology and holder of Pfizer stock.

Abstract 5655: AP26113 possesses pan-inhibitory activity versus crizotinib-resistant ALK mutants and oncogenic ROS1 fusions.

Abstract AP26113 is a potent, reversible inhibitor of ALK fusions and mutant (but not native) EGFR. To overcome mutation-based resistance, AP26113 was designed to maintain activity against crizotinib-resistant ALK variants such as the gatekeeper ALK mutant L1196M. In an ongoing phase 1 dose-escalation study, AP26113 has achieved steady-state trough concentrations in excess of 1 μM and demonstrated promising clinical activity in both crizotinib-resistant and naïve ALK-positive NSCLC patients and preliminary evidence of activity in patients with mutant EGFR (#439O, ESMO 2012). To further assess the activity of AP26113 against crizotinib-resistant ALK mutants, and the structurally related ROS1 fusions recently identified in NSCLC, we engineered Ba/F3 cells to express the appropriate oncogenic drivers and evaluated their sensitivities to crizotinib and AP26113. Ba/F3 cell lines expressing clinically-identified EML4-ALK mutants (T1151T insertion, S1206Y, D1203N, L1196M, G1202R, F1174C and C1156Y) had substantially reduced sensitivity to crizotinib (viability IC50= 363-1296 nM) compared with native EML4-ALK (IC50= 137 nM). These data are consistent with the identification of these mutants in patients with acquired crizotinib resistance. AP26113 potently inhibited both native (IC50= 21 nM) and crizotinib-resistant ALK mutants (IC50= 26-254 nM) at concentrations substantially below the clinically achievable trough levels of AP26113 (1 μM), suggesting it may possess a pan-ALK inhibitory profile. AP26113 also effectively inhibited the viability of Ba/F3 cells expressing CD74-ROS1 (IC50= 18 nM), FIG-ROS1 (IC50= 31 nM), SDC4-ROS1 (IC50= 16 nM) and EZR-ROS1 (IC50= 41 nM) thus demonstrating that it is an equipotent inhibitor of ALK and ROS1. In a Ba/F3 CD74-ROS1 xenograft model, AP26113 inhibited tumor growth in a dose-dependent manner, with 50 mg/kg AP26113 inducing substantial tumor regression. Since ROS1 and ALK are structurally related and similarly sensitive to crizotinib, we reasoned that acquired drug resistance in ROS1-driven tumors may also occur via mutation. We therefore generated Ba/F3 cells driven by L2026M gatekeeper mutant forms of CD74-ROS1 and FIG-ROS1 and tested their drug sensitivity. Interestingly, the inhibitory capacity of AP26113 was unaffected by L2026M. In contrast, crizotinib potencies were reduced approximately 4-fold. In conclusion, we have demonstrated that AP26113 inhibits clinically relevant crizotinib- resistant ALK mutants and oncogenic ROS1 fusions recently identified in NSCLC irrespective of the fusion partner. Importantly, since AP26113 maintains potent activity against mutant forms of ALK and ROS1 at concentrations substantially below its human trough concentrations these data suggest that AP26113 may be able to prevent the emergence of drug-resistant mutants in NSCLC patients. Citation Format: Rachel M. Squillace, Rana Anjum, David Miller, Sadanand Vodala, Lauren Moran, Frank Wang, Tim Clackson, Andrew P. Garner, Victor M. Rivera. AP26113 possesses pan-inhibitory activity versus crizotinib-resistant ALK mutants and oncogenic ROS1 fusions. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5655. doi:10.1158/1538-7445.AM2013-5655

Abstract 2461: Design and synthesis of AZD3463, a novel orally bioavailable dual ALK and IGF1R inhibitor, inhibits growth of crizotinib resistance cell lines with multiple mechanisms of acquired resistance.

Abstract Although the ALK inhibitor crizotinib has clinical efficacy in selected ALK positive NSCLC patients, the majority of patients who initially respond eventually relapse. Several mechanisms of resistance have been proposed including amplification, resistance mutations, as well as alternative pathway drivers including EGFR, cKIT and IGF1R. We report here the discovery of a novel scaffold of ALK inhibitors and optimization effort that led to the discovery of AZD3463 a novel dual in vivo active ALK and IGF1R inhibitor. An in house subset screening of kinase inhibitors and de novo studies identified 4-(1H-indol-3-yl)pyrimidin-2-amine analogs as potent ALK inhibitors. Modeling studies were utilized to guide the SAR strategy around the aminopyrimidine group which afforded several lead compounds. Early SAR efforts quickly determined that smaller substituents, chloro and methyl, were optimal in the C5 position of the pyrimidine, and that aniline is preferred over several other amino heterocycles investigated. Parallel medicinal chemistry strategies were executed for the optimization of the aniline and indole. These studies suggested that a 2,4-substituted aniline provided optimal potency and selectivity in conjunction with a variety of heterocycles in C4 position of the pyrimdine. Cyclic amines in the C4 position of the aniline led to simultaneous improvement of potency and metabolic stability. The inhibition of IGF1R in vitro was maintained and modulation of glucose levels in vivo was observed with the optimized compounds and AZD3463. AZD3463 demonstrated superior potency to crizotinib in vivo (H3122 PD unbound EC50=0.16 nM). In summary, detailed SAR studies were executed on the 4-(1H-indol-3-yl)pyrimidin-2-amine template that produced potent inhibitors of ALK with improved physical chemical and ADME properties, and identified AZD3463, a novel equipotent ALK and IGF1R inhibitor, potent in ALK-driven preclinical models and in a variety of crizotinib-resistant models. We present herein the design and synthesis of AZD3463 as well as its overall properties. Citation Format: Jamal C. Saeh, Bin Yang, Tim Pontz, Kumar Thakur, Bo Peng, Lisa Drew, Caroline Rivard, Dan Widzowski, Jane Cheng, Douglas Ferguson, Brenda McDermott, Minhui Shen, John McNulty, Ryohei Katayama, Jeffrey Engleman, Alice Shaw, Daniel Russell, Graeme Smith. Design and synthesis of AZD3463, a novel orally bioavailable dual ALK and IGF1R inhibitor, inhibits growth of crizotinib resistance cell lines with multiple mechanisms of acquired resistance. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2461. doi:10.1158/1538-7445.AM2013-2461

Favorable clinical outcomes of pemetrexed treatment in anaplastic lymphoma kinase positive non-small-cell lung cancer

The development of anaplastic lymphoma kinase (ALK) inhibitor has just followed the recent discovery of ALK rearrangement in lung cancer, therefore not much is yet known about the clinical course and treatment outcomes to chemotherapy in ALK-positive patients. The purpose of this study was to investigate the clinical characteristics and treatment outcomes in patients with ALK-positive NSCLC treated with conventional chemotherapy during pre-ALK inhibitor period. We retrospectively screened 381 consecutive NSCLC patients without known epidermal growth factor receptor (EGFR) or KRAS mutation who were diagnosed between 2007 and 2008 at a single center, and identified ALK rearrangements by fluorescence in situ hybridization. Additional 44 ALK-positive patients who were identified since 2009 by central lab for participation on clinical trial were included for the analysis of clinical outcomes. Of the 381 tumors screened, 21 (5.6%) showed ALK rearrangements, with twenty adenocarcinomas and one pleomorphic carcinoma. Of 65 ALK-positive patients including additional 44 ALK-positive patients, 32 patients received pemetrexed as a second- or further-line therapy, in whom the response rate was 34.4% (11/32), median progression-free survival (PFS) was 4.0 months (range: 0-22.0 months) and median overall survival (OS) was 50.8 months (95% confidence interval [CI]: 38.7-62.8). The prevalence of ALK rearrangement was 5.6% among EGFR and/or KRAS wild-type/unknown NSCLC population. Pemetrexed, given as a second- or further-line therapy, showed favorable clinical outcomes in ALK-positive NSCLC patients.

Abstract SY33-01: The development of crizotinib in molecularly targeted patient populations

Abstract SY33-01: The development of crizotinib in molecularly targeted patient populations