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Background: The data of sequential therapy of anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) in clinical practice have been limited., Methods: We reviewed the clinical data of patients with ALK-rearranged non-small cell lung cancer who received crizotinib (CRZ) or alectinib (ALEC) between May 2012 and December 2016. Patients were divided into two groups based on the first-administered ALK-TKI, the CRZ or ALEC group. The combined time-to-treatment failure (TTF) was defined as the sum of the 'TTF of CRZ' plus the 'TTF of ALEC' if patients were treated with CRZ followed by ALEC in the CRZ group. The primary end-point is the comparison between the combined TTF and the TTF of ALEC in the ALEC group., Results: Of 864 patients enrolled from 61 institutions, 840 patients were analysed. There were 535 of 305 patients in the CRZ/ALEC groups. The combined TTF in the CRZ group was significantly longer than TTF in the ALEC group (median, 34.4 versus 27.2 months; hazard ratio [HR], 0.709; P = 0.0044). However, there was no significant difference in overall survival (OS) between the patients who received ALEC after CRZ in the CRZ group and the patients in the ALEC group (median, 88.4 months versus. not reached; HR, 1.048; P = 0.7770). In the whole population, the CRZ group had a significantly shorter OS than the ALEC group (median, 53.6 months versus not reached; HR, 1.821, P < 0.0001)., Conclusion: The combined TTF in the CRZ group was significantly longer than the TTF in the ALEC group; however, OS benefit of sequential therapy against ALEC as the first ALK-TKI was not shown., Competing Interests: Conflict of interest statement K.I. reported receiving personal fees from Boehringer Ingelheim, AstraZeneca, Pfizer, Eli Lilly, Chugai Pharmaceutical, Merck Sharp & Dohme (MSD), Ono Pharmaceutical and Taiho Pharmaceutical. T.Y. reported receiving grants from Takeda Pharmaceutical, Chugai Pharmaceutical, Boehringer Ingelheim, Taiho Pharmaceutical, Daiichi Sankyo, Ono Pharmaceutical, Bayer, Astellas and Eli Lilly and receiving personal fees from Takeda Pharmaceutical, Chugai Pharmaceutical, Boehringer Ingelheim, Taiho Pharmaceutical, Daiichi Sankyo, Bayer, Merck Serono, Pfizer, Huya Bioscience, Gilead Sciences and EP-CRSU. H.H. reported receiving grants from MSD, A2 Healthcare Corp., inVentiv Health Japan, Astellas, Daiichi Sankyo, Novartis, AbbVie, Quintiles/IQVIA Services, ICON Japan, Chugai Pharmaceutical, Takeda Pharmaceutical, EP-CRSU CO., GRITSTONE ONCOLOGY, Linical Co., Eli Lilly, Eisai Co., Bristol Myers Squibb company, Boehringer Ingelheim, Taiho Pharmaceutical, Pfizer, PAREXEL International Corp., SymBio Pharmaceuticals Limited, Ono Pharmaceutical, Merck Serono Co./Merck Biopharma, AstraZeneca, CMIC Shift Zero, Kissei Pharmaceutical, Kyowa Hakko Kirin, EPS Corporation, Bayer Yakuhin, Syneos Health, EPS International, Pfizer R&D Japan G.K and Otsuka Pharmaceutical and receiving personal fees from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Chugai Pharmaceutical, Eli Lilly, Kyorin Pharmaceutical, MSD, Ono Pharmaceutical, Novartis, Pfizer, Shanghai Haihe Biopharm and Taiho Pharmaceutical. Y.H. reported receiving grants from Janssen Pharmaceutical, MSD and Ono Pharmaceutical and receiving personal fees from AstraZeneca, Boehringer Ingelheim, Chugai Pharmaceutical, Eli Lilly, MSD, Novartis, Ono Pharmaceutical and Taiho Pharmaceutical. K.N. reported receiving grants from Boehringer Ingelheim and receiving personal fees from Chugai Pharmaceutical, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Novartis, Pfizer, Ono Pharmaceutical and Roche Diagnostics. H.K. reported receiving personal fees from Eli Lilly and Taiho Pharmaceutical. Y.O. reported no relevant conflicts of interests. T.Y. reported receiving personal fees from Boehringer Ingelheim, AstraZeneca, Taiho Pharmaceutical, Ono Pharmaceutical, Eli Lilly, Bristol Myers Squibb, Chugai Pharmaceutical, Novartis, Pfizer and MSD. T.S. reported receiving grants from AstraZeneca, Chugai Pharmaceutical, Daiichi Sankyo, Eli Lilly, MSD, Boehringer Ingelheim, Novartis, Pfizer, Takeda Pharmaceutical, AbbVie, Bayer Yakuhin, Kissei Pharmaceutical, LOXO Oncology and Merck Serono and receiving personal fees from AstraZeneca, Chugai Pharmaceutical, Daiichi Sankyo, Eli Lilly, MSD, Boehringer Ingelheim, Novartis, Pfizer, Takeda Pharmaceutical, Astellas, Bristol Myers Squibb, Kyowa Hakko Kirin, Ono Pharmaceutical, Taiho Pharmaceutical, Thermo Fisher Scientific and Precision Medicine Asia Co. Ltd. K.A. reported receiving personal fees from Chugai Pharmaceutical, AstraZeneca, MSD, Bristol Myers Squibb and Ono Pharmaceutical. T.F. reported receiving personal fees from AstraZeneca, Boehringer Ingelheim, Chugai Pharmaceutical, MSD, Novartis, Ono Pharmaceutical, Pfizer and Taiho Pharmaceutical. T.K. reported receiving grants from Chugai Pharmaceutical, AstraZeneca, Eli Lilly, Taiho Pharmaceutical, Bristol Meyers Squibb and Merck Biopharma and receiving personal fees from Chugai Pharmaceutical, AstraZeneca, Eli Lilly, Taiho Pharmaceutical, Bristol Meyers Squibb, Ono Pharmaceutical, MSD, Pfizer, Kyowa Hakko Kirin, Boehringer Ingelheim, Nippon Kayaku and Novartis. A.N. reported receiving personal fees from MSD, Chugai Pharmaceutical, AstraZeneca, Eli Lilly, Taiho Pharmaceutical, Boehringer Ingelheim and Kyowa Kirin. K.T. reported receiving grants from Boehringer Ingelheim, Chugai Pharmaceutical and Ono Pharmaceutical and receiving personal fees from Eli Lilly, Boehringer Ingelheim, Chugai Pharmaceutical, Ono Pharmaceutical, Taiho Pharmaceutical, AbbVie, Pfizer, SRL, MSD, Novartis and Kyowa Kirin. K.H. reported receiving personal fees from AstraZeneca, Eli Lilly, Boehringer Ingelheim, Ono Pharmaceutical, Chugai Pharmaceutical, Pfizer and Taiho Pharmaceutical. T.Y. reported receiving grants from Ono Pharmaceutical and receiving personal fees from AstraZeneca, Chugai Pharmaceutical, Ono Pharmaceutical, Bristol Myers Squibb, MSD and Boehringer Ingelheim. H.D. reported receiving grants from Chugai Pharmaceutical, Pfizer and Eli Lilly and receiving personal fees from Chugai Pharmaceutical and Boehringer Ingelheim. S.S. reported no relevant conflicts of interests. D.F. reported receiving grants from AstraZeneca and Chugai Pharmaceutical and receiving personal fees from AstraZeneca, Ono Pharmaceutical, Bristol Myers Squibb, Taiho Pharmaceutical, Chugai Pharmaceutical, MSD, Boehringer Ingelheim, Eli Lilly and Novartis. M.M. reported receiving personal fees from AstraZeneca, MSD, Ono Pharmaceutical, Eli Lilly, Boehringer Ingelheim, Chugai Pharmaceutical, Shionogi, Taiho Pharmaceutical and Novartis. K.M. reported receiving grants from Boehringer Ingelheim and Eli Lilly and receiving personal fees from Chugai Pharmaceutical and Novartis. T.A. reported no relevant conflicts of interests. A.T. reported no relevant conflicts of interests. S.M. reported receiving personal fees from Chugai Pharmaceutical, Boehringer Ingelheim, MSD, Eli Lilly, AstraZeneca, Ono Pharmaceutical, Taiho Pharmaceutical, Novartis, Bristol Myers Squibb and Kyowa Hakko Kirin. S.W. reported receiving grants from Boehringer Ingelheim and receiving personal fees from Eli Lilly, Pfizer, Novartis Pharma, AstraZeneca, Chugai Pharma, Bristol Meyers Squibb, Boehringer Ingelheim, MSD, Ono Pharmaceutical, Daiichi Sankyo and Taiho Pharmaceutical. H.A. reported receiving grants from Chugai Pharmaceutical and receiving personal fees from Chugai Pharmaceutical, Pfizer and Novartis. O.H. reported receiving grants from GlaxoSmithKline, AstraZeneca, Novartis, Kyorin, Bayer Yakuhin, Boehringer Ingelheim and Daiichi Sankyo and receiving personal fees from GlaxoSmithKline, AstraZeneca, Novartis, Bayer Yakuhin and Boehringer Ingelheim. K.S. reported no relevant conflict of interests. S.H. reported no relevant conflict of interests. K.A. reported no relevant conflict of interests. A.B. reported receiving personal fees from Chugai Pharmaceutical, Pfizer and Novartis. A.K. reported receiving grants from the Japan Society for the Promotion of Science, Boehringer Ingelheim, Chugai Pharmaceutical, Lilly and Ono Pharmaceutical and receiving personal fees from Boehringer Ingelheim, Chugai Pharmaceutical, Lilly, Ono Pharmaceutical, Novartis, Taiho Pharmaceutical and Pfizer. M.O. reported no relevant conflict of interests. K.N. reported receiving grants from MSD, A2 Healthcare Corp., inVentiv Health Japan, Astellas, Daiichi Sankyo, Novartis, AbbVie, Quintiles/IQVIA Services, ICON Japan, Chugai Pharmaceutical, Takeda Pharmaceutical, EP-CRSU CO., GRITSTONE ONCOLOGY, Linical Co., Eli Lilly, Eisai Co., Bristol Myers Squibb company, Boehringer Ingelheim, Taiho Pharmaceutical, Pfizer, PAREXEL International Corp., SymBio Pharmaceuticals Limited, Ono Pharmaceutical, Merck Serono Co./Merck Biopharma, AstraZeneca, CMIC Shift Zero, Kissei Pharmaceutical, Kyowa Hakko Kirin, EPS Corporation, Bayer Yakuhin, Syneos Health, EPS International, Pfizer R&D Japan G.K and Otsuka Pharmaceutical; receiving personal fees from AstraZeneca, Nichi-Iko Pharmaceutical, Astellas, Takeda Pharmaceutical, MSD, Taiho Pharmaceutical, Ono Pharmaceutical, Bristol Myers Squibb company, Boehringer Ingelheim, Eli Lilly, Novartis, SymBio Pharmaceuticals Limited, Pfizer, Chugai Pharmaceutical, Clinical Trials Co., NANZANDO Co., MEDICUS SHUPPAN, Publishers Co., YODOSHA CO., Care Net, Nikkei Business Publications, Reno. Medical, Daiichi Sankyo, KYORIN Pharmaceutical, Thermo Fisher Scientific, Medical Review Co., YOMIURI TELECASTING CORPORATION, Roche Diagnostics, Nippon Kayaku Co., Bayer Yakuhin, Merck Biopharma Co., Medical Mobile Communications Co., AbbVie and 3H Clinical Trial Inc. and receiving consulting and advisor fees from Takeda Pharmaceutical, KYORIN Pharmaceutical, Ono Pharmaceutical, Pfizer and Eli Lilly. N.Y. reported receiving grants from Taiho Pharmaceutical, Chugai Pharmaceutical, Eli Lilly, Boehringer Ingelheim, Daiichi Sankyo, Ono Pharmaceutical, Astellas, MSD, Pfizer, Takeda, AstraZeneca, Terumo and Toppan and receiving personal fees from Chugai Pharmaceutical, Eli Lilly, MSD, AstraZeneca, Ono Pharmaceutical, Novartis, Pfizer and Boehringer Ingelheim., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: BRAF inhibitors are effective in melanoma and other cancers with BRAF mutations; however, patients ultimately develop therapeutic resistance through the activation of alternative signaling pathways such as RAF/RAS or MET. The authors hypothesized that combining the BRAF inhibitor vemurafenib with either the multikinase inhibitor sorafenib or the MET inhibitor crizotinib could overcome therapeutic resistance., Methods: Patients with advanced cancers and BRAF mutations were enrolled in a dose-escalation study (3 + 3 design) to determine the maximum tolerated dose (MTD) and the dose-limiting toxicities (DLTs) of vemurafenib with sorafenib (VS) or vemurafenib with crizotinib (VC)., Results: In total, 38 patients (VS, n = 24; VC, n = 14) were enrolled, and melanoma was the most represented tumor type (VS, 38%; VC, 64%). In the VS arm, vemurafenib 720 mg twice daily and sorafenib 400 mg am/200 mg pm were identified as the MTDs, DLTs included grade 3 rash (n = 2) and grade 3 hypertension, and partial responses were reported in 5 patients (21%), including 2 with ovarian cancer who had received previous treatment with BRAF, MEK, or ERK inhibitors. In the VC arm, vemurafenib 720 mg twice daily and crizotinib 250 mg daily were identified as the MTDs, DLTs included grade 3 rash (n = 2), and partial responses were reported in 4 patients (29%; melanoma, n = 3; lung adenocarcinoma, n = 1) who had received previous treatment with BRAF, MEK, and/or ERK inhibitors. Optional longitudinal collection of plasma to assess dynamic changes in circulating tumor DNA demonstrated the elimination of BRAF-mutant DNA from plasma during therapy (P = .005)., Conclusions: Vemurafenib combined with sorafenib or crizotinib was well tolerated with encouraging activity, including among patients who previously received treatment with BRAF, MEK, or ERK inhibitors., (© 2020 American Cancer Society.)

Lessons Learned: The combination of axitinib and crizotinib has a manageable safety and tolerability profile, consistent with the profiles of the individual agents when administered as monotherapy.The antitumor activity reported here for the combination axitinib/crizotinib does not support further study of this combination treatment in metastatic renal cell carcinoma given the current treatment landscape., Background: Vascular endothelial growth factor (VEGF) inhibitors have been successfully used to treat metastatic renal cell carcinoma (mRCC); however, resistance eventually develops in most cases. Tyrosine protein kinase Met (MET) expression increases following VEGF inhibition, and inhibition of both has shown additive effects in controlling tumor growth and metastasis. We therefore conducted a study of axitinib plus crizotinib in advanced solid tumors and mRCC., Methods: This phase Ib study included a dose-escalation phase (starting doses: axitinib 3 mg plus crizotinib 200 mg) to estimate maximum tolerated dose (MTD) in patients with solid tumors and a dose-expansion phase to examine preliminary efficacy in treatment-naïve patients with mRCC. Safety, pharmacokinetics, and biomarkers were also assessed., Results: No patients in the dose-escalation phase ( n = 22) experienced dose-limiting toxicity; MTD was estimated to be axitinib 5 mg plus crizotinib 250 mg. The most common grade ≥3 adverse events were hypertension (18.2%) and fatigue (9.1%). In the dose-expansion phase, overall response rate was 30% (95% confidence interval [CI], 11.9-54.3), and progression-free survival was 5.6 months (95% CI, 3.5-not reached)., Conclusion: The combination of axitinib plus crizotinib, at estimated MTD, had a manageable safety profile and showed evidence of modest antitumor activity in mRCC., (© AlphaMed Press; the data published online to support this summary are the property of the authors.)

Aim: We analyzed cardiac function in two Phase III studies of previously treated (PROFILE 1007) or untreated (PROFILE 1014) ALK-positive advanced non-small-cell lung cancer., Patients & Methods: Adverse events associated with cardiac failure were compared between treatment arms in each study separately. Cardiac function was assessed prospectively by multigated acquisition scans or echocardiograms., Results: In PROFILE 1007 and 1014, incidence of cardiac failure adverse events was 0% (crizotinib) versus 0.6% (chemotherapy) and 2.3% versus 0.6%, respectively. In crizotinib versus chemotherapy arms, respectively, >20% left ventricular ejection fraction decreases occurred in 0/19 (0%) versus 1/16 (6.3%) patients from PROFILE 1007 and 4/150 (2.7%) versus 10/150 (6.7%) patients from PROFILE 1014., Conclusion: These analyses did not reveal any clinically meaningful changes in myocardial function with crizotinib in patients with ALK-positive non-small-cell lung cancer. Clinicaltrials.gov identifier: PROFILE 1007, NCT00932893; PROFILE 1014, NCT01154140.

Introduction: Crizotinib was approved to treat anaplastic lymphoma kinase (ALK)- positive non-small cell lung cancer (NSCLC) by the Food and Drug Administration in 2011.We conducted a systematic review of clinical trials and retrospective studies to compare the efficacy and safety of crizotinib with chemotherapy., Methods: We searched electronic databases from inception to Dec. 2016. Clinical trials and retrospective studies regarding crizotinib and crizotinib versus chemotherapy in treatment of NSCLC were eligible. The primary outcomes were the objective response rate (ORR) and disease control rate (DCR)., Results: Nine studies (five clinical trials and four retrospective studies) including 729 patients met the inclusion criteria. Crizotinib treatment revealed 1-year OS of 77.1% and PFS of 9.17 months. And crizotinib had a better performance than chemotherapy in ORR (OR: 4.97, 95%CI: 3.16 to 7.83, P<0.00001, I2=35%). DCR revealed superiority with crizotinib than chemotherapy (OR: 3.42, 95% CI: 2.33 to 5.01, P<0.00001, I2=0%). PR (partial response) were significant superior to that of chemotherapy through direct systematic review. No statistically significant difference in CR (complete response) was found between crizotinib-treated group and chemotherapy-treated group. Regarding SD (stable disease), chemotherapy-treated group had a better performance than crizotinib-treated group. Common adverse events associated with crizotinib were visual disorder, gastrointestinal side effects, and elevated liver aminotransferase levels, whereas common adverse events with chemotherapy were fatigue, nausea, and hematologic toxicity., Conclusion: This systematic review revealed improved objective response rate and increased disease control rate in crizotinib group comparing with chemotherapy group. Crizotinib treatment would be a favorable treatment option for patients with ALK-positive NSCLC. ALK inhibitors may have future potential applications in other cancers driven by ALK or c-MET gene mutations., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Purpose The phase III PROFILE 1014 trial compared crizotinib with chemotherapy as first-line treatment in patients with anaplastic lymphoma kinase (ALK) -positive advanced nonsquamous non-small-cell lung cancer. Here, we report the final overall survival (OS) results. Patients and Methods Patients were randomly assigned to receive oral crizotinib 250 mg twice daily (n = 172) or intravenous pemetrexed 500 mg/m 2 plus cisplatin 75 mg/m 2 or carboplatin (area under the concentration-time curve of 5 to 6 mg·mL/min) every 3 weeks for a maximum of six cycles (n = 171). Crossover to crizotinib was permitted after disease progression. OS was analyzed using a stratified log-rank test and a prespecified rank-preserving structural failure time model to account for crossover. Results Median follow-up duration for OS was approximately 46 months for both arms. In the chemotherapy arm, 144 patients (84.2%) received crizotinib in subsequent lines. Hazard ratio for OS was 0.760 (95% CI, 0.548 to 1.053; two-sided P = .0978). Median OS was not reached (NR) with crizotinib (95% CI, 45.8 months to NR) and 47.5 months with chemotherapy (95% CI, 32.2 months to NR). Survival probability at 4 years was 56.6% (95% CI, 48.3% to 64.1%) with crizotinib and 49.1% (95% CI, 40.5% to 57.1%) with chemotherapy. After crossover adjustment, there was an improvement in OS that favored crizotinib (hazard ratio, 0.346; 95% bootstrap CI, 0.081 to 0.718). The longest OS was observed in crizotinib-treated patients who received a subsequent ALK tyrosine kinase inhibitor. No new safety signals were identified. Conclusion The final analysis of the PROFILE 1014 study provides a new benchmark for OS in patients with ALK-rearranged non-small-cell lung cancer and highlights the benefit of crizotinib for prolonging survival in this patient population.

Background Both MET and c-SRC are important mediators of cancer progression and there is cross talk between the two molecules. Preclinical studies have demonstrated combination of MET and c-SRC inhibitors is effective in multiple cancer types. Methods We analyzed the safety and efficacy of administering a c-SRC inhibitor (dasatinib) in combination with a MET inhibitor (crizotinib) in a two-arm concurrent phase I study. Arm A consisted of crizotinib fixed at 250 mg twice per day with escalation of dasatinib. Arm B consisted of dasatinib fixed at 140 mg daily with escalation of crizotinib. Endpoints included dose-limiting toxicities (DLTs), recommended phase II dose (RP2D), and response (RECIST 1.1). Results We enrolled 61 patients (arm A: 31, arm B: 30). The most common cancers were sarcoma (21%) and prostate cancer (16%). In Arm A, at dose level 2 (DL2), 40% (2/5) experienced DLTs. In the expanded DL1, 21% (4/19) experienced DLTs (all grade 3). In Arm B, at DL2, 50% (2/4) experienced DLTs. In the expanded DL1, 22% (4/18) experienced DLTs (all grade 3). RP2D was determined to be arm A, DL1 (250 mg crizotinib orally twice per day plus 50 mg dasatinib orally daily). Partial response (N = 1) and stable disease for ≥6 months (N = 3) were seen. Conclusions The combination of crizotinib and dasatinib is safe to administer but tolerability is limited given the high rate of adverse events. Responses and durable stable disease were limited. Further precision therapy approach using this specific combination may be difficult given the toxicity.

Introduction: Crizotinib, an anaplastic lymphoma kinase (ALK) inhibitor, is a first-line treatment for ALK translocation-positive advanced non-small cell lung cancer (NSCLC); however, patients eventually progress. Immunotherapies, including the programmed death-1 inhibitor nivolumab, have resulted in durable responses and long-term overall survival in patients with NSCLC. We hypothesized that combining targeted therapy with immunotherapy could result in more patients with responses and/or more durable responses. Herein we report data from a study assessing nivolumab plus crizotinib in patients with previously untreated advanced ALK translocation-positive NSCLC., Methods: Group E in CheckMate 370 was a single-arm cohort designed to evaluate the safety of first-line nivolumab (240 mg every 2 weeks) plus crizotinib (250 mg twice daily) in patients with ALK translocation-positive NSCLC. The primary endpoint of safety would be met if ≤20% of patients discontinued treatment due to treatment-related adverse events by week 17. Objective response rate was a secondary endpoint. A planned safety review occurred in November 2016; the data cutoff was May 26, 2017., Results: Of the first 13 patients treated with nivolumab plus crizotinib, 5 (38%) developed severe hepatic toxicities leading to the discontinuation of the combination. Of these, two patients died and the presence of severe hepatic toxicities may have contributed to death. Enrollment was closed and combination treatment discontinued due to observed grade ≥3 hepatic toxicities. Five patients (38%) had a partial response., Conclusions: These findings do not support further evaluation of nivolumab 240 mg every 2 weeks plus crizotinib 250 mg twice daily., (Copyright © 2018 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)