Search

Background: The ALEX study demonstrated significantly improved progression-free survival (PFS) with alectinib versus crizotinib in treatment-naive ALK-positive non-small-cell lung cancer (NSCLC) at the primary data cut-off (9 February 2017). We report mature PFS (cut-off: 30 November 2018) and overall survival (OS) data up to 5 years (cut-off: 29 November 2019)., Patients and Methods: Patients with stage III/IV ALK-positive NSCLC were randomized to receive twice-daily alectinib 600 mg (n = 152) or crizotinib 250 mg (n = 151) until disease progression, toxicity, withdrawal or death. Primary end point: investigator-assessed PFS. Secondary end points included objective response rate, OS and safety., Results: Mature PFS data showed significantly prolonged investigator-assessed PFS with alectinib [hazard ratio (HR) 0.43, 95% confidence interval (CI) 0.32-0.58; median PFS 34.8 versus 10.9 months crizotinib]. Median duration of OS follow-up: 48.2 months alectinib, 23.3 months crizotinib. OS data remain immature (37% of events). Median OS was not reached with alectinib versus 57.4 months with crizotinib (stratified HR 0.67, 95% CI 0.46-0.98). The 5-year OS rate was 62.5% (95% CI 54.3-70.8) with alectinib and 45.5% (95% CI 33.6-57.4) with crizotinib, with 34.9% and 8.6% of patients still on study treatment, respectively. The OS benefit of alectinib was seen in patients with central nervous system metastases at baseline [HR 0.58 (95% CI 0.34-1.00)] and those without [HR 0.76 (95% CI 0.45-1.26)]. Median treatment duration was longer with alectinib (28.1 versus 10.8 months), and no new safety signals were observed., Conclusions: Mature PFS data from ALEX confirmed significant improvement in PFS for alectinib over crizotinib in ALK-positive NSCLC. OS data remain immature, with a higher 5-year OS rate with alectinib versus crizotinib. This is the first global randomized study to show clinically meaningful improvement in OS for a next-generation tyrosine kinase inhibitor versus crizotinib in treatment-naive ALK-positive NSCLC., Clinical Trials Number: NCT02075840., Competing Interests: Disclosure TM declares a leadership role with Sanonics Ltd, Hutchinson ChiMed and AstraZeneca; honoraria/consulting fees from ACEA Biosciences, AstraZeneca, Boehringer-Ingelheim, Bristol-Myers Squibb (BMS), Celgene, Chimed, Cirina, Fishawack Facilitate, Ignyta, Janssen, Lilly, Merck Serono, Merck Sharp & Dohme (MSD), Novartis, OncoGenex, Pfizer, Roche/Genentech, SFJ Pharmaceutical, Takeda and Vertex; and research funding from AstraZeneca, BMS, Clovis Oncology, MSD, Novartis, Pfizer, Roche, SFJ Pharmaceutical and XCovery. DRC declares honoraria/consulting fees from Abbvie, Ariad, Array, Celgene, Clovis Oncology, Eli Lilly, Genoptix, G1 Therapeutics, Novartis, Orion and Roche/Genentech. SMG declares honoraria/consulting fees from Ariad, AstraZeneca, BMS, Pfizer and Roche/Genentech. RR has nothing to disclose. RD declares honoraria/consulting fees from Roche, Pfizer, Novartis, Boehringer-Ingelheim, AstraZeneca, Takeda, Yuhan, XCovery, SeattleGenetics and Celon Pharma. DWK declares non-financial support from Roche for travel to meetings for the study, and provision of writing assistance, medicines, equipment or administrative support; and non-financial support from Amgen and Daiichi-Sankyo for travel to advisory meetings. His institution has received funding from Alpha Biopharma, AstraZeneca/Medimmune, Boehringer-Ingelheim, Hanmi, Janssen, Merus, Mirati Therapeutics, MSD, Novartis, Ono, Pfizer, Roche/Genentech, Takeda, TP Therapeutics, XCovery and Yuhan. MP declares honoraria/consulting fees from Roche/Genentech, Pfizer, Eli Lilly, Boehringer-Ingelheim, Clovis Oncology, MSD, Chugai, BMS, Amgen, Novartis, Pierre Fabre, AstraZeneca and Takeda; and institutional grants for clinical/translational research from Roche, AstraZeneca, Chugai and Takeda. SHIO declares honoraria/consultancy fees from ARIAD, AstraZeneca, Pfizer, Roche/Genentech and TP Therapeutics; speakers' bureau participation for ARIAD, AstraZeneca and Roche/Genentech; research funding from ARIAD, AstraZeneca, Daiichi Sankyo, Pfizer and Roche/Genentech; and stock ownership in TP Therapeutics. JSA declares honoraria from Pfizer, AstraZeneca, Menarini, Roche, Eisai, Boehringer-Ingelheim, BMS-Ono, MSD, Janssen, Samsung Bioepis, Takeda and Amgen. ATS is currently an employee of Novartis and has received honoraria or consulting fees from F. Hoffmann La-Roche Ltd, Genentech, Pfizer, Novartis, Ariad, Ignyta, Daiichi-Sankyo, Taiho, Blueprint medicines, LOXO, EMD Serono and Foundation medicine. WB, VS, MH, JN and TR are employees of F. Hoffmann-La Roche Ltd. SP declares educational grants or honoraria for advisory board attendance and/or lectures from Abbvie, Amgen, AstraZeneca, Bayer, Biocartis, Boehringer-Ingelheim, BMS, Clovis, Daiichi Sankyo, Debiopharm, Eli Lilly, Roche, Foundation Medicine, Illumina, Janssen, MSD, Merck Serono, Merrimack, Novartis, Pharma Mar, Pfizer, Regeneron, Sanofi, Seattle Genetics and Takeda., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: In the ongoing phase I PROFILE 1001 study, crizotinib showed antitumor activity in patients with ROS1-rearranged advanced non-small-cell lung cancer (NSCLC). Here, we present updated antitumor activity, overall survival (OS) and safety data (additional 46.2 months follow-up) for patients with ROS1-rearranged advanced NSCLC from PROFILE 1001., Patients and Methods: ROS1 status was determined by FISH or reverse transcriptase-polymerase chain reaction. All patients received crizotinib at a starting dose of 250 mg twice daily., Results: Fifty-three patients received crizotinib, with a median duration of treatment of 22.4 months. At data cut-off, treatment was ongoing in 12 patients (23%). The objective response rate (ORR) was 72% [95% confidence interval (CI), 58% to 83%], including six confirmed complete responses and 32 confirmed partial responses; 10 patients had stable disease. Responses were durable (median duration of response 24.7 months; 95% CI, 15.2-45.3). ORRs were consistent across different patient subgroups. Median progression-free survival was 19.3 months (95% CI, 15.2-39.1). A total of 26 deaths (49%) occurred (median follow-up period of 62.6 months), and of the remaining 27 patients (51%), 14 (26%) were in follow-up at data cut-off. Median OS was 51.4 months (95% CI, 29.3 to not reached) and survival probabilities at 12, 24, 36, and 48 months were 79%, 67%, 53%, and 51%, respectively. No correlation was observed between OS and specific ROS1 fusion partner. Treatment-related adverse events (TRAEs) were mainly grade 1 or 2, per CTCAE v3.0. There were no grade ≥4 TRAEs and no TRAEs associated with permanent discontinuation. No new safety signals were reported with long-term crizotinib treatment., Conclusions: These findings serve as a new benchmark for OS in ROS1-rearranged advanced NSCLC, and continue to show the clinically meaningful benefit and safety of crizotinib in this molecular subgroup., Trial Registration Number: ClinicalTrials.gov identifier NCT00585195., (© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society for Medical Oncology.)

Background: The phase III ALEX study in patients with treatment-naive advanced anaplastic lymphoma kinase mutation-positive (ALK+) non-small-cell lung cancer (NSCLC) met its primary end point of improved progression-free survival (PFS) with alectinib versus crizotinib. Here, we present detailed central nervous system (CNS) efficacy data from ALEX., Patients and Methods: Overall, 303 patients aged ≥18 years underwent 1:1 randomization to receive twice-daily doses of alectinib 600 mg or crizotinib 250 mg. Brain imaging was conducted in all patients at baseline and every subsequent 8 weeks. End points (analyzed by subgroup: patients with/without baseline CNS metastases; patients with/without prior radiotherapy) included PFS, CNS objective response rate (ORR), and time to CNS progression., Results: In total, 122 patients had Independent Review Committee-assessed baseline CNS metastases (alectinib, n = 64; crizotinib, n = 58), 43 had measurable lesions (alectinib, n = 21; crizotinib, n = 22), and 46 had received prior radiotherapy (alectinib, n = 25; crizotinib, n = 21). Investigator-assessed PFS with alectinib was consistent between patients with baseline CNS metastases [hazard ratio (HR) 0.40, 95% confidence interval (CI): 0.25-0.64] and those without (HR 0.51, 95% CI: 0.33-0.80, P interaction = 0.36). Similar results were seen in patients regardless of prior radiotherapy. Time to CNS progression was significantly longer with alectinib versus crizotinib and comparable between patients with and without baseline CNS metastases (P < 0.0001). CNS ORR was 85.7% with alectinib versus 71.4% with crizotinib in patients who received prior radiotherapy and 78.6% versus 40.0%, respectively, in those who had not., Conclusion: Alectinib demonstrated superior CNS activity and significantly delayed CNS progression versus crizotinib in patients with previously untreated, advanced ALK+ NSCLC, irrespective of prior CNS disease or radiotherapy., Clinical Trial Registration: ClinicalTrials.gov NCT02075840.

Background: In clinical trials of patients with anaplastic lymphoma kinase (ALK)-positive non-small-cell lung cancer (NSCLC) treated with crizotinib, evaluation of the relationship between the percentage of ALK-positive cells by fluorescence in situ hybridization (FISH)-particularly near the cut-off defining positive status-and clinical outcomes have been limited by small sample sizes., Patients and Methods: Data were pooled from three large prospective trials (one single-arm and two randomized versus chemotherapy) of crizotinib in patients with ALK-positive NSCLC determined by Vysis ALK Break Apart FISH using a cut-off of ≥15% ALK-positive cells. Logistic regression and proportional hazards regression analyses were used to explore the association of percent ALK-positive cells with objective response and progression-free survival (PFS), respectively., Results: Of 11 081 screened patients, 1958 (18%) were ALK positive, 7512 (68%) were ALK negative, and 1540 (14%) were uninformative. Median percentage of ALK-positive cells was 58% in ALK-positive patients and 2% in ALK-negative patients. Of ALK-positive patients, 5% had 15%-19% ALK-positive cells; of ALK-negative patients, 2% had 10%-14% ALK-positive cells. Objective response rate for ALK-positive, crizotinib-treated patients with ≥20% ALK-positive cells was 56% (n = 700/1246), 55% (n = 725/1312) for those with ≥15% ALK-positive cells, and 38% for those with 15%-19% ALK-positive cells (n = 25/66). As a continuous variable, higher percentages of ALK-positive cells were estimated to be associated with larger differences in objective response and PFS between crizotinib and chemotherapy; however, tests for interaction between treatment and percentage of ALK-positive cells were not significant (objective response, P = 0.054; PFS, P = 0.17)., Conclusions: Patients with ALK-positive NSCLC benefit from treatment with crizotinib across the full range of percentage of ALK-positive cells, supporting the clinical utility of the 15% cut-off. The small number of patients with scores near the cut-off warrant additional study given the potential for misclassification of ALK status due to technical or biologic reasons.

Background We report results of the first interim analysis (IA) of BRG vs CRZ in ALK TKI-naive, ALK+ NSCLC from ALTA-1L (NCT02737501). Methods This open-label, multicenter study enrolled pts with advanced ALK+ NSCLC who had ≤1 prior systemic therapy; asymptomatic CNS metastases were allowed. Pts were randomized 1:1 to BRG 180 mg QD with 7-day lead-in at 90 mg or CRZ 250 mg BID. Primary endpoint: blinded independent review committee (BIRC)-assessed PFS (RECIST v1.1). Secondary efficacy endpoints included BIRC-assessed ORR, intracranial (i) ORR (iORR), and PFS (iPFS). IAs were planned at 50% and 75% of 198 expected PFS events. Results 275 pts were randomized (BRG/CRZ, n = 137/138); median age: 58/60 y. 26%/27% received prior chemotherapy for advanced disease; 29%/30% had baseline brain metastases. At data cutoff (19Feb2018), median follow-up of BRG/CRZ was 11.0/9.25 mo. With 99 PFS events, BRG met the prespecified threshold for statistical superiority vs CRZ in the primary endpoint, BIRC-assessed PFS (HR 0.49, 95% CI 0.33-0.74, log-rank P =0.0007); BRG median PFS (95% CI) was not reached (NR; NR) vs CRZ 9.8 months (9.0-12.9). Investigator-assessed PFS HR 0.45 (95% CI 0.30-0.68), log-rank P =0.0001. Confirmed ORR for BRG was 71% (62-78) vs CRZ 60% (51-68). In pts with any iCNS disease (BRG/CRZ, n = 43/47), confirmed iORR was 67% (51-81) vs 17% (8-31), P <0.0001. BRG median iPFS was NR (11 mo-NR) vs CRZ 6 mo (4-9); HR 0.27 (95% CI 0.13-0.54); log-rank P <0.0001. In pts with measurable iCNS disease (BRG/CRZ, n = 18/21), confirmed iORR was BRG 78% (52-94) vs CRZ 29% (11-52); P =0.0028. Most common grade ≥3 TEAEs for BRG were increased CPK (16.2%) and lipase (13.2%), hypertension (9.6%), and for CRZ were increased ALT (9.5%), AST (5.8%), and lipase (5.1%). Any grade ILD/pneumonitis (BRG/CRZ): 3.7%/2.2%; discontinuations due to AE: 11.8%/8.8%. Conclusions BRG showed a statistically and clinically significant improvement in PFS vs CRZ in ALK inhibitor-naive ALK+ NSCLC. [ABSTRACT FROM AUTHOR]