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BACKGROUND The early-generation ROSl tyrosine kinase inhibitors (TKIs) that are approved for the treatment of ROS1 fusion-positive non-small-cell lung cancer (NSCLC) have antitumor activity, but resistance develops in tumors, and intracranial activity is suboptimal. Repotrectinib is a next-generation ROSl TKI with preclinical activity against ROSI fusion-positive cancers, including those with resistance mutations such as ROS1 62032. METHODS In this registrational phase 1-2 trial, we assessed the efficacy and safety of repotrec-tinib in patients with advanced solid tumors, including ROS1 fusion-positive NSCLC. The primary efficacy end point in the phase 2 trial was confirmed objective response; efficacy analyses included patients from phase 1 and phase 2. Duration of response, progression-free survival, and safety were secondary end points in phase 2. RESULTS On the basis of results from the phase 1 trial, the recommended phase 2 dose of repotrectinib was 160 mg daily for 14 days, followed by 160 mg twice daily. Response occurred in 56 of the 71 patients (79°/o; 95°6 confidence interval [CI], 68 to 88) with ROS1 fusion-positive NSCLC who had not previously received a ROS1 TKI; the median duration of response was 34.1 months (95% CI, 25.6 to could not be estimated), and median progression-free survival was 35.7 months (95% CI, 27.4 to could not be estimated). Response occurred in 21 of the 56 patients (3896; 95% CI, 25 to 52) with ROS1 fusion-positive NSCLC who had previously received one ROSl TKI and had never received chemotherapy; the median duration of response was 14.8 months (95% CI, 7.6 to could not be estimated), and median progression-free survival was 9.0 months (95% CI, 6.8 to 19.6). Ten of the 17 patients (5996; 95% CI, 33 to 82) with the ROS1 G2032R mutation had a response. A total of 426 patients received the phase 2 dose; the most common treatment-related adverse events were dizziness (in 58% of the patients), dysgeusia (in 5090), and paresthesia (in 30°6), and 3% discontinued repotrectinib owing to treatment-related adverse events. CONCLUSIONS Repotrectinib had durable clinical activity iii patients with ROS1 fusion-positive NSCLC, regardless of whether they had previously received a ROS1 TKI. Adverse events were mainly of low grade and compatible with long-term administration. (Funded by Turning Point Therapeutics, a wholly owned subsidiary of Bristol Myers Squibb; TRIDENT-1 ClinicalTrials.gov number, NCT03093116.). [ABSTRACT FROM AUTHOR]

Objectives: The ALTA-1L phase 3 open-label trial demonstrated increased progression-free survival (PFS) with brigatinib versus crizotinib in patients with anaplastic lymphoma kinase-positive (ALK-positive) locally advanced or metastatic non-small cell lung cancer (NSCLC) previously untreated with ALK-targeted therapy. This post-hoc analysis of data from the ALTA-1L trial used the quality-adjusted (QA) time without symptoms of disease or toxicity (Q-TWiST) methodology to compare the QA survival benefit of brigatinib versus crizotinib in this patient population., Patients and Methods: The Q-TWiST analysis was performed using final (January 29, 2021) individual patient-level blinded independent review committee (BIRC)- and investigator-assessed survival data for brigatinib (n = 137) and crizotinib (n = 138) in adult patients (N = 275) with ALK-positive locally advanced or metastatic NSCLC previously untreated with ALK-targeted therapy. Q-TWiST was compared between the two treatments. Subgroup analyses were performed in patients stratified by various clinicopathological characteristics, including presence or absence of brain metastases at baseline., Results: Brigatinib was associated with significantly longer time without symptoms of disease or toxicity (P < 0.001) than crizotinib, with significantly greater Q-TWiST (mean [SE] months: BIRC-assessed, 28.2 [1.2] versus 25.1 [1.1], P = 0.045; investigator-assessed, 28.5 [1.2] versus 24.8 [1.1], P = 0.018). Relative gains in Q-TWiST with brigatinib compared to crizotinib were clinically meaningful (BIRC-assessed, 10.4%; investigator-assessed, 12.3%). Patients with brain metastases at baseline receiving brigatinib had significantly greater Q-TWiST (mean [SE] months: BIRC-assessed, 29.0 [1.9] versus 19.0 [1.9], P = 0.0001) than those receiving crizotinib., Conclusion: First-line brigatinib treatment was associated with significant and clinically meaningful gains in Q-TWiST compared to crizotinib in patients with ALK-positive locally advanced or metastatic NSCLC, supporting the results of the ALTA-1L trial and brigatinib as a safe and effective first-line treatment for ALK-positive NSCLC., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

Objectives: To better understand genetic determinants of response to ceritinib, an exploratory analysis was conducted using tumor biopsies from anaplastic lymphoma kinase (ALK)-rearranged (ALK+) non-small-cell lung cancer (NSCLC) patients treated with ceritinib at doses of ≥ 300 mg in the ASCEND-1 study., Methods: ASCEND-1 was an open-label, multicentre, phase 1, dose-escalation and expansion study of ceritinib (fasted) in ALK inhibitor (ALKi)-naïve or ALKi-pretreated patients with locally advanced or metastatic ALK + NSCLC. Biopsies were assayed by next-generation sequencing (NGS) using a Foundation Medicine panel targeting 295 genes. Somatic alterations were correlated with clinical outcome (cut-off 14-Apr-2014). A total of 285 ALK + NSCLC patients were treated with ceritinib at doses ≥ 300 mg., Results: NGS data were generated for 85 pts (ALKi-pretreated [n = 54]; ALKi-naïve [n = 31]), 57 were collected from patients before exposure to any ALKi. NGS did not detect ALK rearrangement in 14 of 85 patients; several of these ALK NGS negative cases harbored alternative drivers, e.g. EGFR mutation. Of the 71 biopsies with NGS confirmed ALK rearrangement, the most frequently detected rearrangements were EML4-ALK variant 1 (V1) and EML4-ALK V3 (36.6% [26/71] and 32.4% [23/71] respectively). Eight (six crizotinib-pretreated and two pretreated with crizotinib followed by alectinib) of the 21 ALKi-pretreated patients carried a point mutation of the ALK TKD, and had the biopsy collected between 1 and 14 days before ceritinib; with the exception of one patient with a G1202R point mutation, all patients derived clinical benefit from ceritinib treatment. Of the 14 ALKi-naïve patients, ceritinib was effective in almost all patients, including a patient carrying a concomitant ERBB4 and HGF amplification., Conclusions: This exploratory analysis highlights the potential role of NGS in improving our understanding of response and resistance to ceritinib. It also illustrates that ceritinib is active against almost all ALK resistance mutations found in ALKi-pretreated patients., Trial Registration: ClinicalTrials.gov, NCT01283516. Registered January 26, 2011, https://clinicaltrials.gov/ct2/show/NCT01283516., (Copyright © 2021. Published by Elsevier B.V.)