Efficacy and Tolerability of / Combinations in Patients With -Rearranged Lung Cancer With Acquired Amplification: A Retrospective Analysis.

Introduction: amplification is a potentially actionable resistance mechanism in -rearranged (ALK+) lung cancer. Studies describing treatment outcomes of this molecular subgroup are lacking.

Methods: We assembled a cohort of patients with ALK+ lung cancer and acquired amplification (identified by tissue or plasma) who received regimens targeting both ALK and MET. Efficacy and safety were assessed using the Response Evaluation Criteria in Solid Tumors version 1.1 and Common Terminology Criteria for Adverse Events version 4.03, respectively.

Results: A total of 12 patients were included in the series. amplification was detected after a median of 1.5 (range 1-5) lines of therapy. Four distinct regimens were implemented to address amplification: crizotinib (n = 2), lorlatinib plus crizotinib (n = 6), alectinib plus capmatinib (n = 3), and alectinib plus crizotinib (n = 1). Partial responses were observed in five (42%) of 12 patients, including patients who received crizotinib (n = one of two), lorlatinib plus crizotinib (n = three of six), and alectinib plus capmatinib (n = one of three). Primary progression was observed in four patients (33%). Grades 1 to 2 peripheral edema, occurring in seven (58%) patients, was found with both crizotinib and capmatinib. One patient required dose reduction of capmatinib plus alectinib for persistent grade 2 edema. Across the regimens, one patient discontinued therapy for toxicity, specifically neurocognitive toxicity from lorlatinib plus crizotinib. At progression on ALK+ MET therapy, potential resistance mechanisms included copy number changes and kinase domain mutations.

Conclusions: Combined ALK and MET inhibition is associated with moderate antitumor activity in patients with ALK+ NSCLC with concurrent amplification. Prospective studies are indicated to confirm activity and identify individuals most likely to benefit from the treatment.