Actionability of on-target ALK Resistance Mutations in Patients With Non-Small Cell Lung Cancer: Local Experience and Review of the

ALK -fusion-positive NSCLC patients treated with ALK inhibitors frequently develop on-target resistance mutations. We provide clinical evidence for targeting these mutations with currently available inhibitors using a pooled population of 387 patients. The majority achieved clinical benefit, but the likelihood of clinical benefit differed for each mutation-inhibitor combination. Our comprehensive overview can facilitate guidance for treating similar patients in clinical practice. Introduction: Non-small cell lung cancer (NSCLC) patients with Anaplastic Lymphoma Kinase (ALK) gene fusions respond well to ALK inhibitors but commonly develop on-target resistance mutations. The objective of this study is to collect clinical evidence for subsequent treatment with ALK inhibitors. Patients and Methods: Local experience with on-target ALK resistance mutations and review of the literature identified 387 patients with ALK inhibitor resistance mutations. Clinical benefit of mutation-inhibitor combinations was assessed based on reported response, progression free survival and duration of treatment. Furthermore, this clinical evidence was compared to previously reported in vitro sensitivity of mutations to the inhibitors. Results: Of the pooled population of 387 patients in this analysis, 239 (62%) received at least 1 additional line of ALK inhibition after developing on-target resistance to ALK inhibitor therapy. Clinical benefit was reported for 177 (68%) patients, but differed for each mutation-inhibitor combination. Agreement between in vitro predicted sensitivity of 6 published models and observed clinical benefit ranged from 69% to 89%. The observed clinical evidence for highest probability of response in the context of specific on-target ALK inhibitor resistance mutations is presented. Conclusion: Molecular diagnostics performed on tissue samples that are refractive to ALK inhibitor therapy can reveal new options for targeted therapy for NSCLC patients. Our comprehensive overview of clinical evidence of drug actionability of ALK on-target resistance mechanisms may serve as a practical guide to select the most optimal drug for individual patients.

Automated summary

This study provides clinical evidence for targeting on-target resistance mutations in ALK-fusion-positive NSCLC patients treated with ALK inhibitors. The clinical benefit varies for different mutation-inhibitor combinations. Such comprehensive overview can guide the treatment of similar patients in clinical practice.