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

Bart Koopman,Harry J.M Groen,Ed Schuuring,T Jeroen N Hiltermann,Wim Timens,Wilfred F.A Den Dunnen,Anke Van Den Berg,Arja Ter Elst,Michel Van Kruchten,Joost L Kluiver,Birgitta I Hiddinga,Lucie B.M Hijmering-Kappelle,Matthew R Groves,Juliana F Vilacha,Léon C Van Kempen,Anthonie J Van Der Wekken

doi:10.1016/j.cllc.2021.06.011

Abstract

IntroductionNon-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 MethodsLocal 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. ResultsOf 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. ConclusionMolecular 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.

Highlights

Soon after the discovery of the echinoderm microtubule-associated protein-like 4 gene (EML4)-Anaplastic Lymphoma Kinase gene (ALK) oncogene,[1] lung cancers harboring ALK fusions were shown to be highly sensitive to the ALK inhibitor crizotinib,[5] leading to its FDA approval in 2011.6 Various other ALK inhibitors targeting the ATP-binding pocket of ALK have since been approved for the treatment of patients with ALK fusion-positive non-small cell lung cancer (NSCLC), including second-generation inhibitors ceritinib,[7] alectinib, 8 and brigatinib,[9] and the thirdgeneration inhibitor lorlatinib.[10]
We evaluated the clinical tumor response of ALK inhibitors directed towards different on-target ALK mutations of 14 ALK fusion-positive NSCLC patients treated at the University Medical Center Groningen (UMCG) and 373 cases published by others, as well as the predictive value of the currently reported preclinical data
Between January 1, 2014 and June 19, 2020, patients treated with ALK fusion-positive NSCLC who relapsed on an ALK inhibitor and harbored one or more therapy-induced ALK mutations were identified using the pathology and Molecular Tumor Boards (MTBs) databases of the UMCG.[20]

Summary

Introduction

Oncogenic fusions involving the Anaplastic Lymphoma Kinase gene (ALK) are detected in approximately four percent of patients with advanced non-small cell lung cancer (NSCLC).[1,2] In the majority of patients, an inversion of a small part of chromosome 2p causes a fusion of the amino-terminal coiled-coil domain of Submitted: Apr 30, 2021; Revised: Jun 9, 2021; Accepted: Jun 26, 2021; Epub: xxx. In vitro studies testing the efficiency of multiple on-target mutations to crizotinib, ceritinib, alectinib and brigatinib, indicated a distinct inhibitor specific efficacy spectrum.[13]

Objectives

Methods

Results

Discussion

Conclusion