EBioMedicine | 2019

Refining precision cancer therapy in ALK-positive NSCLC



The treatment approach to advanced anaplastic lymphoma kinase certain I1171N-based double mutants could be overcome by earlierfusion-positive (ALK-positive) non-small cell lung cancer (NSCLC) serves as a paradigm for precision oncology. To date, five ALK-tyrosine kinase inhibitors (TKIs)—crizotinib, ceritinib, alectinib, brigatinib, and lorlatinib—have been approved by the US Food and Drug Administration [1,2]. Although each TKI has significant efficacy in ALK-positive NSCLC, the duration of benefit is invariably limited by the development of acquired resistance. Alectinib, a second-generation ALK-TKI, is the current standard initial therapy for advanced ALK-positive NSCLC [3,4]. Once patients develop alectinib resistance, second-line options include lorlatinib, chemotherapy, or a clinical trial. Lorlatinib is a potent, brainpenetrant, third-generation ALK/ROS1-TKI with efficacy against most known ALK resistancemutations including G1202R [2,5], themost common alectinib-resistant mutation [6]. Based on phase II results demonstrating its activity in patients who progressed on second-generation ALK-TKIs [2], lorlatinib recently received FDA approval for secondor third-line treatment of ALK-positive NSCLC. Sequential therapy with alectinib followed by lorlatinib is therefore anticipated to be a common treatment approach. Yet, resistance to lorlatinib invariably develops, and thus, elucidating mechanisms of resistance to lorlatinib is critical to developing effective next-line treatments. In this issue of EBioMedicine, Okada and colleagues report the identification of 14 lorlatinib-resistant compound ALKmutations [7]. Using an ENUmutagenesis screen of Ba/F3 cells expressing EML4-ALK-I1171N or -G1202R—the most common alectinib-resistant mutations [6]—the authors identified nine I1171N-based and four G1202R-based double mutants. A G1202R/G1269A double mutant was additionally identified in an EML4-ALK-G1202R mouse model made lorlatinib-resistant. Indeed, three of these compound mutations (G1202R/G1269A, G1202R/ L1196 M, and I1171N/L1198F) had previously been reported based on lorlatinib-resistant tumour biopsies [8]. The ALK mutations identified herein expand upon those reported in an independent mutagenesis study [7,8], suggesting lorlatinib resistance may emerge from a diverse array of compound ALK mutations as patients receive sequential alectinib then lorlatinib. Importantly, the authors evaluated the in vitro sensitivity of several compound ALK mutants to approved ALK inhibitors. Interestingly,

Volume 41
Pages 9 - 10
DOI 10.1016/j.ebiom.2019.01.059
Language English
Journal EBioMedicine

Full Text