Lorlatinib Should Not be Considered as the Preferred First-Line Option in Patients With Advanced ALK Rearranged NSCLC

In theory, you might think there should be no debate over whether lorlatinib should be the preferred first-line ALK inhibitor. If the CROWN study data are viewed in isolation, lorlatinib seems to have the best-in-class differential progression-free survival (PFS) benefit over crizotinib (hazard ratio [HR] = 0.28, 95% confidence interval [CI]: 0.19–0.41). 1 In contrast, other next-generation ALK inhibitors alectinib, brigatinib, and ensartinib with comparable head-to-head trials versus crizotinib generated PFS HRs ranging from 0.51 to 0.37. 2 , 3 , 4 , 5 , 6 , 7 Whereas, admittedly, for the lowest of these estimates (from the J-ALEX study [alectinib versus crizotinib in a Japanese population]), the CIs of the PFS HR (0.37, 95% CI: 0.26–0.52) overlap with those of the CROWN study, there is a clear delineation between the upper limit of CROWNs HR CIs and the lower limit of the HR CIs for the other studies. Yet, here we are in a pro and con debate, because, frankly, there is something abou..... READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2020.12.022

Authors: David Ross Camidge

EditorialKirk SmithMarch 27, 2021Lorlatinib, First-Line, ALK-Rearranged NSCLC

Lorlatinib Should Be Considered as the Preferred First-Line Option in Patients With Advanced ALK-Rearranged NSCLC

Since the discovery of ALK-positive (ALK+) fusion in NSCLC in 2007, 1 ,2 we now know patients with ALK+ NSCLC can live up to 9 years after stage 4 diagnosis 3 , 4 , 5 but are constantly overshadowed by an unrelenting cumulative incidence of brain metastasis with time (>60% by year 6). 6 At the molecular level, the two most common EML4-ALK fusion variants, variant 1 (v1) and variant 3 (v3), have differential responses to ALK tyrosine kinase inhibitors (TKIs) 7 ,8 with the recalcitrant solvent-front ALK G1202R mutation arising more often from the background of EML4-ALK variant 3. READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2020.12.021

Authors: Misako Nagasaka, Sai-Hong Ignatius Ou

EditorialKirk SmithMarch 27, 2021lorlatinib, First-Line, ALK-Rearranged, NSCLC