From preclinical efficacy to 2022 (36.7 months median follow -up) updated CROWN trial, lorlatinib is the preferred 1st-line treatment of advanced ALK+ NSCLC
Sai‐Hong Ignatius Ou, Alexandria TM Lee, Misako Nagasaka
Abstract
Six ALK TKIs (crizotinib, ceritinib, alectinib, brigatinib, lorlatinib, ensartinib) have received first-line treatment indication of advanced ALK+ NSCLC in various countries. In Ba/F3 cells, lorlatinib achieved lowest IC 50 among these 6 ALK TKIs against EML4-ALK variant 1 or 3. In 2022, 7 abstracts reported updated efficacy and safety data from CROWN. With a median follow-up time of 36.7 months, the 3-year progression-free survival (PFS) rate was 63.5% for lorlatinib-treated patients and the median PFS of lorlatinib still has not been reached. Importantly, post-lorlatinib treatment median PFS2 was 74.0% at 3-years. Lorlatinib-treated Asian patients achieved similar 3-year PFS rate as overall lorlatinib-treated patients. Median PFS was 33.3 months among lorlatinib-treated EML4-ALK v3 patients. CNS AE occurred fewer than 1 event per patient over the median follow-up time of 36.7 months and most resolved without intervention. Altogether these data affirm our belief that lorlatinib should be the treatment of choice of advanced ALK+ NSCLC. • At 36.7 months follow up time, 3-year PFS rate for lorlatinib was 63.5 % with median PFS not reached. • Post-lorlatinib progression treatment resulted in a 3-year PFS2 rate of 74 %. • Lorlatinib was efficacious (3-yr PFS rate = 61 %) and tolerable (5 % discontinuation) among Asians. • EML4-ALK variant 3 achieved a mPFS of 33 months on lorlatinib. • CNS adverse event was < 1 per patient over a median 36.7 months and 59 % resolved without intervention.