Which lorlatinib resistance mechanisms did ctDNA reveal in ALK-positive NSCLC?<\/p>\n
Baseline ALK rearrangements were detected by ctDNA in 59% of patients with baseline samples (n = 120). Paired baseline and post-progression samples (n = 17) revealed no new ALK resistance mutations at the end of treatment. Instead, changes in genomic alteration status suggested that resistance may be driven by bypass mechanisms and other cancer-related pathways, with no dominant pathway identified.<\/p>\n
Among patients with paired samples, alterations were observed in DNA damage repair genes (35%), inflammatory-response genes such as AXL, MET, MYC, and ROS1 (35%), RTK\/RAS\/MAPK pathway genes (35%), oncogene amplification of MET, MYC, or NOTCH2 (29%), tumor suppressor genes (29%), FLT1\/VEGFR1 (18%), and HDAC6 (12%). <\/p>\n
Inflammatory response was also the predominant pathway associated with early progression at baseline, observed in 32% of early progressors vs 7% of long-term responders. Ahead of the meeting, Dylan Fortman, MD, a hematology\/oncology fellow at the University of Michigan Medical School, noted that resistance to first-line lorlatinib appears to be largely off-target.<\/a>4<\/p>\n Did EML4::ALK variant or TP53 status affect PFS with lorlatinib vs crizotinib in CROWN?<\/p>\n Lorlatinib prolonged PFS vs crizotinib regardless of baseline TP53 status; in the crizotinib arm, median PFS was 10.9 months (95% CI, 9.0-12.8) in patients with TP53 wild-type disease (n = 65) and 7.2 months (95% CI, 5.6-9.3) in those with TP53-mutated disease (n = 44; HR, 0.78; 95% CI, 0.513-1.186).1<\/p>\n PFS with lorlatinib was durable across EML4::ALK variants. Median PFS was NR (95% CI, 26.0-NR) with variants 1\/2 (n = 25) and 60.0 months (95% CI, 33.3-NR) with variant 3 (n = 22), with 7-year PFS rates of 52.7% (95% CI, 35.7%-77.7%) and 42.6% (95% CI, 24.1%-75.4%), respectively (HR, 1.09; 95% CI, 0.463-2.579). With crizotinib, median PFS was 7.4 months (95% CI, 3.7-9.3) and 7.2 months (95% CI, 5.4-9.3), respectively. Among lorlatinib-treated patients with variant 2 (n = 6), the objective response rate was 100% and median PFS was NR.<\/p>\n Next steps for identifying early progression risk with lorlatinib<\/p>\n The investigators concluded that baseline genomic complexity and inflammatory-response alterations may help identify patients at risk of early progression, and that methylation-based tumor fraction was prognostic both at baseline and on treatment. <\/p>\n Solomon noted that further work is needed to more precisely identify patients at early risk of progression to inform earlier therapeutic interventions, including treatment intensification. Overall survival follow-up in CROWN is ongoing.2<\/p>\n Disclosures: Solomon reported serving in consulting or advisory roles with Amgen, AstraZeneca, BeiGene, Bristol Myers Squibb, D3 Bio, GlaxoSmithKline, Johnson & Johnson\/Janssen, Lilly, MSD, Nuvalent, Pfizer, Revolution Medicine, Roche\/Genentech, and Takeda; and receiving honoraria from Amgen, AstraZeneca, MSD, Pfizer, and Roche\/Genentech.<\/p>\n ReferencesSolomon BJ, Mok TSK, Wang IM, et al. Characterizing resistance mechanisms and predictors of early progression and long-term response to lorlatinib: ctDNA analyses from the CROWN study. Presented at: 2026 European Society for Medical Oncology Congress; October 23-27, 2026; Madrid, Spain. Abstract 2636RO.Shaw AT, Solomon BJ, Felip E, et al. Lorlatinib versus crizotinib as first-line treatment for advanced ALK-positive non-small-cell lung cancer: 7-year update from the phase III CROWN study. Ann Oncol. 2026;37(9):1242-1252. doi:10.1016\/j.annonc.2026.05.692Solomon BJ, Liu G, Felip E, et al. Lorlatinib versus crizotinib in patients with advanced ALK-positive non-small cell lung cancer: 5-year outcomes from the phase III CROWN study. J Clin Oncol. 2024;42(29):3400-3409. doi:10.1200\/JCO.24.00581Stay Ahead of ESMO 2026: See What Lung Cancer Experts Are Prioritizing. OncLive. Published October 15, 2026. Accessed October 24, 2026. https:\/\/www.onclive.com\/view\/stay-ahead-of-esmo-2026-see-what-lung-cancer-experts-are-prioritizing<\/a> <\/p>\n","protected":false},"excerpt":{"rendered":"Which lorlatinib resistance mechanisms did ctDNA reveal in ALK-positive NSCLC? 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