CROWN study ctDNA analyses show off-target lorlatinib resistance

ctDNA Analysis Reveals Off-Target Resistance Pathways in First-Line Lorlatinib Treatment

Circulating tumor DNA (ctDNA) analyses from the phase III CROWN study presented at the 2026 European Society for Medical Oncology Congress in Madrid reveal that resistance to first-line lorlatinib in advanced ALK-positive non-small cell lung cancer appears largely off-target, OncLive reported. Baseline ALK rearrangements were detected by ctDNA in 59% of patients with baseline samples totaling 120 individuals. Paired baseline and post-progression samples across 17 patients demonstrated no new ALK resistance mutations at the end of treatment.

Instead, shifts in genomic alteration status point toward bypass mechanisms and alternative cancer-related pathways driving resistance. Among patients with paired samples, investigators observed alterations in DNA damage repair genes in 35% of cases, inflammatory-response genes such as AXL, MET, MYC, and ROS1 in 35%, and RTK/RAS/MAPK pathway genes in 35%. Oncogene amplification of MET, MYC, or NOTCH2 occurred in 29% of patients, tumor suppressor gene alterations in 29%, FLT1/VEGFR1 alterations in 18%, and HDAC6 alterations in 12%.

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. The inflammatory response also emerged as the predominant pathway linked to early progression at baseline, appearing in 32% of early progressors compared with just 7% of long-term responders.

Progression-Free Survival Across TP53 Status and EML4::ALK Variants

Lorlatinib extended progression-free survival (PFS) compared with crizotinib regardless of baseline TP53 status in the CROWN trial. In the crizotinib arm, median PFS reached 10.9 months with a 95% CI of 9.0 to 12.8 in patients with TP53 wild-type disease totaling 65 patients. For the 44 patients with TP53-mutated disease, median PFS was 7.2 months with a 95% CI of 5.6 to 9.3, yielding a hazard ratio of 0.78 and a 95% CI of 0.513 to 1.186.

PFS outcomes remained durable with lorlatinib across various EML4::ALK variants. Median PFS was not reached with a 95% CI of 26.0 to not reached for variants 1 and 2 in 25 patients, and reached 60.0 months with a 95% CI of 33.3 to not reached for variant 3 in 22 patients. Seven-year PFS rates stood at 52.7% with a 95% CI of 35.7% to 77.7% and 42.6% with a 95% CI of 24.1% to 75.4% for those respective groups, with a hazard ratio of 1.09 and a 95% CI of 0.463 to 2.579. In contrast, crizotinib yielded a median PFS of 7.4 months for variants 1 and 2 and 7.2 months for variant 3. Among lorlatinib-treated patients with variant 2 numbering 6 individuals, the objective response rate reached 100% and median PFS was not reached.

Next Steps for Identifying Early Progression Risk

Trial investigators concluded that baseline genomic complexity and inflammatory-response alterations may help identify patients at elevated risk of early progression. Methylation-based tumor fraction proved prognostic both at baseline and during treatment. Solomon noted that further work is required to precisely identify patients at early risk of progression to inform earlier therapeutic interventions, including treatment intensification. Overall survival follow-up in the CROWN study remains ongoing.

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