Activity of Brigatinib in Patients With Crizotinib-Resistant ALK-positive Non-Small-Cell Lung Cancer According to ALK Fusion and Mutation Status.

BACKGROUND

Brigatinib, a selective ALK inhibitor, demonstrated preclinical activity against a range of crizotinib-resistant ALK alterations in NSCLC. We examined associations between brigatinib efficacy and tumor- and plasma-detected driver mutations in crizotinib-resistant ALK fusion-positive NSCLC.

PATIENTS AND

METHODS

Tumor tissue and plasma circulating tumor DNA (ctDNA) from patients with crizotinib-exposed ALK-positive NSCLC receiving brigatinib in phase 1/2 and phase 2 ALTA trials were analyzed by next-generation sequencing. Objective response rate (ORR) and progression-free survival (PFS) were assessed by mutation status.

RESULTS

Ninety-three patients were molecularly profiled at baseline (tumor, 26; ctDNA, 59; 8 with both). Patients received a range of doses, most commonly 90 mg QD. For patients with baseline tumor samples, ORR was 78% (7/9) and median PFS was 11.1 months in patients with secondary ALK mutations co-occurring with ALK fusion, compared with 89% (17/19) and 12.9 months, respectively, in those without ALK mutations. For patients with ctDNA-detectable ALK fusion, ORR was 60% (6/10) and median PFS was 9.2 months in those with secondary ALK mutations, and 50% (10/20) and 21.4 months, respectively, without secondary ALK mutations. The 1 patient with baseline G1202R responded. Six patients had baseline alterations in non-ALK secondary drivers (EGFR, KRAS, NRAS, BRAF, MET); none had response. Emergent G1202R was noted in 3 patients and ALK amplification in 3 patients.

CONCLUSION

Brigatinib showed substantial activity in crizotinib-pretreated ALK-positive NSCLC with ALK-dependent mechanisms of resistance. Patients with non-ALK canonical drivers did not respond to brigatinib, suggesting alternative therapeutic approaches in that cohort.