Efficacy of Brigatinib in Patients With Advanced Anaplastic Lymphoma Kinase-Positive Non-Small Cell Lung Cancer Who Progressed on Alectinib or Ceritinib: ALTA-2 Study

Introduction: Brigatinib is a potent next-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI) approved for treatment-naive and crizotinib-refractory advanced ALK+ non-small cell lung cancer (NSCLC). We evaluated brigatinib following other next-generation ALK TKIs. Methods: In this single-arm, phase 2, ALTA-2 trial (NCT03535740), patients with advanced ALK+ NSCLC whose disease progressed on alectinib or ceritinib received brigatinib 180 mg once daily (QD; after 7-day 90-mg lead-in). Primary endpoint was independent review committee (IRC)-assessed overall response rate (ORR). Circulating tumor DNA (ctDNA) was analyzed. Results: Among 103 patients (data cutoff: September 30, 2020; median follow-up [range]: 10.8 months [0.5-17.7]), confirmed IRC-ORR was 26.2% (95% CI: 18.0-35.8), median duration of response, 6.3 months (95% CI: 5.6-not reached [NR]), median progression-free survival (mPFS), 3.8 months (95% CI: 3.5-5.8). mPFS was 1.9 months (95% CI: 1.8-3.7) in patients with ctDNA-detectable baseline ALK fusion (n=64). Among 86 patients who progressed on alectinib, IRC-ORR was 29.1% (95% CI: 19.8-39.9); mPFS was 3.8 months (95% CI: 1.9-5.4). Resistance mutations were present in 33.3% (26/78) of baseline ctDNA; 14/26 (54%) mutations were G1202R; 52% (33/64) of patients with detectable ALK fusion had EML4-ALK variant 3. Most common all-grade treatment-related adverse events were increased creatine phosphokinase (32%) and diarrhea (27%). The mean dose intensity of brigatinib (180 mg QD) was 85.9%. Conclusion: In ALTA-2, brigatinib demonstrated limited activity in patients with ALK+ NSCLC post-ceritinib or post-alectinib therapy. Median PFS was longer with brigatinib in patients without baseline detectable plasma ALK fusion.