Phase 2 trial of amivantamab-lazertinib-bevacizumab for EGFR-mutant aNSCLC with acquired resistance to third-generation EGFR-TKI

MET and angiogenic pathways are activated in EGFR-mutant non-small cell lung cancer (NSCLC) upon resistance to TKIs. The EGFR and MET bispecific antibody amivantamab is approved in combination with chemotherapy for EGFR-mutant NSCLC post-osimertinib progression. The multinational phase 2 ETOP 18-21 AMAZE-lung trial evaluated the combination of amivantamab with lazertinib and bevacizumab as a chemotherapy-sparing strategy for EGFR-mutant (exon 19 del or exon 21 L858R, or both) advanced NSCLC with required resistance to a third-generation EGFR TKI. The primary outcome was 12-week objective response rate (ORR) among the first 60 patients. A total of 61 patients were enrolled from 17 sites in Europe (median age 65 years; IQR 61-70; 70% female; 61% never smoked; 62% ECOG performance status 1; 61% stage IVB cancer; 30% with asymptomatic brain metastases at screening). At the time of the primary analysis, median follow-up was 9.0 months (IQR 5.8-12.6) and 28 patients were still receiving study treatment. Twelve-week ORR was 33% (95.6% CI 21-47), successfully rejecting an ORR of 20% or less. Overall 24 of 61 patients showed partial response (39%; 95% CI 27-53), with 22 confirmed at subsequent tumor evaluation. The most common treatment-emergent adverse events (TRAEs) of any grade were infusion-related reaction (58% of patients) and acneiform rash (50%). Grade 3-4 TRAEs occurred in 43%, with serious TRAEs in 20%. Treatment-related venous thromboembolism of any grade and grade 3-4 were reported in 17% and 3%, respectively. No treatment-related deaths were observed. The authors conclude that the study treatment represents a promising chemotherapy-sparing alternative after progression on third-generation EGFR TKIs.