Amivantamab plus Chemotherapy for EGFR+ NSCLC After Osimertinib

Currently, patients with EGFR-mutant non–small-cell lung cancer (NSCLC) are generally treated with platinum-based chemotherapy after progression on osimertinib. Unfortunately, durations of response are short. In an effort to improve outcomes, researchers conducted an industry-funded, open-label, phase 3 trial in which 657 patients with progression on osimertinib were randomized to receive amivantamab plus lazertinib plus chemotherapy, chemotherapy alone, or amivantamab plus chemotherapy.

After excess hematologic toxicity was noted in the amivantamab-lazertinib-chemotherapy arm, lazertinib was started after the completion of chemotherapy. As the investigators thought amivantamab would not have significant central nervous system penetration, they considered it important to study lazertinib in this population.

Progression-free survival (PFS) — the primary endpoint — was longer in both the amivantamab-chemotherapy and amivantamab-lazertinib-chemotherapy arms compared with the chemotherapy arm (median, 6.3 and 8.3 vs. 4.2 months, respectively; hazard ratios, 0.48 and 0.44, respectively; P<0.001 for both). Objective response rates were higher in both amivantamab arms compared with chemotherapy alone (64% and 63% vs. 36%, respectively; P<0.001 for both). Of note, intracranial PFS was improved in the amivantamab arms compared to chemotherapy alone. There was a trend toward improved overall survival with amivantamab-chemotherapy but not with amivantamab-lazertinib-chemotherapy; however, follow-up for patients on the modified lazertinib arm was considerably shorter.

The most common adverse events in the amivantamab arms were hematologic, EGFR- and MET-related toxicities. Grade 3 or higher treatment-emergent adverse events were reported in 92% of patients on amivantamab-lazertinib-chemotherapy, 72% on amivantamab-chemotherapy, and 48% on chemotherapy alone. Treatment-related deaths were reported in 5%, 2%, and 1% respectively.