Combined amivantamab, lazertinib, and bevacizumab in patients with EGFR-mutant advanced non-small-cell lung cancer with acquired resistance to a third-generation EGFR tyrosine-kinase inhibitor (ETOP 18-21 AMAZE-lung): a prospective, international, multicentre, single-arm, phase 2 trial.

Background

MET and angiogenic pathways are activated in EGFR-mutant non-small-cell lung cancer (NSCLC) upon resistance to tyrosine-kinase inhibitors (TKIs). Amivantamab, an EGFR and MET bispecific antibody, is approved in combination with chemotherapy for EGFR-mutant NSCLC post-osimertinib progression based on results of the MARIPOSA-2 trial. We assessed the activity and safety of combined amivantanab, lazertinib, and bevacizumab-a chemotherapy-sparing strategy-for patients with EGFR-mutant NSCLC and acquired resistance to a third-generation EGFR TKI.

Methods

ETOP 18-21 AMAZE-lung was a prospective, international, multicentre, single-arm, phase 2 trial. Adults (aged ≥18 years) with advanced stage, pathologically confirmed non-squamous NSCLC harbouring a sensitising EGFR mutation (exon 19 deletion or exon 21 L858R, or both) with disease progression following treatment with a third-generation EGFR TKI (osimertinib or lazertinib) given in the first-line or second-line setting were included. Patients received intravenous amivantamab at a fixed dose of 1400 mg or 1750 mg (if bodyweight ≥80 kg) every 3 weeks for two cycles, then 1750 mg or 2100 mg (if bodyweight ≥80 kg) every 3 weeks from cycle three; oral lazertinib at a daily dose of 240 mg; and bevacizumab at a dose of 15 mg per kg every 3 weeks. Treatment was given until progression or intolerable toxicity. The primary outcome was 12-week objective response rate (defined by Response Evaluation Criteria in Solid Tumours version 1.1), evaluated in the first 60 patients enrolled (intention-to-treat population). To reject an objective response rate of 20% or less versus 40%, at least 19 responses needed to be observed (2·2% significance level with 93% power). Safety was evaluated in terms of any-cause adverse events and treatment-related adverse events (TRAEs) graded according to Common Terminology Criteria for Adverse Events version 5.0, assessed in all enrolled patients who received at least one dose of trial treatment. The trial is registered on ClinicalTrials.gov (NCT05601973) and in the European Medicines Agency's Clinical Trials Information System (EU CT number 2021-002337-42); the primary analysis is complete but follow-up for patients on treatment is ongoing.

Findings

Between March 27, 2023, and May 21, 2024, 61 patients were enrolled from 17 sites in Europe. Median age was 65 years (IQR 61-70), and most patients were female (43 [70%]) and White (50 [82%]). 37 (61%) patients had never smoked, 38 (62%) had Eastern Cooperative Oncology Group performance status 1, and 37 (61%) had stage IVB cancer. All tumours were of adenocarcinoma histology and 18 (30%) patients had asymptomatic brain metastases at screening. At the time of the primary analysis (database cutoff Aug 26, 2024), median follow-up was 9·0 months (IQR 5·8-12·6) and 28 patients were still receiving the treatment combination. Objective response by 12 weeks was shown for 20 patients among the first 60 enrolled (objective response rate 33% [95·6% CI 21-47]), successfully rejecting an objective response rate of 20% or less. Overall, 24 of 61 (39% [95% CI 27-53]) patients showed partial response (22 confirmed at subsequent tumour evaluation). The most commonly reported TRAEs of any grade were infusion-related reaction (35 [58%] of 60 patients) and acneiform rash (30 [50%] of 60 patients). Treatment-related venous thromboembolism of any grade and grade 3-4 was reported in ten (17%) and two (3%) patients, respectively. No treatment-related deaths were observed. Grade 3-4 TRAEs occurred in 26 (43%) of 60 patients, with serious TRAEs observed in 12 (20%) of 60 patients.

Interpretation

Combined amivantamab, lazertinib, and bevacizumab showed durable anti-tumour activity, representing a promising chemotherapy-sparing alternative after progression on third-generation EGFR TKIs. Safety was consistent with known toxicity profiles.

Funding

The ETOP IBCSG Partners Foundation and Janssen Pharmaceutica.