Researchers in Switzerland suggest a three-drug combination may be effective for patients with EGFR-mutant advanced non-small cell lung cancer (NSCLC) who progressed on a third-generation EGFR tyrosine kinase inhibitor (TKI), according to the results of their single-arm phase 2 trial.
MedPage Today reports that for patients receiving amivantamab (Rybrevant), lazertinib (Lazcluze), and bevacizumab, the 12-week objective response rate was 33% and the best overall response rate was 39%, meeting the study’s primary outcome, reported Rolf Stahel, MD, of the ETOP IBCSG Partners Foundation in Bern, Switzerland, and colleagues in Lancet Respiratory Medicine.
The median duration of response was 13.9 months, and the median progression-free survival (PFS) was 10.9 months. Updated data showed a median overall survival of 19.9 months with the chemotherapy-sparing triplet.
“This is the first prospective trial to explore a triplet biologic combination targeting the EGFR, MET, and angiogenic pathways, and provides preliminary evidence for the potential benefit of combined amivantamab, lazertinib, and bevacizumab in patients with EGFR-mutant advanced NSCLC with acquired resistance to third-generation EGFR TKIs,” Stahel and colleagues wrote.
They noted that third-generation EGFR TKIs such as osimertinib (Tagrisso) or lazertinib are standard first-line treatments for patients with advanced NSCLC harbouring common sensitising EGFR mutations. However, acquired resistance and disease progression are inevitable with these therapies.
Amivantamab, an EGFR and MET bispecific antibody, is approved in combination with lazertinib for the first-line treatment of these patients based on results from the phase III MARIPOSA trial, in which the combination improved PFS by about 7 months compared with single-agent osimertinib.
In addition, the phase III MARIPOSA-2 study showed that amivantamab with or without lazertinib plus standard second-line chemotherapy improved median PFS by about two to four months compared with chemotherapy in patients with EGFR-mutant advanced NSCLC who progressed after first-line osimertinib.
In an accompanying comment, Yun Fan, MD, PhD, of Zhejiang Cancer Hospital in Hangzhou, China, noted that the efficacy results in the current study “are, in several respects, encouraging”.
The median PFS and duration of response are among the longest reported in the setting of third-generation EGFR TKI resistance, Fan pointed out. “This durable efficacy suggests that a subgroup of patients could derive sustained benefit from simultaneous EGFR, MET, and VEGF inhibition.”
“However, the discordance between the modest objective response rate and the prolonged PFS raises important questions,” she wrote, suggesting that “without a randomised comparator, the favourable progression-free survival could equally reflect the enrolment of a lower-risk population”.
“Furthermore, the trial was statistically powered against a historical objective response rate of 20%, a benchmark derived from early amivantamab monotherapy data that appears outdated when contemporary platinum-based chemotherapy alone consistently leads to objective response rates between 27% and 43%, and combinations approved in the past two years surpass 50%,” she added.
The ETOP 18-21 AMAZE-lung trial enrolled 61 patients from 17 sites across Europe between March 2023 and May 2024. Median age was 65, 70% were women, and 82% were white. Most patients (61%) had never smoked, 62% had an Eastern Co-operative Oncology Group performance status score of 1, and 61% had stage IVB cancer.
The most commonly reported treatment-related adverse events (TRAEs) of any grade were infusion-related reactions (58%) and acneiform rash (50%). Grade 3-4 TRAEs occurred in 43% of patients, with serious TRAEs observed in 20%.
Treatment-related venous thromboembolism of any grade and grade 3-4 were reported in 17% and 3% of patients, respectively, which Fan suggested indicates a “substantial treatment burden” with this combination, considering most patients in the study received prophylactic anticoagulation.
TRAEs leading to treatment interruptions, dose reductions, and permanent discontinuations occurred in 67%, 37%, and 20% of patients, respectively. Discontinuation was attributed to amivantamab in 10% of patients, bevacizumab in 13%, and lazertinib in 5% (with some patients discontinuing more than one drug).
No treatment-related deaths were observed.
Stahel and colleagues noted that given the trial’s single-arm design, results should be interpreted with caution. Randomised studies are needed to support the findings, they added.
The study was funded by the ETOP IBCSG Partners Foundation and Janssen Pharmaceutica.
Study details
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
Ross Soo, Sanjay Popat, Urania Dafni et al.
Published in Lancet Respiratory Medicine on 5 October 2026
Summary
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.
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