Chemo-Free Regimen May Be Effective Option for EGFR-Mutant Lung Cancer

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 a single-arm phase II trial.

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 A. 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 study 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 harboring common sensitizing 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 2 to 4 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 randomized comparator, the favorable progression-free survival could equally reflect the enrollment 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 2 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 years, 70% were women, and 82% were white. Most patients (61%) had never smoked, 62% had an Eastern Cooperative 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. Randomized studies are needed to support the findings, they added.