Dr William on First-Line EGFR-Mutant NSCLC in AMIGO-1

I think the most promising data coming out of AMIGO-1 is the subgroup analysis for those patients with TP53 co-mutations. These patients do really poorly, and when we compare the outcomes on AMIGO-1 with what was seen in MARIPOSA for the TP53 co-mutant population, we see an almost 20% improvement in 18-month PFS.

In an interview with OncLive during the IASLC 2026 World Conference on Lung Cancer (WCLC) in Seoul, William N. William Jr, MD, MSc, PhD, National Leader of Thoracic Oncology, Grupo Oncoclínicas, discussed the phase 2 AMIGO-1 trial of first-line amivantamab (Rybrevant), lazertinib (Lazcluze), and pemetrexed in EGFR-mutant non–small cell lung cancer (NSCLC).

William presented primary results from the single-arm AMIGO-1 trial (LACOG 0821; NCT05299125), which enrolled 54 patients with previously untreated recurrent or metastatic EGFR-mutant NSCLC in Brazil. The 18-month progression-free survival (PFS) rate was 66.7%, meeting the primary end point against a historical benchmark of approximately 50% with osimertinib (Tagrisso) monotherapy from the phase 3 FLAURA trial, and median PFS was 25.1 months at a median follow-up of 22.9 months. The trial was designed before data from FLAURA2 or MARIPOSA were available.

The regimen was originally planned as a four-drug combination with carboplatin, William said, but emerging data suggested the quadruplet would be less tolerable than pemetrexed alone, and pemetrexed can be given continuously and is highly active in adenocarcinoma, which made up the vast majority of enrolled histologies.

The rationale was added activity plus early elimination of clones that chemotherapy targets differently than the antibody and the TKI do. Post-treatment ctDNA data are pending, and he hopes patients with deep responses and ctDNA clearance will prove to be the ones with the most durable benefit, though longer follow-up is needed.

The regimen is highly active, William said, but toxicity required attention. The protocol was amended midway through to cap pemetrexed at 8 cycles, after which tolerability improved substantially. Any further study would aim to preserve the efficacy with a manageable toxicity profile, and would focus on patients with poor prognosis, where the balance of efficacy and toxicity favors intensification.

Response rate is a weak end point in EGFR-mutant disease because nearly all patients respond, William said, which is why the trial used 18-month PFS. Against the osimertinib benchmark, the improvement was clear; against FLAURA2 and MARIPOSA, an improvement was still seen but much smaller.

The strongest signal was in patients with TP53 co-mutations, in whom the triplet effectively compensated for the poor prognosis conferred by the co-mutation, with a nearly 20% improvement in 18-month PFS relative to the TP53 co-mutant population in MARIPOSA. Those are the patients who may warrant more intensification than is done today, he said, pending confirmation in larger datasets.

The standard of care remains FLAURA2 or MARIPOSA, and AMIGO-1 is not sufficient to change it, William said. The group is still deciding whether to run a randomized trial. If they do, it would enroll a poor-prognosis population. On sequencing, he noted that oncology has generally seen better results when the best regimens are given up front, and patients who progress on the triplet remain platinum-naive and have not received antibody-drug conjugates, so options at progression remain. Outside a clinical trial, he said, he would be very cautious about using the regimen.