AMIGO-1 Trial Meets 18-Month PFS End Point With Frontline Amivantamab Triplet in EGFR+ NSCLC

First-line amivantamab-vmjw (Rybrevant), lazertinib (Lazcluze), and pemetrexed produced an 18-month progression-free survival (PFS) rate of 66.7% (80% CI, 57.5%-74.4%) in patients with recurrent or metastatic EGFR-mutant non–small cell lung cancer (NSCLC), meeting the primary end point of the phase 2 AMIGO-1 trial (LACOG 0821; NCT05299125), according to data presented at the International Association for the Study of Lung Cancer (IASLC) 2026 World Conference on Lung Cancer (WCLC).¹

At a median follow-up of 22.9 months (IQR, 21.4-23.8), the median PFS was 25.1 months (80% CI, 20.2-not estimable [NE]), with 21 of 54 patients (39%) experiencing a PFS event. The 18-month PFS rate significantly exceeded the historical benchmark of approximately 50% achieved with osimertinib (Tagrisso) monotherapy in the phase 3 FLAURA trial (NCT02296125; P = .0045), the threshold against which the single-arm study was statistically powered.²

How was the AMIGO-1 trial designed?

AMIGO-1 is a multicenter, single-arm, phase 2 trial conducted at 13 Brazilian sites that enrolled 54 patients with treatment-naive, recurrent or metastatic NSCLC harboring an EGFR exon 19 deletion (61%) or exon 21 L858R mutation (39%); patients with asymptomatic or previously treated, stable brain metastases were eligible, and 43% of patients had brain metastases at baseline. The study was designed before results from the phase 3 MARIPOSA trial (NCT04487080), which reported an approximately 60% 18-month PFS rate with amivantamab plus lazertinib alone, were available, and tested whether adding pemetrexed to that doublet could further improve outcomes.³

Patients received amivantamab and lazertinib per the MARIPOSA dosing schedule, plus pemetrexed 500 mg/m² on day 1 of each 21-day cycle; a March 2025 protocol amendment, following a planned safety review, capped pemetrexed at 8 cycles. The primary end point was the 18-month PFS rate, with OS and ORR as secondary end points; the trial was powered to detect a difference between a null 18-month PFS rate of 50% and an alternative rate of 65%.

What did the efficacy and survival findings show?

The confirmed ORR was 85% (n = 46 of 54), including complete responses in 2 patients (4%) and partial responses in 44 (81%); 7 patients (13%) had stable disease and 1 (2%) was not evaluable. Median duration of response was not reached ([NR] 95% CI, 23.6-NR).

At 18 months, the OS rate was 74.3% (80% CI, 65.4%-81.3%; 13 deaths), median OS was not reached, and the lung cancer–specific survival rate was 91.1% (80% CI, 83.8%-95.2%; 4 lung cancer deaths). The 18-month time-to-progression rate was 80.3% (80% CI, 71.4%-86.7%), and the 18-month cumulative incidence of progression, with death as a competing risk, was 17.6% (80% CI, 11.3%-25.0%). Median treatment duration was 19.9 months (IQR, 13.8-24.1), including 11.5 months (IQR, 6.5-14.1) of pemetrexed, 19.9 months (IQR, 13.8-24.1) of lazertinib, and 12.9 months (IQR, 7.6-17.3) of amivantamab.

How did outcomes vary across key subgroups?

Exploratory 18-month PFS rates were numerically higher among patients with an EGFR exon 19 deletion (70.8%; 80% CI, 58.7%-79.9%) vs L858R (60.0%; 80% CI, 44.6%-72.4%; HR, 0.81; 80% CI, 0.46-1.42) and among those without baseline brain metastases (72.0%; 80% CI, 59.5%-81.2%) vs those with brain metastases (60.9%; 80% CI, 46.6%-72.4%; HR, 2.00; 80% CI, 1.12-3.56). Rates were similar regardless of TP53 co-mutation status (69.6% altered vs 66.9% not altered; HR, 0.63; 80% CI, 0.34-1.18) and baseline EGFR-mutant ctDNA detection on FoundationOne Liquid testing (68.0% detected vs 68.2% not detected; HR, 0.82; 80% CI, 0.44-1.53).

Investigators noted that outcomes in the poor-prognostic TP53-altered and ctDNA-detected subgroups compared favorably with historical rates reported for amivantamab plus lazertinib alone in MARIPOSA subgroup analyses (48.0% and 54.4%, respectively).⁴ Related chemotherapy-intensification strategies with EGFR-directed therapy, including by baseline TP53 status, have also been reported with osimertinib plus platinum-pemetrexed in the phase 3 FLAURA2 trial (NCT04035486),⁵ while amivantamab-based combinations with chemotherapy have shown durable benefit in other EGFR-altered NSCLC populations, including a 34.3-month median OS with frontline amivantamab plus chemotherapy in EGFR exon 20 insertion–positive disease in the phase 3 PAPILLON trial (NCT04538664).⁶

What did the safety analysis show?

The most common treatment-related adverse effects (TRAEs) linked to EGFR inhibition were paronychia (81%; grade 3, 15%), rash (65%; grade 3, 26%), stomatitis (54%; grade 3, 9%), and diarrhea (41%; grade 3, 6%); those linked to MET inhibition included hypoalbuminemia (80%; grade 3, 17%) and peripheral edema (33%; grade 3, 4%). Chemotherapy-related AEs included neutropenia (63%; grade 3, 31%; grade 4, 20%; febrile neutropenia, 11%), anemia (54%; grade 3, 19%; grade 4, 2%), and thrombocytopenia (44%; grade 3, 7%; grade 4, 7%). Infusion-related reactions occurred in 50% of patients and venous thromboembolism in 15% (grade 3, 2%).

Grade 5 AEs occurred in 9 patients (17%); 6 (11%) were treatment related (5 infections, 1 pancreatitis) and 3 (6%) were not (2 infections, 1 aortic stenosis). After the March 2025 amendment capping pemetrexed at 8 cycles, no further treatment-related deaths occurred. Investigators concluded that toxicity may have limited the regimen's overall benefit but could potentially be mitigated by pemetrexed dose adjustments and contemporary prophylactic measures, and that further evaluation of the modified regimen may be warranted, particularly among patients with poor prognostic features such as TP53 co-mutations.

References

1. William WN Jr, da Silva FAF, Gelatti ACZ, et al. A single-arm phase 2 study of first-line amivantamab, lazertinib, pemetrexed in EGFR-mutant NSCLC: AMIGO-1 (LACOG 0821). Presented at: International Association for the Study of Lung Cancer (IASLC) 2026 World Conference on Lung Cancer; September 12-15, 2026; Seoul, South Korea. Abstract OA12.04.
2. Ramalingam SS, Vansteenkiste J, Planchard D, et al. Overall survival with osimertinib in untreated, EGFR-mutated advanced NSCLC. N Engl J Med. 2020;382(1):41-50. doi:10.1056/NEJMoa1913662
3. Cho BC, Lu S, Felip E, et al. Amivantamab plus lazertinib in previously untreated EGFR-mutated advanced NSCLC. N Engl J Med. 2024;391(16):1486-1498. doi:10.1056/NEJMoa2403614
4. Felip E, Cho BC, Gutiérrez V, et al. Amivantamab plus lazertinib vs osimertinib in first-line EGFR-mutant advanced non-small cell lung cancer (NSCLC) with biomarkers of high-risk disease: a secondary analysis from the phase 3 MARIPOSA study. J Clin Oncol. 2024;42(suppl 16):8504. doi:10.1200/JCO.2024.42.16_suppl.8504
5. FLAURA2 data show osimertinib-chemotherapy benefit holds regardless of baseline TP53 status in EGFR+ NSCLC. OncLive. Published September 15, 2026. Accessed September 16, 2026. https://www.onclive.com/view/flaura2-data-show-osimertinib-chemotherapy-benefit-holds-regardless-of-baseline-tp53-status-in-egfr-nsclc
6. PAPILLON: frontline amivantamab plus chemotherapy yields 34.3-month median OS in EGFR exon 20 insertion–positive NSCLC. OncLive. Published September 13, 2026. Accessed September 16, 2026. https://www.onclive.com/view/frontline-amivantamab-chemotherapy-34-3-month-median-os-egfr-exon-20-insertion-nsclc-papillon