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

September 16, 2026 | OncLive Staff

Key Takeaways

• A Brazilian multicenter, single-arm phase 2 design tested amivantamab/lazertinib plus pemetrexed, with an amended cap of 8 pemetrexed cycles after safety review.
• Efficacy signals were strong: 66.7% 18-month PFS, 25.1-month median PFS, and 85% ORR, with median DoR not reached.
• Baseline brain metastases were associated with inferior exploratory 18-month PFS (60.9% vs 72.0%) and higher hazard, whereas exon 19 del modestly outperformed L858R.
• High-risk biology appeared less detrimental: TP53 alteration and baseline EGFR-mutant ctDNA detection showed similar 18-month PFS, comparing favorably with reported MARIPOSA subgroup rates.
• Safety burden was high, driven by dermatologic/mucosal EGFR effects, MET-related hypoalbuminemia/edema, and significant myelosuppression; treatment-related grade 5 events ceased after pemetrexed limitation.

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.

AMIGO-1 Trial Takeaways

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

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.

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

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

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

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

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

March 26, 2026 | Kyle Doherty

The addition of local consolidative therapy (LCT) to osimertinib (Tagrisso) significantly prolonged progression-free survival (PFS) compared with osimertinib monotherapy in patients with EGFR-mutated non–small cell lung cancer (NSCLC), according to findings from a secondary analysis of the phase 2 NorthStar trial (NCT03410043) presented during the 2026 European Lung Cancer Congress.¹ Moreover, consolidative radiotherapy led to excellent local control rates, with disease recurrence primarily occurring outside of the radiotherapy field at new distant metastatic sites.

Prior data from NorthStar presented during the 2025 ESMO Congress showed that patients who received LCT plus osimertinib (n = 56) achieved a median PFS of 25.3 months (95% CI, 19.4-45.0) compared with 17.5 months (95% CI, 14.5-24.4) among patients who received osimertinib monotherapy (n = 63; HR, 0.66; 95% CI, 0.50-0.87; 1-sided log-rank P = .025).²

Findings from the secondary analysis revealed that patients who received radiation BED therapy at a minimum dose of 75 Gy (n = 14) achieved a median PFS of 49.1 months (95% CI, 21.6-not estimable [NE]) vs 22.3 months (95% CI, 11.6-39.7) among those who received radiation BED therapy at less than 75 Gy (n = 16; HR, 0.31; 95% CI, 0.14-0.70; P = .006).¹

“[The] addition of LCT to osimertinib prolonged PFS [and] post-induction clearance of thoracic nodes, as well as pleural effusion, were potential predictors of benefit from LCT,” Saumil N. Gandhi, MD, PhD, an associate professor in the Department of Radiation Oncology, Division of Radiation Oncology, at The University of Texas MD Anderson Cancer Center in Houston, said during the presentation.

How was the secondary analysis of NorthStar designed?

NorthStar was a randomized, multicenter trial that enrolled patients with locally advanced or metastatic NSCLC.² Other key enrollment criteria included having an ECOG performance status of 0 or 1, measurable disease, and TKI-naive EGFR exon 19 deleted or L858R-mutated disease or acquired T790-mutated disease without receiving a prior third-generation TKI.

Patients were randomly assigned 1:1 to receive osimertinib or osimertinib plus LCT; both arms received 6 to 12 weeks of osimertinib induction therapy. The primary end point was PFS. Key secondary end points included safety, overall survival, PFS in patients with at least 3 metastatic sites, and PFS in TKI-naive patients.

The real-world, secondary analysis of NorthStar sought to elucidate how safe and effective radiation therapy can be delivered in this patient population; which patients derive the greatest benefit from LCT after induction osimertinib; and where patients fail following LCT.

At baseline, patients included in the secondary analysis had oligometastatic (n = 35) or polymetastatic (n = 84) disease. After induction therapy, patients had oligometastatic (n = 35), induced oligometastatic (n = 15), or polymetastatic (n = 69) disease. Fifty-six patients were randomly assigned to receive LCT; 100%, 71%, and 56% of patients with oligometastatic, induced oligometastatic, or polymetastatic disease, respectively, completed LCT.

What other data were shared from the secondary analysis?

Assessment of potential predictors of benefit with this approach revealed that nodal clearance following induction osimertinib was associated with improved outcomes after osimertinib plus radiation therapy. Specifically, patients with present nodes (n = 18) achieved a median PFS of 22.3 months (95% CI, 11.6-27.9) compared with 49.1 months (95% CI, 21.6-NE) among those with absent nodes (n = 12; HR, 0.34; 90% CI, 0.15-0.76; P = .011). Patients with thoracic nodes present at random assignment who received osimertinib plus LCT (n = 34) and osimertinib monotherapy (n = 34) experienced a median PFS of 19.0 months (95% CI, 12.6-23.2) and 15.9 months (95% CI, 10.9-23.9), respectively (HR, 0.93; 90% CI, 0.60-1.43; P = .388). Patients in the combination (n = 22) and monotherapy (n = 28) arms who had absent thoracic nodes at random assignment had a median PFS of 41.5 months (95% CI, 31.2-NE) and 19.6 months (95% CI, 9.1-31.5), respectively (HR, 0.43; 95% CI, 0.23-0.78; P = .008).

Pleural effusion clearance after induction osimertinib was also found to be predictive of a benefit with LCT. Patients in the combination (n = 17) and monotherapy (n = 26) arms who had a pleural effusion present at random assignment experienced a median PFS of 15.3 months (95% CI, 11.6-23.9) and 12.9 months (95% CI, 8.5-20.9), respectively (HR, 0.90; 90% CI, 0.52-1.55; P = .373). Comparatively, the median PFS values were 32.7 months (95% CI, 19.7-48.2) and 22.3 months (95% CI, 14.5-28.1) in the combination (n = 37) and monotherapy (n = 36) among patients who did not have a pleural effusion at random assignment (HR, 0.63; 90% CI, 0.39-1.02; P = .057).

“We [also] found that that [approximately] 20% of patients had local, regional-only recurrence as their first site of recurrence, but the recurrences were predominantly distant, as one might expect,” Gandhi added. “In fact, when these recurrences happen, they tended to happen at new sites that were never involved at baseline or at presentation in the patients [who] received radiation. Radiation provided excellent local control [rates] over 90% with the vast majority of patients failing outside the prior radiation field, and the most common sites of recurrences were [the] lung, bone, and the central nervous system.”

In terms of safety, patients in the radiation cohort experienced grade 1 pneumonitis (2.3%), esophagitis (7.1%), and dyspnea (28.5%), These events occurred at grade 2 severity at respective rates of 11.9%, 2.3%, and 2.3%. Grade 3 pneumonitis was reported in 2.3% of patients.

Disclosures: Gandhi received research support from and serves on the scientific advisory board for Johnson & Johnson. He also received research grants from Nanobiotix Inc, Takeda Pharmaceuticals, and AstraZeneca.

References

Gandhi SN, Chang E, Antonoff MB, et al. Predictors of benefit from local consolidative therapy and patterns of failure for metastatic EGFR-mutant NSCLC: a secondary analysis of NorthStar, a randomized phase II clinical trial. Presented at: 2026 European Lung Cancer Congress; March 25-28, 2026; Copenhagen, Denmark. Abstract LBA3.

Elamin YY, Gandhi S, Antonoff M, et al. NorthStar: a phase II randomized study of osimertinib (OSI) with or without local consolidative therapy (LCT) for metastatic EGFR-mutant non-small cell lung cancer (NSCLC). Ann Oncol. 2025;36(suppl 2):S1614. doi:10.1016/j.annonc.2025.09.086