Amivantamab-Chemotherapy Shows Longest OS Reported in EGFR Exon 20 NSCLC

According to updated results from the phase 3 PAPILLON trial (NCT04538664) presented at the 2026 World Conference on Lung Cancer, first-line amivantamab (Rybrevant) plus carboplatin-pemetrexed produced the longest median overall survival (OS) reported to date in patients with EGFR exon 20 insertion (Ex20ins)-positive advanced non–small cell lung cancer (NSCLC).¹

At a data cutoff of March 20, 2026, after a median follow-up of 48.6 months, the primary OS analysis showed a median OS of 34.3 months with amivantamab plus chemotherapy vs 27.9 months with chemotherapy alone, a numerical improvement of 6.4 months (HR, 0.87; 95% CI, 0.66-1.14; P = .307).¹ Investigators attributed the non-significant hazard ratio in part to extensive crossover: of 128 patients randomized to chemotherapy alone who discontinued for progressive disease, 97 (76%) went on to receive second-line amivantamab monotherapy. An exploratory analysis adjusted for crossover using inverse probability of censoring weighting (IPCW) showed a more pronounced OS benefit with amivantamab-chemotherapy (HR, 0.57; 95% CI, 0.39-0.82; nominal P = .003).

Study Design

PAPILLON is a randomized, open-label, phase 3 trial that enrolled 308 patients with previously untreated, locally advanced or metastatic, EGFR Ex20ins-mutated, nonsquamous NSCLC.² Patients were randomized in a 1:1 ratio to amivantamab plus carboplatin-pemetrexed (n = 153) or carboplatin-pemetrexed alone (n = 155).^1,2 The trial's primary end point was progression-free survival by blinded independent central review; OS was a key secondary end point.² EGFR exon 20 insertions account for approximately 12% of EGFR-mutated NSCLC, a population that has historically had limited targeted treatment options and has relied on platinum-based chemotherapy as first-line standard of care.¹

PAPILLON's primary PFS analysis supported the FDA's March 2024 approval of amivantamab plus carboplatin-pemetrexed as a first-line option for this population; the updated OS data reported here mark the trial's longest-follow-up survival analysis to date.²

Patient-reported outcomes favored the amivantamab-chemotherapy arm, with prolonged time to worsening observed across key symptom scales compared with chemotherapy alone. The safety profile reported with this update was consistent with prior reports of intravenous amivantamab collected before the introduction of the subcutaneous formulation and prophylactic strategies now used to manage treatment-related adverse events.

Clinical Context and Limitations

Investigators cautioned that the unadjusted OS analysis did not meet statistical significance, a result they linked to the high rate of crossover among patients initially randomized to chemotherapy alone. The IPCW-adjusted analysis, while supportive of a survival benefit, relies on a nonrandomized comparison and should be considered hypothesis-generating rather than confirmatory.¹ The findings were presented at the International Association for the Study of Lung Cancer 2026 World Conference on Lung Cancer, held in Seoul, Republic of Korea.

“PAPILLON demonstrated the longest reported median overall survival to date in EGFR exon 20 insertion-positive advanced NSCLC with first-line amivantamab-chemotherapy. While crossover likely attenuated the hazard-ratio-based overall survival estimate, the adjusted analysis showed a substantially longer estimated survival benefit, supporting amivantamab-chemotherapy as a foundational first-line regimen for patients with Ex20ins advanced NSCLC,” Chul Kim, MD, Division of Hematology and Oncology, Georgetown Cancer Institute, Washington, DC, said in a news release.

REFERENCES

1. In the PAPILLON study, first-line amivantamab-chemotherapy demonstrates the longest overall survival reported for EGFR exon 20 insertion-positive advanced NSCLC. News release. International Association for the Study of Lung Cancer. September 14, 2026. Accessed September 14, 2026. https://tinyurl.com/ytyh5y4y

2. A randomized, open-label phase 3 study of combination amivantamab and carboplatin-pemetrexed therapy, compared with carboplatin-pemetrexed, in patients with EGFR exon 20ins mutated locally advanced or metastatic non-small cell lung cancer (PAPILLON). ClinicalTrials.gov. Accessed September 14, 2026. https://clinicaltrials.gov/study/NCT04538664