PAPILLON: Frontline Amivantamab Plus Chemotherapy Yields 34.3-Month Median OS in EGFR Exon 20 Insertion–Positive NSCLC

First-line amivantamab-vmjw (Rybrevant) plus carboplatin and pemetrexed produced a median overall survival (OS) of 34.3 months (95% CI, 27.0 - 40.8) versuss 27.9 months (95% CI, 24.0 - 32.4) with lone chemotherapy in patients with previously untreated advanced non–small cell lung cancer (NSCLC) harboring EGFR exon 20 insertion mutations, according to the protocol-specified final OS analysis of the phase 3 PAPILLON trial (NCT04538664) presented at the IASLC 2026 World Conference on Lung Cancer (WCLC).¹

At a data cutoff of March 20, 2026, and a median follow-up of 48.6 months (range, 0.3 - 59.4), the difference was not statistically significant in the intention-to-treat (ITT) population (HR, 0.87; 95% CI, 0.66 - 1.14; P = .307). Investigators noted that 97 of 128 patients (76%) in the chemotherapy arm who discontinued because of progressive disease crossed over to second-line amivantamab monotherapy.

After adjustment for on-protocol crossover with the prespecified inverse probability of censoring weighting (IPCW) model, the median OS in the chemotherapy arm was 22.1 months (95% CI, 16.4 - 27.6), and amivantamab plus chemotherapy was associated with a 43% reduction in the risk of death (HR, 0.57; 95% CI, 0.35 - 0.77; nominal P = .002).

Median progression-free survival from randomization to second progression (PFS2) was 28.3 months (95% CI, 21.8 - 36.2) versus 17.5 months (95% CI, 15.2 - 21.0), respectively (HR, 0.59; 95% CI, 0.45 - 0.77; P < .0001).

"PAPILLON demonstrated the longest reported median overall survival to date in EGFR exon 20 insertion-positive advanced NSCLC with first-line amivantamab-chemotherapy," presenting author Chul Kim, MD, director of thoracic oncology at MedStar Georgetown University Hospital, said in a news release issued by the IASLC.² "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."

What Did PAPILLON Previously Establish?

EGFR exon 20 insertions account for approximately 5 - 12% of EGFR-mutated NSCLC, and before amivantamab, median real-world OS in this population was approximately 16 to 24 months. PAPILLON met its primary end point, with amivantamab plus chemotherapy reducing the risk of progression or death by 60% vs chemotherapy (HR, 0.40; P <.001), which supported the US Food and Drug Administration (FDA) approval of the combination in this setting in March 2024.

The frontline landscape for EGFR exon 20 insertion–positive disease continues to evolve. In August 2026, zipalertinib plus chemotherapy produced a statistically significant progression-free survival improvement versus chemotherapy alone at a planned interim analysis of a phase 3 trial,³ and oral TKIs are increasingly being weighed against amivantamab-based regimens in frontline sequencing decisions.⁴

How Was the PAPILLON Trial Designed?

The trial enrolled 308 treatment-naive patients with locally advanced or metastatic NSCLC, a documented EGFR exon 20 insertion, and an ECOG performance status of 0 - 1 between December 2020 and November 2022 across 24 countries. Patients with brain metastases were eligible if definitively treated, asymptomatic, and off corticosteroids for at least 2 weeks.

Patients were randomly assigned 1:1 to amivantamab 1400 mg (1750 mg if ≥80 kg) weekly for the first 4 weeks, then 1750 mg (2100 mg if ≥80 kg) every 3 weeks starting at week 7, plus carboplatin at AUC 5 for 4 cycles and pemetrexed at 500 mg/m² until progression (n = 153), or chemotherapy alone (n = 155).

Randomization was stratified by ECOG performance status and history of brain metastases. Patients in the chemotherapy arm could cross over to amivantamab monotherapy every 3 weeks after blinded independent central review–confirmed progression.

The primary end point was progression-free survival (PFS) by blinded independent central review. OS was a key secondary end point tested hierarchically after PFS and objective response rate, and the trial was estimated to have approximately 56% power to detect a statistically significant OS difference, with power further attenuated by crossover. Other prespecified end points included IPCW crossover-adjusted OS, PFS2, safety, and patient-reported outcomes.

At the data cutoff, 18 patients (12%) in the amivantamab arm remained on treatment versus none in the chemotherapy arm; 87 chemotherapy-arm patients crossed over on protocol and 10 received amivantamab off protocol. Among patients who received a first subsequent therapy, 97 of 129 in the chemotherapy arm received amivantamab, whereas 31 of 83 in the amivantamab arm received another EGFR-targeted or TKI-based regimen, including sunvozertinib (Zegfrovy), mobocertinib, and zipalertinib.

Investigators attributed the difference to the crossover design and the lack of active second-line options when the trial was conducted.

How Did OS Compare Across Subgroups and Sensitivity Analyses?

OS results generally favored amivantamab plus chemotherapy across predefined subgroups, although investigators cautioned that subgroup analyses were not part of hypothesis testing.

Hazard ratios were as follows for key demographics:

• 0.58 (95% CI, 0.40 - 0.84) in female patients versus 1.33 (95% CI, 0.88 - 2.01) in male patients
• 0.63 (95% CI, 0.44-0.91) in never-smokers versus 1.22 (95% CI, 0.81-1.85) in patients with a smoking history
• 0.82 (95% CI, 0.60-1.13) in patients without a history of brain metastases versus 0.97 (95% CI, 0.57-1.62) in those with
• 0.90 (95% CI, 0.63-1.28) in Asian versuss 0.74 (95% CI, 0.47 - 1.17) in non-Asian patients.

Landmark OS rates were 66% versus 58% at 2 years, and 47% versus 38% at 3 years.

Two additional crossover-adjustment models were consistent with IPCW: two-stage estimation yielded an HR of 0.54 (95% CI, 0.38 - 0.77), and rank-preserving structural failure time yielded an HR of 0.71 (95% CI, 0.37 - 1.36).

Time to treatment discontinuation was 14.1 versus 7.6 months (HR, 0.36; 95% CI, 0.28 - 0.46; P <.0001), and time to subsequent therapy was 16.9 versus 9.9 months (HR, 0.37; 95% CI, 0.29 - 0.48; P <.0001).

What Were the Safety and Patient-Reported Outcomes?

Median treatment duration was 13.4 months with amivantamab plus chemotherapy (n = 151) versus 6.9 months with chemotherapy (n = 155), and no new safety signals were identified. T

he most common any-grade adverse events (AEs) with the combination were paronychia (60%), neutropenia (60%), rash (58%), anemia (53%), hypoalbuminemia (46%), and infusion-related reactions (44%).

The most common grade ≥3 AEs were neutropenia (34% vs 23% with chemotherapy), rash (15% vs 0%), anemia (13% vs 13%), leukopenia (11% vs 3%), paronychia (10% vs 0%), and thrombocytopenia (10% vs 10%).

Investigators noted that the trial predated subcutaneous amivantamab and prophylactic strategies for dermatologic and infusion-related AEs.

Time to worsening on EORTC QLQ-C30 symptom scales favored the combination for nausea and vomiting (HR, 0.75; 95% CI, 0.58 - 0.98), pain (HR, 0.73; 95% CI, 0.56 - 0.96), dyspnea (HR, 0.68; 95% CI, 0.51 - 0.90), insomnia (HR, 0.69; 95% CI, 0.52 - 0.93), and diarrhea (HR, 0.72; 95% CI, 0.54 - 0.96). Time to symptomatic progression was 28.8 versus 22.4 months (HR, 0.77; 95% CI, 0.59 - 1.01; P = .055).

References

1. Kim C, Tang KJ, Cho BC, et al. First-line amivantamab-chemotherapy vs chemotherapy in NSCLC with EGFR exon 20 insertions: overall survival from PAPILLON. 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 PL03.03.
2. 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.
3. Zipalertinib Plus Chemotherapy Improves PFS in First-Line EGFR Exon 20 Insertion+ NSCLC. OncLive. Published August 13, 2026. Accessed September 14, 2026. https://www.onclive.com/view/zipalertinib-plus-chemotherapy-improves-pfs-in-first-line-egfr-exon-20-insertion-nsclc
4. Dr Raez on Oral Options Reshaping ROS1+, HER2-Mutant, and EGFR Exon 20+ NSCLC. OncLive. Published September 14, 2026. Accessed September 14, 2026. https://www.onclive.com/view/dr-raez-on-oral-options-reshaping-ros1-her2-mutant-and-egfr-exon-20-nsclc