Clinical Summary:

• Design/Population: The phase 3 PAPILLON trial randomized patients with previously untreated, advanced EGFR exon 20 insertion-mutated non-small cell lung cancer (NSCLC) to receive either amivantamab plus carboplatin and pemetrexed or chemotherapy alone. Overall survival (OS) was a key secondary end point, with prespecified analyses adjusting for crossover. 
• Key Outcomes: At final OS analysis, amivantamab plus chemotherapy numerically prolonged OS, although the unadjusted difference was not statistically significant. Most patients in the chemotherapy arm who discontinued due to progression subsequently received amivantamab, and the prespecified crossover-adjusted analysis showed a greater estimated OS benefit with first-line amivantamab plus chemotherapy. 
• Clinical Relevance: These long-term findings reinforce amivantamab plus chemotherapy for EGFR exon 20 insertion-mutated NSCLC while demonstrating the impact of extensive crossover on the unadjusted OS comparison.Patient-reported outcomes also favored the combination across several symptom measures.

Final overall survival (OS) results from the phase 3 PAPILLON trial demonstrated numerically longer survival with first-line amivantamab plus carboplatin and pemetrexed compared with chemotherapy alone in patients with advanced non-small cell lung cancer (NSCLC) harboring EGFR exon 20 insertion mutations. 

These results were presented in a plenary session at the World Conference on Lung Cancer by Chul Kim, MD, MedStar Georgetown University Hospital, Washington, DC. 

In this trial, 308 previously untreated patients were randomized 1:1 to receive either amivantamab plus carboplatin and pemetrexed (n = 153) or chemotherapy alone (n = 155). Patients assigned to chemotherapy were permitted to cross over to second-line amivantamab monotherapy following disease progression confirmed by blinded independent central review. 

The protocol-specified analysis evaluated OS as a key secondary end point after approximately 210 deaths had occurred across the treatment groups. Prespecified crossover-adjusted OS analyses were also conducted.

At a median follow-up of 48.6 months, median OS was 34.3 months in the amivantamab arm and 27.9 months in the chemotherapy arm, representing a numerical improvement of more than 6 months. The unadjusted analysis showed a 13% reduction in the risk of death with the combination (hazard ratio [HR], 0.87; 95% confidence interval [CI], 0.66 to 1.14; P = .307), which was not statistically significant. 

Interpretation of OS was complicated by substantial crossover to amivantamab following chemotherapy. Among 128 patients in the chemotherapy arm who discontinued because of progressive disease, 76% subsequentially received second-line amivantamab monotherapy. This included 87 patients who crossed over on protocol and 10 who received amivantamab off protocol. 

After adjusting for on-protocol crossover using the prespecified inverse probability of censoring weighting model, estimated median OS in the chemotherapy arm was 22.1 months. The crossover-adjusted analysis favored first-line amivantamab plus chemotherapy (HR, 0.57; 95% CI, 0.39 to 0.82; P = .003).

At the data cutoff, 12% of patients assigned to amivantamab plus chemotherapy remained on treatment compared with no patients assigned to chemotherapy alone.

The safety profile of amivantamab plus chemotherapy remained consistent with previous reports of amivantamab before implementation of optimized prophylactic measures.

Patient-reported outcomes also favored amivantamab plus chemotherapy, with a longer time to worsening across several key symptom scales compared with chemotherapy alone. 

This final analysis demonstrates that the previously reported PFS advantage with first-line amivantamab plus chemotherapy was accompanied by a numerical improvement in median OS. Although the primary unadjusted OS comparison was not statistically significant, extensive subsequent amivantamab use in the chemotherapy arm likely affected the between-group comparison, with the prespecified crossover-adjusted analysis estimating a larger survival effect.

Source:

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 the World Conference on Lung Cancer; September 12-15, 2026; Seoul, South Korea. Abstract PL03.03.