New data from two phase 3 trials add complexity to the first-line treatment landscape for advanced non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 20 insertions.

In the final overall survival (OS) analysis of PAPILLON, which involved treatment-naive patients with locally advanced or metastatic NSCLC harboring EGFR exon 20 insertions, those given amivantamab plus chemotherapy had a numerical improvement of 6.4 months over those who received chemotherapy alone.

The trial demonstrated the longest reported median OS to date — more than 34 months — for its patient group. This supports it as a “foundational” first-line regimen, said Chul Kim, MD, of Georgetown University, Washington, DC, during his presentation of the PAPILLON results at the World Conference on Lung Cancer (WCLC) 2026.

In the other trial, REZILIENT3, a statistically significant and clinically meaningful 6-month improvement in progression-free survival (PFS) was seen with zipalertinib added to chemotherapy vs chemotherapy alone in patients with advanced NSCLC with EGFR exon 20 insertions.

Separate phase 3 trials now support amivantamab plus chemotherapy, sunvozertinib monotherapy, and zipalertinib plus chemotherapy in first-line NSCLC with EGFR exon 20 insertions, said Lyudmila Bazhenova, MD, who served as a discussant in a session where both PAPILLON and REZILIENT3 results were presented at the conference.

None of the three trials has demonstrated a statistically significant OS benefit in the primary randomized analysis, she said.

EGFR exon 20 insertions account for about 5%-10% of EGFR mutations in NSCLC and represent a molecularly heterogeneous subgroup that has historically been relatively resistant to conventional EGFR-directed TKI.

PAPILLON, which involved 308 patients being randomly assigned to receive amivantamab plus carboplatin-pemetrexed or chemotherapy alone, previously met its primary endpoint, demonstrating superior PFS (hazard ratio [HR], 0.40; P < .001) for amivantamab plus chemotherapy.

In the final OS analysis after a median follow-up of 48.6 months, median OS was 34.3 vs 27.9 months with amivantamab plus chemotherapy vs chemotherapy alone (HR, 0.87; P = .307). Prior to amivantamab, median real-world OS for EGFR exon 20 insertion-positive NSCLC was roughly 16-24 months, Kim noted.

Among 128 patients in PAPILLON assigned to chemotherapy who discontinued treatment due to progressive disease, 97 (76%) received second-line amivantamab monotherapy. After adjusting for substantial on-protocol crossover using the prespecified inverse probability of censoring weighting model, amivantamab plus chemotherapy demonstrated a significant OS benefit (HR, 0.57; nominal P = .002).

The most common adverse events with amivantamab plus chemotherapy included paronychia, rash, neutropenia, anemia, infusion-related reactions, and hypoalbuminemia.

Kim noted that the PAPILLON safety experience predates several strategies now used to mitigate amivantamab-related toxicities. The trial was conducted before prophylactic regimens to reduce amivantamab-related rash and other dermatologic toxicities were routinely used, and before the availability of subcutaneous amivantamab, which “reduces the rate of infusion-related reactions significantly.” He said no new safety signals were seen in the trial.

REZILIENT3: Zipalertinib Combo Nearly Cuts Progression Risk by Half

Daniel Tan, MD, of the National Cancer Centre Singapore and Duke-NUS Medical School in Singapore, presented results from REZILIENT3 at the WCLC. In this trial, 279 patients were randomly assigned (1:1) to receive either platinum-pemetrexed chemotherapy or 100 mg twice-daily zipalertinib, an oral irreversible TKI designed to selectively inhibit EGFR exon 20 insertions while sparing wild-type EGFR, plus chemotherapy. Stable brain metastases were permitted. Patients assigned to chemotherapy alone could cross over to zipalertinib after disease progression.

At the prespecified interim analysis, median PFS was 14.5 vs 8.5 months with zipalertinib plus chemotherapy vs chemotherapy alone (HR, 0.50; P = .00015). The PFS benefit was consistent across subgroups, including patients with brain metastases (HR, 0.38).

Objective response rates were also higher when zipalertinib was added to chemotherapy (65.0% vs 40.3%; P < .0001). Median duration of response was also longer with the combination (14.2 vs 9.9 months).

After a median follow-up of 10.9 months, median OS had not been reached in either group. The HR for death with zipalertinib plus chemotherapy vs chemotherapy alone was 0.72 (P = .11082).

The combination resulted in more grade 3 or higher adverse events, which Tan said were largely related to cytopenias and associated sequelae, particularly during the first four cycles of treatment.

Although PAPILLON showed a significant survival advantage after adjustment for crossover, Bazhenova, from UC San Diego Moores Cancer Center, characterized the analysis as “hypothesis-generating” due to it depending on modeling assumptions. There are no head-to-head data establishing one regimen as superior, she continued.

For now, Bazhenova said, the key practical differentiators are likely to be “CNS [central nervous system] activity, toxicity, treatment burden, access, and patient preference,” whereas exon 20 insertion subtype, anticipated resistance, and sequencing “should not yet determine first-line therapy.”

PAPILLON was sponsored by Johnson & Johnson. REZILIENT3 was sponsored by Taiho Oncology, Inc. Kim, Tan, and Bazhenova disclosed having relationships with various pharmaceutical companies.