PAPILLON reports longest OS in EGFR ex20ins NSCLC with amivantamab–chemo

First-line (1L) amivantamab plus chemotherapy improves overall survival (OS) in patients with treatment-naïve, locally advanced or metastatic non-small cell lung cancer (NSCLC) with EGFR exon 20 insertion (ex20ins) mutations, according to the results from the protocol-specified final OS analysis of the phase III PAPILLON study.

“PAPILLON demonstrated the longest median OS to date in EGFR ex20ins-positive advanced NSCLC with 1L amivantamab–chemo,” said Dr Chul Kim from Georgetown Cancer Institute, Washington, DC, US, at WCLC 2026.

At a median follow-up of 48.6 months, median OS was 34.3 months with amivantamab–chemo. “This is nearly 3 years, which we have not seen in the past … Prior to amivantamab, real-world median OS for EGFR ex20ins NSCLC was approximately 16–24 months,” Kim noted. With chemo alone, median OS was 27.9 months.

A comparison between the investigational and chemo groups yielded a hazard ratio (HR) of 0.87. However, statistical significance was not met (p=0.307), partly due to the high crossover rate—76 percent of participants in the chemo group discontinued treatment upon disease progression and crossed over to second-line amivantamab.

Statistical significance was achieved after adjusting for substantial on-protocol crossover using the prespecified IPCW* method (median OS 34.3 vs 22.1 months; HR, 0.57; p_nominal=0.003). [WCLC 2026, abstract PL03.03]

“Although the crossover likely attenuated the HR-based OS estimate, the adjusted analysis showed a substantially longer estimated survival benefit, supporting amivantamab–chemo as a foundational 1L regimen for patients with EGFR ex20ins advanced NSCLC,” Kim said.

OS generally favoured the combination regimen over chemo alone across most predefined subgroups, with the most pronounced effect among females (HR, 0.58) and those without smoking history (HR, 0.63).

Other endpoints

Twelve percent of participants in the combination group remained on 1L therapy, whereas none did in the chemo group. First subsequent therapy was administered in 54 percent of participants in the experimental group (primarily chemo or ICI** regimen, followed by other EGFR-targeted or TKI***-based regimens) and 83 percent of those in the chemo group (mostly amivantamab).

Progression-free survival 2 was longer with amivantamab–chemo vs chemo alone (median 28.3 vs 17.5 months; HR, 0.59; p<0.0001). The proportion of participants who were progression-free at 36 months was more than twofold higher with the former vs the latter (42 percent vs 19 percent).

The safety profile of the combo regimen aligns with previous reports, with no new safety signals identified. Most adverse events were grade 1/2, Kim said. “It is important to note that PAPILLON was conducted prior to the evaluation of prophylactic strategies (eg, COCOON, SKIPPirr) and SC amivantamab, which have significantly reduced infusion reactions.”

Compared with chemo alone, amivantamab–chemo prolonged time to deterioration of symptoms, including dyspnoea (median 12.4 vs 7.8 months; HR, 0.68), insomnia (median 13.8 vs 8.5 months; HR, 0.69), diarrhoea (median 16.9 vs 11.7 months; HR, 0.72), pain (median 9.5 vs 6 months; HR, 0.73), and nausea and vomiting (median 6.9 vs 4.3 months; HR, 0.75), as well as time to symptomatic progression (median 28.8 vs 22.4 months; HR, 0.77; p=0.055).

“The safety profile of amivantamab–chemo was consistent with prior reports before SC amivantamab and prophylactic strategies, with patient-reported outcomes favouring the amivantamab–chemo [regimen],” noted Kim.

A total of 308 individuals were randomized 1:1 to amivantamab–chemo or chemo alone. Amivantamab was given intravenously at a dose of 1,400 mg (1,750 mg if ≥80 kg) for the first 4 weeks, then 1,750 mg (2,100 mg if ≥80 kg) Q3W starting at week 7 (day 1, cycle 3). Chemotherapy (day 1 of each 21-day cycle) comprised carboplatin (AUC5 for the first four cycles) and pemetrexed (500 mg/m² until disease progression).