PAPILLON: Adding Amivantamab to First-Line Chemotherapy Prolongs Progression-Free Survival in NSCLC Subset

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In the phase III PAPILLON trial, the addition of the bispecific antibody amivantamab-vmjw to chemotherapy resulted in a near doubling in median progression-free survival vs chemotherapy alone in patients with untreated non–small cell lung cancer (NSCLC) and epidermal growth factor receptor (EGFR) exon 20 insertions. The primary results were presented during the Presidential Symposium at the European Society for Medical Oncology (ESMO) Congress 2023 by Nicolas Girard, MD, of the Curie Institute, Paris.1 These findings were also reported in The New England Journal of Medicine.2

Nicolas Girard, MD

Nicolas Girard, MD

“Amivantamab plus chemotherapy represents the new standard of care for the first-line treatment of EGFR exon 20 insertion advanced non–small cell lung cancer,” Dr. Girard said. “This regimen significantly improved progression-free survival and, in addition, showed consistent progression-free survival benefits across all predefined subgroups, significantly higher response rate, longer duration of response, and a deeper reduction in tumor size.”

Dr. Girard reported median progression-free survival was 11.4 months with amivantamab plus chemotherapy vs 6.7 months with chemotherapy (hazard ratio [HR] = 0.395; P < .0001). “We have a 60% reduction in the risk of disease progression, and the curves divided early and widened. We have a sustained benefit with amivantamab and chemotherapy, as highlighted by the 18-month progression-free survival rate of 31% vs 2%. We also have a tendency for the progression-free survival curves to plateau, showing a long-term effect, with consistent benefit across predefined subgroups,” Dr. Girard said.

Amivantamab is a bispecific antibody directed against EGFR and the mesenchymal-epithelial transition (MET) receptor. It has received accelerated approval for treatment of patients with NSCLC who have EGFR exon 20 insertion mutations and have experienced disease progression on platinum chemotherapy.


PAPILLON enrolled 308 patients with treatment-naive locally advanced or metastatic NSCLC and EGFR exon 20 insertion mutations. They were randomly assigned to receive amivantamab (1,400 mg for the first 4 weeks, then 1,750 mg every 3 weeks) plus chemotherapy with carboplatin (AUC = 5 for the first four cycles) and pemetrexed (500 mg/m2 until disease progression). Approximately 61% of the patients were Asian, and 23% had a history of brain metastases.

Upon disease progression, 65 of the 155 patients randomly assigned to receive chemotherapy crossed over to receive amivantamab monotherapy as part of the study, and 6 patients did so off-protocol. At the study’s end, 46% of the experimental arm and 15% of the chemotherapy were continuing on their assigned treatment.

Other Outcomes

Outcomes by investigator assessment mirrored those of the primary endpoint, showing median progression-free survivals of 12.9 months with amivantamab and 6.9 months in the control arm (HR = 0.38; P < .0001). The addition of amivantamab also significantly boosted objective responses, which were observed in 73% (4% complete responses) vs 47% (1% complete response; odds ratio [OR] = 3.0; P < .0001) by blinded independent review and 66% vs 43% by investigator assessment (OR = 2.6; P < .0001). Median duration of response was 9.7 months vs 4.4 months, respectively; at 18 months, 34% and 4%, respectively, were still responding to treatment.

The new regimen was also favored in terms of median progression-free survival after first subsequent therapy, which was not estimable with amivantamab plus
chemotherapy and was 17.2 months with chemotherapy (HR = 0.493; P = .001). At 24 months, 57% of the experimental arm remained progression-free vs 35% of the control arm. In the chemotherapy-alone arm, 94 patients started subsequent therapy after disease progression, which for 71 patients was amivantamab monotherapy.

Despite 66% of the control arm receiving second-line amivantamab, interim overall survival analysis at 33% maturity showed a favorable trend for amivantamab plus chemotherapy (HR = 0.675; 95% confidence interval = 0.42–1.09; P = .106). At 24 months, 72% of the experimental arm were alive, vs 54% of the chemotherapy arm, Dr. Girard reported.

Safety Profile

“The safety profile of amivantamab plus chemotherapy was consistent with the individual agents,” noted Dr. Girard. The most common treatment-emergent adverse events with amivantamab plus chemotherapy were neutropenia, paronychia, rash, anemia, infusion-related reactions, and hypoalbuminemia. Grade ≥ 3 toxicities were experienced by 75% of the combination arm and 54% of the chemotherapy-alone arm, but 7% of patients discontinued amivantamab because of toxicity.

As expected, EGFR- and MET-related adverse events were increased with amivantamab plus chemotherapy but were primarily grade 1 or 2. Chemotherapy-associated hematologic and gastrointestinal toxicities were comparable between the arms except for more neutropenia with the combination, and these events were mostly transient and minor. Pneumonitis was reported in 3% of patients receiving the combination therapy. 

DISCLOSURE: Dr. Girard reported financial relationships with AstraZeneca, BMS, MSD, Roche, Pfizer, Mirati Therapeutics, Amgen, Novartis, Sanofi, Gilead Sciences, Janssen, Boehringer Ingelheim, AbbVie, Eli Lilly, Grünenthal, Takeda, Owkin, Leo Pharma, Daiichi Sankyo, Ipsen, Sivan, and Janssen.


1. Girard N, et al: ESMO Congress 2023. Abstract LBA5. Presented October 21, 2023.

2. Zhou C, et al: N Engl J Med. October 21, 2023 (early release online).

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