Prof Nicolas Girard: PAPILLON

At ESMO 2023, the results of the Papillon study, a phase 3 trial comparing amivantamab plus chemotherapy to chemotherapy alone in first-line treatment for EGFR exon 20 insertion-mutated non-transcendent (Ex20ins) advanced NSCLC, were presented.

Patients with Ex20ins cancer have a dismal prognosis, with a 5-year OS below 10%, and traditional EGFR TKIs are ineffective, making chemotherapy the standard of care. Amivantamab, a bispecific EGFR and MET antibody approved in the second-line setting for Ex20ins NSCLC was studied to evaluate its role in the first-line setting. The study randomised 308 patients to either amivantamab plus chemotherapy or chemotherapy alone, with the option for crossover at disease progression.

The primary endpoint of the Papillon study was met in an interim analysis, demonstrating a median PFS of 11.4 months with amivantamab plus chemotherapy, compared to 6.7 months with chemotherapy alone, resulting in a 60% reduction in the risk of disease progression. Amivantamab plus chemotherapy exhibited prolonged responses, higher response rates, and a potential overall survival benefit, although this still requires further confirmation. Notably, even with a high rate of crossover in the control arm, PFS2 favoured amivantamab.

Regarding safety, the profile was consistent with that of chemotherapy and amivantamab as individual agents. Although there was a higher risk of neutropenia in the amivantamab plus chemotherapy arm, it primarily occurred during the first cycle and was not considered a serious adverse event. Less than 10% of patients had to discontinue amivantamab due to treatment-related adverse events.

In conclusion, the Papillon study is poised to change clinical practice by establishing amivantamab plus chemotherapy as a new standard of care for Ex20ins lung cancer patients in the first-line setting. With no competing agents available, amivantamab stands as the sole standard of care. Other EGFR exon 20 insertion mutation-targeting TKIs are in development, such as furmonertinib and sunvozertinib, but their role in the second-line setting remains uncertain, necessitating further research into sequencing and molecular resistance mechanisms.