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Background <p>In the PAPILLON study, first-line amivantamab-chemotherapy in epidermal growth factor receptor (<i>EGFR)</i> exon 20 insertion-mutated non-small cell lung cancer demonstrated significantly prolonged progression-free survival and favorable overall survival over chemotherapy; a consistent benefit was also observed across some secondary endpoints. However, the complete clinical benefit of first-line amivantamab-chemotherapy is not fully understood, nor is the survival advantage in the presence of per-protocol crossover from chemotherapy to amivantamab after progression.</p> Objective <p>We aimed to assess time to treatment discontinuation (TTD) and time to subsequent therapy (TTST), at the time of primary analysis for progression-free survival, and the effect of the crossover design on overall survival at the time of interim analysis.</p> Methods <p>In the phase III PAPILLON study, 308 participants were randomized (amivantamab-chemotherapy, <i>n</i> = 153; chemotherapy, <i>n</i> = 155). Intravenous amivantamab was administered every 3 weeks. Chemotherapy was administered as carboplatin for four cycles and pemetrexed until disease progression. TTD and TTST were evaluated using Kaplan–Meier and Cox proportional hazards models. Crossover-adjusted survival estimates were generated using three established statistical methods.</p> Results <p>At a median follow-up of 14.9 months, median TTD was 13.2 versus 7.5 months for amivantamab-chemotherapy versus chemotherapy (hazard ratio [HR] 0.38 [95% confidence interval 0.28–0.51]; nominal <i>p</i> &lt; 0.0001). Median TTST was 17.7 versus 9.9 months (HR 0.35 [95% confidence interval 0.25–0.49]; nominal <i>p</i> &lt; 0.0001). A total of 65/155 participants crossed over from chemotherapy to amivantamab after progression. The crossover-adjusted overall survival continued to demonstrate a favorable survival benefit for amivantamab-chemotherapy versus chemotherapy with HRs of 0.52–0.60, which is more pronounced than the planned interim intention-to-treat overall survival (HR of 0.67; 95% confidence interval 0.42–1.09).</p> Conclusions <p>In PAPILLON, TTD and TTST were substantially longer for amivantamab-chemotherapy versus chemotherapy at primary analysis (cut-off on 3 May 2023). Crossover-adjusted analyses of the planned interim overall survival demonstrated a greater benefit for amivantamab-chemotherapy versus chemotherapy, further supporting amivantamab-chemotherapy as the first-line standard of care in <i>EGFR</i> exon 20 insertion-mutated non-small cell lung cancer.</p> Clinical Trial Registration <p>ClinicalTrials.gov Identifier: NCT04538664.</p>

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Amivantamab-Chemotherapy in Non-Small Cell Lung Cancer with EGFR Exon 20 Insertions: Impact of Treatment Crossover and Other Endpoints from the Phase III PAPILLON Study

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月3日

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  • Rachel E. Sanborn,
  • Caicun Zhou,
  • Ke-Jing Tang,
  • Byoung Chul Cho,
  • Susanna Cheng,
  • Sanjay Popat,
  • Akira Ono,
  • Shun Lu,
  • Margarita Majem,
  • Andres Aguilar,
  • Maria Del Rosario Garcia Campelo,
  • Hidetoshi Hayashi,
  • Kang-yun Lee,
  • Se-Hoon Lee,
  • Angelo Delmonte,
  • Jorge Alatorre-Alexander,
  • Gary Richardson,
  • Victor Santos,
  • Christophe Dooms,
  • Joshua K. Sabari,
  • Catherine A. Shu,
  • Nicolas Girard,
  • Aaron S. Mansfield,
  • Keunchil Park,
  • Yichuan Xia,
  • Archan Bhattacharya,
  • Nasuh Buyukkaramikli,
  • Nolen Perualila,
  • Joris Diels,
  • Sandip Acharya,
  • Conor Chandler,
  • Irina Proskorovsky,
  • Lindsay Dearden,
  • Honeylet Wortman-Vayn,
  • Parthiv J. Mahadevia,
  • Roland E. Knoblauch,
  • Trishala Agrawal,
  • Mahadi Baig,
  • Enriqueta Felip

摘要

Background

In the PAPILLON study, first-line amivantamab-chemotherapy in epidermal growth factor receptor (EGFR) exon 20 insertion-mutated non-small cell lung cancer demonstrated significantly prolonged progression-free survival and favorable overall survival over chemotherapy; a consistent benefit was also observed across some secondary endpoints. However, the complete clinical benefit of first-line amivantamab-chemotherapy is not fully understood, nor is the survival advantage in the presence of per-protocol crossover from chemotherapy to amivantamab after progression.

Objective

We aimed to assess time to treatment discontinuation (TTD) and time to subsequent therapy (TTST), at the time of primary analysis for progression-free survival, and the effect of the crossover design on overall survival at the time of interim analysis.

Methods

In the phase III PAPILLON study, 308 participants were randomized (amivantamab-chemotherapy, n = 153; chemotherapy, n = 155). Intravenous amivantamab was administered every 3 weeks. Chemotherapy was administered as carboplatin for four cycles and pemetrexed until disease progression. TTD and TTST were evaluated using Kaplan–Meier and Cox proportional hazards models. Crossover-adjusted survival estimates were generated using three established statistical methods.

Results

At a median follow-up of 14.9 months, median TTD was 13.2 versus 7.5 months for amivantamab-chemotherapy versus chemotherapy (hazard ratio [HR] 0.38 [95% confidence interval 0.28–0.51]; nominal p < 0.0001). Median TTST was 17.7 versus 9.9 months (HR 0.35 [95% confidence interval 0.25–0.49]; nominal p < 0.0001). A total of 65/155 participants crossed over from chemotherapy to amivantamab after progression. The crossover-adjusted overall survival continued to demonstrate a favorable survival benefit for amivantamab-chemotherapy versus chemotherapy with HRs of 0.52–0.60, which is more pronounced than the planned interim intention-to-treat overall survival (HR of 0.67; 95% confidence interval 0.42–1.09).

Conclusions

In PAPILLON, TTD and TTST were substantially longer for amivantamab-chemotherapy versus chemotherapy at primary analysis (cut-off on 3 May 2023). Crossover-adjusted analyses of the planned interim overall survival demonstrated a greater benefit for amivantamab-chemotherapy versus chemotherapy, further supporting amivantamab-chemotherapy as the first-line standard of care in EGFR exon 20 insertion-mutated non-small cell lung cancer.

Clinical Trial Registration

ClinicalTrials.gov Identifier: NCT04538664.