Amivantamab plus Chemotherapy in NSCLC with EGFR Exon 20 Insertions

Author(s): Caicun Zhou, M.D., Ph.D., Ke-Jing Tang, M.D., Ph.D., Byoung Chul Cho, M.D., Ph.D., Baogang Liu, M.D., Luis Paz-Ares, M.D., Ph.D., Susanna Cheng, M.D., Satoru Kitazono, M.D., Ph.D., Muthukkumaran Thiagarajan, M.D., Jonathan W. Goldman, M.D., Joshua K. Sabari, M.D., Rachel E. Sanborn, M.D., Aaron S. Mansfield, M.D., et al., for the PAPILLON Investigators*
Source: N Engl J Med 2023; 389:2039-2051 DOI: 10.1056/NEJMoa2306441
Anjan J Patel MD

Dr. Anjan Patel's Thoughts

Phase III study of amivantamab + chemotherapy vs. chemotherapy alone as first-line therapy in patients with Exon-20 EGFR mutations. While the results of this study are impressive, one wonders what the results would be if the comparator arm were a targeted option.  This is not yet reflected in the NCCN guidelines but likely will be added.


Amivantamab has been approved for the treatment of patients with advanced non–small-cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 20 insertions who have had disease progression during or after platinum-based chemotherapy. Phase 1 data showed the safety and antitumor activity of amivantamab plus carboplatin–pemetrexed (chemotherapy). Additional data on this combination therapy are needed.


In this phase 3, international, randomized trial, we assigned in a 1:1 ratio patients with advanced NSCLC with EGFR exon 20 insertions who had not received previous systemic therapy to receive intravenous amivantamab plus chemotherapy (amivantamab–chemotherapy) or chemotherapy alone. The primary outcome was progression-free survival according to blinded independent central review. Patients in the chemotherapy group who had disease progression were allowed to cross over to receive amivantamab monotherapy.


A total of 308 patients underwent randomization (153 to receive amivantamab–chemotherapy and 155 to receive chemotherapy alone). Progression-free survival was significantly longer in the amivantamab–chemotherapy group than in the chemotherapy group (median, 11.4 months and 6.7 months, respectively; hazard ratio for disease progression or death, 0.40; 95% confidence interval [CI], 0.30 to 0.53; P<0.001). At 18 months, progression-free survival was reported in 31% of the patients in the amivantamab–chemotherapy group and in 3% in the chemotherapy group; a complete or partial response at data cutoff was reported in 73% and 47%, respectively (rate ratio, 1.50; 95% CI, 1.32 to 1.68; P<0.001). In the interim overall survival analysis (33% maturity), the hazard ratio for death for amivantamab–chemotherapy as compared with chemotherapy was 0.67 (95% CI, 0.42 to 1.09; P=0.11). The predominant adverse events associated with amivantamab–chemotherapy were reversible hematologic and EGFR-related toxic effects; 7% of patients discontinued amivantamab owing to adverse reactions.


The use of amivantamab–chemotherapy resulted in superior efficacy as compared with chemotherapy alone as first-line treatment of patients with advanced NSCLC with EGFR exon 20 insertions. (Funded by Janssen Research and Development; PAPILLON number, NCT04538664. opens in new tab.)

Author Affiliations

From Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai (C.Z.), the Division of Pulmonary and Critical Care Medicine, First Affiliated Hospital of Sun Yat-sen University, Guangzhou (K.-J.T.), and Harbin Medical University Cancer Hospital, Harbin (B.L.) — all in China; the Division of Medical Oncology, Yonsei Cancer Center, Yonsei University College of Medicine (B.C.C.), Asan Medical Center, University of Ulsan College of Medicine (S. Kim), and Samsung Medical Center, Sungkyunkwan University School of Medicine (K.P.) — all in Seoul, South Korea; Hospital Universitario 12 de Octubre, Madrid (L.P.-A.), and Vall d’Hebron University Hospital and Vall d’Hebron Institute of Oncology (E.F.) and Hospital de la Santa Creu I Sant Pau (M.M.), Barcelona — all in Spain; Sunnybrook Odette Cancer Centre, Toronto (S.C.); Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo (S. Kitazono), and Shizuoka Cancer Center, Shizuoka (A.O.) — both in Japan; General Hospital Kuala Lumpur, Kuala Lumpur, Malaysia (M.T.); David Geffen School of Medicine, University of California, Los Angeles, Los Angeles (J.W.G.), and Janssen Research and Development, San Diego (S.M.S.) — both in California; NYU Langone Health, New York (J.K.S.); Earle A. Chiles Research Institute, Providence Cancer Institute of Oregon, Portland (R.E.S.); Mayo Clinic, Rochester, MN (A.S.M.); the Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan (J.-Y.H.); Chris O’Brien Lifehouse, Camperdown, NSW, Australia (M.B.); Royal Marsden Hospital NHS Foundation Trust and the Institute of Cancer Research, London (S.P.), and Janssen Research and Development, High Wycombe (A.B.) — both in the United Kingdom; Barretos Cancer Hospital, Barretos, Brazil (J.M.D.); Istanbul Medeniyet University, Prof. Dr. Suleyman Yalcin City Hospital, Istanbul, Turkey (M.G.); Janssen Research and Development, Raritan, NJ (J.X.); Janssen Research and Development, Spring House, PA (T.A., R.E.K.); and Institut Curie, Institut du Thorax Curie-Montsouris, Paris, and Paris Saclay University, Université de Versailles Saint-Quentin-en-Yvelines, Versailles — both in France (N.G.).

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