Neoadjuvant–Adjuvant or Adjuvant-Only Pembrolizumab in Advanced Melanoma

Sapna P. Patel(The University of Texas MD Anderson Cancer Center), Megan Othus(Cape Town HVTN Immunology Laboratory / Hutchinson Centre Research Institute of South Africa), Yuanbin Chen(The University of Texas MD Anderson Cancer Center), G. Paul Wright(The University of Texas MD Anderson Cancer Center), Kathleen J. Yost(The University of Texas MD Anderson Cancer Center), John Hyngstrom(The University of Texas MD Anderson Cancer Center), Siwen Hu‐Lieskovan(The University of Texas MD Anderson Cancer Center), Christopher D. Lao(The University of Texas MD Anderson Cancer Center), Leslie A. Fecher(The University of Texas MD Anderson Cancer Center), Thach‐Giao Truong(The University of Texas MD Anderson Cancer Center), Jennifer L. Eisenstein(Kaiser Permanente), Sunandana Chandra(The University of Texas MD Anderson Cancer Center), Jeffrey A. Sosman(The University of Texas MD Anderson Cancer Center), Kari Kendra(The University of Texas MD Anderson Cancer Center), Richard C. Wu(The University of Texas MD Anderson Cancer Center), Craig Devoe(Northwell Health), Gary B. Deutsch(Northwell Health), Aparna Hegde(The University of Texas MD Anderson Cancer Center), Maya Khalil(The University of Texas MD Anderson Cancer Center), Ankit Mangla(The University of Texas MD Anderson Cancer Center), Amy M. Reese(The University of Texas MD Anderson Cancer Center), Merrick I. Ross(The University of Texas MD Anderson Cancer Center), Andrew Poklepovic(The University of Texas MD Anderson Cancer Center), Giao Q. Phan(The University of Texas MD Anderson Cancer Center), Adedayo A. Onitilo(The University of Texas MD Anderson Cancer Center), Demet G. Yasar(Marshfield Clinic), Benjamin Powers(The University of Texas MD Anderson Cancer Center), Gary C. Doolittle(The University of Texas MD Anderson Cancer Center), Gino K. In(University of Southern California), Niels Kokot(University of Southern California), Geoffrey T. Gibney(The University of Texas MD Anderson Cancer Center), Michael B. Atkins(The University of Texas MD Anderson Cancer Center), Montaser Shaheen(The University of Texas MD Anderson Cancer Center), James Warneke(The University of Texas MD Anderson Cancer Center), Alexandra P. Ikeguchi(The University of Texas MD Anderson Cancer Center), Jose Eugenio Najera(The University of Texas MD Anderson Cancer Center), Bartosz Chmielowski(The University of Texas MD Anderson Cancer Center), Joseph G. Crompton(The University of Texas MD Anderson Cancer Center), Justin D. Floyd(The University of Texas MD Anderson Cancer Center), Eddy C. Hsueh(The University of Texas MD Anderson Cancer Center), Kim Margolin(The University of Texas MD Anderson Cancer Center), Warren Chow(The University of Texas MD Anderson Cancer Center), Kenneth F. Grossmann(Merck & Co., Inc., Rahway, NJ, USA (United States)), Eliana Dietrich(Cape Town HVTN Immunology Laboratory / Hutchinson Centre Research Institute of South Africa), Víctor G. Prieto(The University of Texas MD Anderson Cancer Center), Michael Lowe(The University of Texas MD Anderson Cancer Center), Elizabeth I. Buchbinder(The University of Texas MD Anderson Cancer Center), John M. Kirkwood(The University of Texas MD Anderson Cancer Center), Larissa A. Korde(The University of Texas MD Anderson Cancer Center), James Moon(Cape Town HVTN Immunology Laboratory / Hutchinson Centre Research Institute of South Africa), Elad Sharon(The University of Texas MD Anderson Cancer Center), Vernon K. Sondak(The University of Texas MD Anderson Cancer Center), Antoni Ribas(The University of Texas MD Anderson Cancer Center)
New England Journal of Medicine
March 1, 2023
10.1056/nejmoa2211437
Cited by 801Open Access
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Abstract

BACKGROUND: Whether pembrolizumab given both before surgery (neoadjuvant therapy) and after surgery (adjuvant therapy), as compared with pembrolizumab given as adjuvant therapy alone, would increase event-free survival among patients with resectable stage III or IV melanoma is unknown. METHODS: In a phase 2 trial, we randomly assigned patients with clinically detectable, measurable stage IIIB to IVC melanoma that was amenable to surgical resection to three doses of neoadjuvant pembrolizumab, surgery, and 15 doses of adjuvant pembrolizumab (neoadjuvant-adjuvant group) or to surgery followed by pembrolizumab (200 mg intravenously every 3 weeks for a total of 18 doses) for approximately 1 year or until disease recurred or unacceptable toxic effects developed (adjuvant-only group). The primary end point was event-free survival in the intention-to-treat population. Events were defined as disease progression or toxic effects that precluded surgery; the inability to resect all gross disease; disease progression, surgical complications, or toxic effects of treatment that precluded the initiation of adjuvant therapy within 84 days after surgery; recurrence of melanoma after surgery; or death from any cause. Safety was also evaluated. RESULTS: At a median follow-up of 14.7 months, the neoadjuvant-adjuvant group (154 patients) had significantly longer event-free survival than the adjuvant-only group (159 patients) (P = 0.004 by the log-rank test). In a landmark analysis, event-free survival at 2 years was 72% (95% confidence interval [CI], 64 to 80) in the neoadjuvant-adjuvant group and 49% (95% CI, 41 to 59) in the adjuvant-only group. The percentage of patients with treatment-related adverse events of grades 3 or higher during therapy was 12% in the neoadjuvant-adjuvant group and 14% in the adjuvant-only group. CONCLUSIONS: Among patients with resectable stage III or IV melanoma, event-free survival was significantly longer among those who received pembrolizumab both before and after surgery than among those who received adjuvant pembrolizumab alone. No new toxic effects were identified. (Funded by the National Cancer Institute and Merck Sharp and Dohme; S1801 ClinicalTrials.gov number, NCT03698019.).

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