Neoadjuvant–Adjuvant or Adjuvant-Only Pembrolizumab in Advanced Melanoma

Author(s): Sapna P. Patel, M.D., Megan Othus, Ph.D., Yuanbin Chen, M.D., Ph.D., G. Paul Wright, Jr., M.D., Kathleen J. Yost, M.D., John R. Hyngstrom, M.D., Siwen Hu-Lieskovan, M.D., Ph.D., Christopher D. Lao, M.D., M.P.H., Leslie A. Fecher, M.D., Thach-Giao Truong, M.D., Jennifer L. Eisenstein, M.D., Sunandana Chandra, M.D., Jeffrey A. Sosman, M.D., Ph.D., Kari L. Kendra, M.D., Ph.D., Richard C. Wu, M.D., Ph.D., Craig E. Devoe, M.D., Gary B. Deutsch, M.D., M.P.H., Aparna Hegde, M.D., Maya Khalil, M.D., Ankit Mangla, M.D., Amy M. Reese, M.D., Merrick I. Ross, M.D., Andrew S. Poklepovic, M.D., Giao Q. Phan, M.D., Adedayo A. Onitilo, M.D., Ph.D., Demet G. Yasar, M.D., Benjamin C. Powers, M.D., Gary C. Doolittle, M.D., Gino K. In, M.D., M.P.H., Niels Kokot, M.D., Geoffrey T. Gibney, M.D., Michael B. Atkins, M.D., Montaser Shaheen, M.D., James A. Warneke, M.D., Alexandra Ikeguchi, M.D., Jose E. Najera, M.D., Bartosz Chmielowski, M.D., Ph.D., Joseph G. Crompton, M.D., Ph.D., Justin D. Floyd, D.O., Eddy Hsueh, M.D., Kim A. Margolin, M.D., Warren A. Chow, M.D., Kenneth F. Grossmann, M.D., Ph.D., Eliana Dietrich, Victor G. Prieto, M.D., Ph.D., Michael C. Lowe, M.D., Elizabeth I. Buchbinder, M.D., John M. Kirkwood, M.D., Larissa Korde, M.D., James Moon, M.S., Elad Sharon, M.D., M.P.H., Vernon K. Sondak, M.D., and Antoni Ribas, M.D., Ph.D.
Source: N Engl J Med 2023; 388:813-823 DOI: 10.1056/NEJMoa2211437
Anjan J Patel MD

Dr. Anjan Patel's Thoughts

Interesting study showing a strong difference in EFS with neoadjuvant + adjuvant vs. adjuvant alone for stage III/IV melanoma. All patients had disease that was amenable to surgery; EFS at 24 months was 72% vs. 49% in favor of the neoadjuvant group. The hypothesis is that neoadjuvant therapy functionally inhibits the immune checkpoint before antitumor T-cells are surgically resected. This concept is also developing in other cancers, including NSCLC, breast and bladder cancers. This should affect clinical practice.


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.


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.


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.


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 number, NCT03698019. opens in new tab.)

Author Affiliations

From the University of Texas M.D. Anderson Cancer Center, Houston (S.P.P., M.I.R., V.G.P.), and the University of Texas Health Science Center at San Antonio, San Antonio (M.S.); Southwest Oncology Group Statistics and Data Management Center (M.O., J.M.) and the Fred Hutchinson Cancer Center (M.O., E.D., J.M.) — both in Seattle; the Cancer Research Consortium of West Michigan National Cancer Institute Community Oncology Research Program (NCORP)–Cancer and Hematology Centers of Western Michigan (Y.C.), the Cancer Research Consortium of West Michigan NCORP–Spectrum Health (G.P.W.), and the Cancer Research Consortium of West Michigan NCORP (K.J.Y.), Grand Rapids, and the University of Michigan Rogel Cancer Center, Ann Arbor (C.D.L., L.A.F.); the University of Utah Huntsman Cancer Institute, Salt Lake City (J.R.H., S.H.-L.); Kaiser Permanente Northern California, Vallejo (T.-G.T.), University of Southern California Norris Comprehensive Cancer Center (G.K.I., N.K.) and University of California Los Angeles Jonsson Comprehensive Cancer Center (B.C., J.G.C., A.R.), Los Angeles, City of Hope Comprehensive Cancer Center–Saint John’s Cancer Institute, Santa Monica (K.A.M.), and City of Hope Comprehensive Cancer Center–University of California, Irvine, Irvine (W.A.C.) — all in California; Kaiser Permanente Colorado, Lafayette (J.L.E.); Northwestern University, Chicago (S.C., J.A.S.), and the Cancer Care Specialists of Illinois–Heartland NCORP, O’Fallon (J.D.F.) — both in Illinois; Ohio State University Wexner Medical Center, Columbus (K.L.K., R.C.W.), and University Hospitals Seidman Cancer Center–Case Western Reserve University Case Comprehensive Cancer Center, Cleveland (A.M., A.M.R.); Northwell Health Cancer Institute, Lake Success, NY (C.E.D., G.B.D.); the University of Alabama at Birmingham, Birmingham (A.H., M.K.); Virginia Commonwealth University–Massey Cancer Center–VCU Massey Cancer Center Minority Underserved NCORP, Richmond (A.S.P., G.Q.P.); Marshfield Medical Center Wisconsin NCORP, Weston (A.A.O.), and Marshfield Medical Center Wisconsin NCORP, Minocqua (D.G.Y.); the University of Kansas Cancer Center, Overland Park (B.C.P.), and the University of Kansas Hospital–Westwood Cancer Center, Westwood (G.C.D.); MedStar Georgetown University Hospital, Washington, DC (G.T.G., M.B.A.); Banner University Medical Center–University of Arizona Cancer Center, Tucson (M.S., J.A.W.); the University of Oklahoma, Oklahoma City (A.I.), and the University of Oklahoma–Cancer Centers of Southwest Oklahoma, Lawton (J.E.N.); Saint Louis University School of Medicine, St. Louis (E.H.); Merck, Rahway, NJ (K.F.G.); Emory University, Atlanta (M.C.L.); Dana–Farber Cancer Institute–Harvard Cancer Center, Boston (E.I.B.); the University of Pittsburgh Medical Center Hillman Cancer Center, Pittsburgh (J.M.K.); the National Cancer Institute Cancer Therapy Evaluation Program, Bethesda, MD (L.K., E.S.); and Moffitt Cancer Center, Tampa, FL (V.K.S.).

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