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.).
N Engl J Med. 2023 Mar 2;388(9):813-823. doi: 10.1056/NEJMoa2211437.
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.).
背景：与单独接受辅助治疗相比，在手术前（新辅助治疗）和手术后（辅助治疗）给予帕博利珠单抗是否会增加可切除 III 期或 IV 期黑色素瘤患者的无事件生存，目前尚不清楚。
方法：在一项 2 期试验中，我们将可手术切除的 IIIB 至 IVC 期有临床可检测、可测量的黑色素瘤患者随机分配至三组：三组分别接受三剂新辅助帕博利珠单抗、手术和 15 剂辅助帕博利珠单抗（新辅助-辅助组），或手术加帕博利珠单抗（每 3 周静脉注射 200mg，共 18 剂），持续约 1 年，或直至疾病复发或出现不可接受的毒性作用（辅助治疗组）。主要终点是在意向治疗人群中的无事件生存。事件定义为疾病进展或毒性作用导致无法手术；无法切除所有肉眼可见的疾病；手术后 84 天内无法切除所有肉眼可见的疾病；因疾病进展、手术并发症或治疗毒性作用而无法开始辅助治疗；手术后黑色素瘤复发；或任何原因导致的死亡。还评估了安全性。
结果：中位随访 14.7 个月时，新辅助-辅助组（154 例患者）的无事件生存显著长于辅助治疗组（159 例患者）（log-rank 检验 P=0.004）。在一个关键时间点分析中，新辅助-辅助组 2 年无事件生存率为 72%（95%置信区间[CI]，64%至 80%），辅助治疗组为 49%（95% CI，41%至 59%）。在治疗期间，新辅助-辅助组有 12%的患者发生 3 级或以上的治疗相关不良事件，辅助治疗组有 14%的患者发生 3 级或以上的治疗相关不良事件。
结论：在可切除的 III 期或 IV 期黑色素瘤患者中，与单独接受辅助治疗相比，新辅助治疗加辅助治疗的患者无事件生存显著延长。未发现新的毒性作用。（由美国国家癌症研究所和默克 Sharp & Dohme 资助；S1801 临床试验.gov 编号，NCT03698019。）
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