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Neoadjuvant–Adjuvant vs Adjuvant-Only Pembrolizumab for Advanced Melanoma
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.
Neoadjuvant-Adjuvant or Adjuvant-Only Pembrolizumab in Advanced MelanomaN. Engl. J. Med 2023 Mar 02;388(9)813-823, SP Patel, M Othus, Y Chen, GP Wright, KJ Yost, JR Hyngstrom, S Hu-Lieskovan, CD Lao, LA Fecher, TG Truong, JL Eisenstein, S Chandra, JA Sosman, KL Kendra, RC Wu, CE Devoe, GB Deutsch, A Hegde, M Khalil, A Mangla, AM Reese, MI Ross, AS Poklepovic, GQ Phan, AA Onitilo, DG Yasar, BC Powers, GC Doolittle, GK In, N Kokot, GT Gibney, MB Atkins, M Shaheen, JA Warneke, A Ikeguchi, JE Najera, B Chmielowski, JG Crompton, JD Floyd, E Hsueh, KA Margolin, WA Chow, KF Grossmann, E Dietrich, VG Prieto, MC Lowe, EI Buchbinder, JM Kirkwood, L Korde, J Moon, E Sharon, VK Sondak, A Ribas
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
SWOG S1801 is the first trial in melanoma that directly compared a neoadjuvant–adjuvant with an adjuvant immunotherapy regimen. Patients with clinically detectable stage IIIB to IV melanoma amenable to surgical resection were randomized to receive three doses of neoadjuvant pembrolizumab followed by surgery and adjuvant pembrolizumab or upfront surgery followed by adjuvant pembrolizumab for a year. The neoadjuvant group had a remarkably longer 2-year event-free survival rate of 72% compared with 49% in the adjuvant-only group (P = .004). For patients on neoadjuvant pembrolizumab, 21% had a complete pathological response (no viable tumor).
This study establishes that strong consideration and preference should be given to neoadjuvant therapy for patients with surgically resectable stage III/IV melanoma and highlights the importance of a multidisciplinary approach with surgeons and oncologists to identify the candidates for this approach and to ensure that patients proceed with surgery in a timely fashion after neoadjuvant therapy. Further follow-up will determine whether this neoadjuvant approach in melanoma has an overall survival benefit over adjuvant therapy alone as well.
Several other questions remain — what is the preferred neoadjuvant regimen in melanoma, for which patient population, and what is the role of adjuvant therapy? Studies have explored regimens such as two cycles of 3 mg/kg nivolumab with 1 mg/kg ipilimumab or BRAF-targeted therapy. Neoadjuvant melanoma trials have also explored whether the adjuvant regimen should be adjusted based on the pathologic response rate — where patients with a complete pathologic response don’t receive any adjuvant therapy, and those with a partial or no pathological response (>50% viable melanoma) are switched to a different adjuvant regimen such as BRAF-targeted therapy or adjuvant radiation with immunotherapy. Trials have also explored de-escalating surgery, such as only surgically removing an index lymph node after neoadjuvant therapy and foregoing complete lymph node dissections in patients with a near or complete pathological response. Future studies will help to answer some of these questions and further define the specifics of neoadjuvant therapy in melanoma.