Timing of Adjuvant Immunotherapy in Stage III Melanoma, Does it Matter?

INTRODUCTION: Immune checkpoint inhibitors (ICI) have been shown to reduce recurrence in patients with stage III cutaneous melanoma; however, the optimal time to initiate adjuvant ICI following oncologic resection remains undefined. Herein, we investigated the impact of time to adjuvant ICI on survival in patients with stage III melanoma.

METHODS: Patients with resected, pathologic stage III cutaneous melanoma receiving adjuvant ICI were identified within a multi-institutional retrospective cohort (2014-2022). Patients were stratified by time to induction of adjuvant ICI: within 6 weeks, 6-12 weeks, and greater than 12 weeks from surgery. The primary outcome was recurrence free survival (RFS) which was compared among time strata with Kaplan Meier and Cox proportional hazards methods. Conditional landmark analysis was performed to limit immortal time bias.

RESULTS: Altogether, 626 patients were identified with a median time to adjuvant ICI of 7.1 weeks (IQR 4.8-10.6). 39% (n=246) patients initiated adjuvant ICI within 6 weeks, 42.2% (n=264) within 6-12 weeks, and 18.8% (n=118) greater than 12 weeks from surgery. The type of adjuvant ICI, in decreasing order of prevalence, included: nivolumab (68.1%), pembrolizumab (18.5%), ipilimumab (11%), or a combination (2.1%). In a multivariable Cox regression model, adjusting for histology, nodal tumor burden (mm), and pathologic stage, we found that increased time to adjuvant ICI (per week) was associated with improved RFS (HR 0.96, 95% CI 0.93- 0.99; p=0.02). Patients who initiated adjuvant ICI within 6 weeks of surgery had worse RFS (40.4 vs. 55.9 vs. 60.8% 36-month RFS, respectively) (Figure). This survival disadvantage was preserved in a conditional landmark analysis.

CONCLUSIONS: Patients with stage III cutaneous melanoma may benefit from waiting at least 6 weeks after oncologic resection before initiating adjuvant ICI. Additional work is needed to better understand the underlying mechanisms and implications of timing of adjuvant ICI on long-term outcomes.

Authors: Kristen E. Rhodin, MD, General Surgery Resident - Duke University Medical Center (Presenter;Submitter;Author); Sin-Ho Jung, PhD, Professor of Biostatistics and Bioinformatics - Duke University (Author); Kelly Elleson, MD, Breast Surgical Oncology Fellow - Moffitt Cancer Center (Author); Danielle DePalo, MD, Research Fellow - Moffitt Cancer Center (Author); Richard Straker, MD, General Surgery Resident - Hospital of the University of Pennsylvania (Author); Sophia McKinley, MD, Complex General Surgical Oncology Fellow - Memorial Sloan Kettering Cancer Center (Author); Kate Beekman, n/a, Medical Student - University of South Florida (Author); Lily Parker, n/a, Medical Student - University of South Florida (Author); Suephy Chen, MD, MS, Professor of Dermatology- Duke University Medical Center (Author); April Salama, MD, Associate Professor of Medicine - Duke University Medical Center (Author); Matthew K. Iyer, MD, PhD, Complex General Surgical Oncology Fellow - Duke University Medical Center (Author); Edmund K. Bartlett, MD, Assistant Attending - Gastric and Mixed Tumor Service, Memorial Sloan Kettering (Author); Giorgos C. Karakousis, MD, Professor of Surgery - Department of Surgery, University of Pennsylvania Health System (Author); Jonathan S. Zager, MD, Professor of Surgery - Moffitt Cancer Center (Author); Douglas S. Tyler, MD, Professor of Surgery - University of Texas Medical Branch (Author); Georgia M. Beasley, MD, MHS, Associate Professor of Surgery - Duke University School of Medicine (Author)