The Push and Pull: Navigating Neoadjuvant and Adjuvant Strategies in Melanoma

The management of resectable stage II and III melanoma is undergoing a paradigm shift as the "push and pull" between adjuvant and neoadjuvant strategies intensifies. While adjuvant therapy has long been the standard of care for reducing recurrence risk, recent data from landmark trials suggest that initiating immunotherapy in the neoadjuvant setting may offer superior event-free survival (EFS) and allow for response-driven personalization of subsequent care.

Omid Hamid, MD, chief of Translational Research and Immuno-Oncology at The Angeles Clinic and Research Institute, a Cedars-Sinai affiliate, co-director of Cutaneous Malignancies and director of Phase I Programs, professor in the Department of Medicine at Cedars-Sinai and heads the Experimental Therapeutics Division Clinicians, presented at the 22nd Annual International Symposium on Melanoma and Other Cutaneous Malignancies about the long-term durability of established adjuvant regimens against the emerging evidence supporting neoadjuvant-adjuvant approaches. Read on for the top 5 takeaways from his presentations.¹

1. Neoadjuvant-Adjuvant Sequencing Improves Outcomes:

Data from the phase 2 SWOG S1801 trial (NCT03698019) demonstrated that initiating pembrolizumab (Keytruda) prior to surgery followed by adjuvant therapy significantly improved event-free survival (EFS) compared with an adjuvant-only approach.² The 2-year EFS was 72% for the neoadjuvant/adjuvant group vs 42% for the adjuvant-only group. Hamid noted the sample size was too small and the data too early to determine if overall survival (OS) differs.

2. NADINA Trial Redefines Stage III Management:

The phase 3 NADINA trial (NCT04949113) showed that 2 cycles of neoadjuvant ipilimumab (Yervoy) plus nivolumab (Opdivo) followed by surgery resulted in a major pathologic response (MPR) of 59% by central review.³ Results presented at the European Society of Medical Oncology 2024 Congress showed that approximately 61% of patients achieved MPR (pathologic complete response [pCR] or near pCR with 10% or less vital tumor cells) do not require further adjuvant treatment, potentially sparing them from additional toxicity.⁴ These data were taken from the relapse-free survival (RFS) and distant metastasis-free survival pathological response analysis in the neoadjuvant arm.

3. Pathologic Response as a Critical Biomarker:

Pathologic response serves as a powerful predictor of long-term prognosis. In the phase 2 PRADO trial, patients achieving an MPR in neoadjuvant trials showed a 5-year EFS of 71% and OS of 86%, whereas those with no pathologic response have outcomes similar to patients treated in the adjuvant setting alone.⁵

4. Adjuvant Standard of Care for Stage IIB/C:

For patients with stage IIB or IIC melanoma (sentinel lymph node negative), adjuvant anti-PD-1 therapy remains the evidence-based standard. Trials such as the phase 3 KEYNOTE-716 (NCT03553836) assessing pembrolizumab and phase 3 CheckMate 76K (NCT04099251) assessing nivolumab have demonstrated significant improvements in RFS compared with placebo in this population.^6,7

5. Long-term Durability of Targeted Therapy:

For BRAF-mutant stage III melanoma, the phase 3 COMBI-AD trial (NCT01682083) 10-year update confirms the long-term benefit of adjuvant dabrafenib (Tafinlar) plus trametinib (Mekinist). The regimen maintained a HR of 0.52 for RFS compared with placebo, providing a durable non-immunotherapy option for eligible patients.⁸

References

1. Hamid O. The push & pull between adjuvant and neoadjuvant therapy. Presented at the 22nd Annual International Symposium on Melanoma and Other Cutaneous Malignancies; February 21, 2026; Long Beach, CA.
2. Patel SP, Othus M, Chen Y, et al. Neoadjuvant-adjuvant or adjuvant-only pembrolizumab in advanced melanoma. N Engl J Med. 2023;388(9):813-823. doi:10.1056/NEJMoa2211437
3. Blank CU, Lucan MW, Scolyer RA, et al. Neoadjuvant nivolumab plus ipilimumab versus adjuvant nivolumab in macroscopic, resectable stage III melanoma: the phase 3 NADINA trial. J Clin Oncol. 2024;42(suppl 17):LBA2. doi:10.1200/JCO.2024.42.17_suppl.LBA2
4. Lucas MW, Menzies AM, Lopez-Yurda, et al. Distant metastasis-free survival of neoadjuvant nivolumab plus ipilimumab versus adjuvant nivolumab in resectable, macroscopic stage III melanoma: the NADINA trial. European Society of Medical Oncology Congress 2024, Barcelona Spain; September 13-17, 2024. Abstract LBA42.
5. Hoeijmakers LL, Dimitriadis P, Wijnen SCMA, et al. Neoadjuvant ipilimumab plus nivolumab in melanoma: 5-year survival and biomarker analysis from the phase 2 PRADO-trial. Nat Med. Published online January 28, 2026. doi:10.1038/s41591-025-04158-9
6. Luke JJ, Rutkowski P, Queirolo P, et al. Pembrolizumab versus placebo as adjuvant therapy in completely resected stage IIB or IIC melanoma (KEYNOTE-716): a randomised, double-blind, phase 3 trial. Lancet. 2022;399(10336):1718-1729. doi:10.1016/S0140-6736(22)00562-1
7. Kirkwood JM, Del Vecchio M, Weber J, et al. Adjuvant nivolumab in resected stage IIB/C melanoma: primary results from the randomized, phase 3 CheckMate 76K trial. Nat Med. 2023;29(11):2835-2843. doi:10.1038/s41591-023-02583-2
8. Long GV, Hauschild A, Santinami M, et al. Final results for adjuvant dabrafenib plus trametinib in stage III melanoma. N Engl J Med. 2024;391(18):1709-1720. doi:10.1056/NEJMoa2404139