Highlights
- In real-world settings, adjuvant targeted therapy with BRAF plus MEK inhibitors shows superior recurrence-free survival (RFS) compared to PD-1 checkpoint inhibition for BRAF-mutant stage III melanoma patients.
- Rapid recurrences are notably higher in PD-1-treated patients with macroscopic lymph node metastases, pointing to distinct risk profiles.
- Shorter treatment duration (<6 months) does not compromise RFS for anti-PD-1 therapy but may adversely affect outcomes in targeted therapy.
- Integration of biomarker and microbiome research is refining neoadjuvant and adjuvant therapeutic strategies, with pathologic response emerging as a key predictor of durable remission.
Background
Stage III melanoma represents a pivotal therapeutic challenge due to its high risk of recurrence and mortality despite complete surgical resection. The development and approval of adjuvant therapies, specifically immune checkpoint inhibitors targeting PD-1 and targeted therapies inhibiting the mutant BRAF and MEK kinases, have revolutionized management by substantially improving recurrence-free and overall survival (OS). However, evidence from real-world clinical practice, which reflects heterogeneous patient populations and treatment adherence patterns, remains critical to fully understand the long-term effectiveness and optimal application of these therapies. This review focuses on synthesizing data from the recent key real-world study by Lodde et al., supplementing it with contemporary trial evidence and translational insights to provide a nuanced picture of adjuvant treatment in stage III melanoma.
Key Content
1. Real-World Long-Term Outcomes of Adjuvant PD-1 and Targeted Therapy (Lodde et al., 2025)
A multicenter German cohort study followed 589 stage III melanoma patients receiving adjuvant PD-1 inhibitors or targeted therapy (TT: combined BRAF plus MEK inhibition) over 4 years. Key findings include:
- 48-month RFS was 42.9% (95% CI, 38.5–47.8) for PD-1-treated patients and 52.6% (95% CI, 43.6–63.3) for TT patients.
- Among patients harboring BRAF mutations, TT demonstrated a significantly lower recurrence risk compared with PD-1 therapy (HR 1.57; 95% CI, 1.09–2.26).
- Four-year OS was numerically higher with TT (87.3%; 95% CI, 81.0–94.0) versus PD-1 therapy (80.8%; 95% CI, 73.6–88.7) in BRAF-mutant patients.
- Patients who initiated PD-1 therapy after resection of macroscopic lymph node metastases had markedly higher rates of rapid recurrence (1-year RFS 58%) compared to TT-treated counterparts (87%).
- Premature treatment discontinuation (≤6 months) increased recurrence risk in TT patients but did not significantly impact PD-1 treated individuals.
These findings emphasize differential relapse patterns and therapeutic durability between immunotherapy and targeted therapy in routine clinical use.
2. Randomized Controlled Trial Evidence of Adjuvant Anti-PD-1 Immunotherapy
The KEYNOTE-054 (EORTC1325) phase 3 trial evaluating pembrolizumab for resected stage III melanoma reported sustained benefit with a 7-year median follow-up (Eggermont et al., 2024). Patients treated with pembrolizumab demonstrated:
- 7-year RFS of 50% versus 36% with placebo (HR 0.63; 95% CI, 0.53–0.74).
- Distant metastasis-free survival (DMFS) was improved (54% versus 42%).
- Benefit was consistent across substage IIIA-IIIC, PD-L1 status, and BRAF mutation subgroups.
This trial underpins the clinical utility of PD-1 blockade in prolonging disease control post-surgery.
3. Neoadjuvant Combination Approaches and Biological Correlates
Emerging therapeutic strategies include neoadjuvant regimens combining targeted therapy and checkpoint inhibitors to enhance pathologic response and leverage immunologic priming before surgery.
- NeoACTIVATE trial: Neoadjuvant cobimetinib and atezolizumab ± vemurafenib in BRAF-mutated and BRAF wild-type stage III melanoma showed favorable major pathologic response rates and prolonged RFS with 49 months median follow-up (Gopalakrishnan et al., 2025). Notably, gut microbiome diversity and functional microbial pathways correlated with distant metastasis-free survival, highlighting the microbiome’s role in modulating T-cell immunity and therapeutic response.
- OpACIN and OpACIN-neo trials: Neoadjuvant ipilimumab plus nivolumab combination yielded high response and survival rates in macroscopic stage III melanoma, with 5-year RFS up to 70–82% and OS 90–92% (Rozeman et al., 2023). Pathologic response emerged as the strongest predictor of relapse risk, serving as a surrogate biomarker for long-term outcomes.
These studies exemplify the translational integration of immunologic mechanisms and neoadjuvant paradigms to improve adjuvant treatment efficacy.
4. Comparative Mechanistic and Clinical Insights
The observed superior RFS with targeted therapy in certain clinical subsets (BRAF-mutant patients, especially with macroscopic nodal disease) may reflect the rapid tumor cell cytotoxicity of BRAF/MEK inhibitors relative to the immunologic kinetics of PD-1 blockade. Conversely, PD-1 inhibitors induce durable immune memory and have demonstrated long-term OS benefit, albeit with a higher initial relapse risk in aggressive disease presentations.
Treatment duration impacts relapse risk differently: targeted therapies rely on continuous dosing to suppress oncogenic signaling, so premature cessation may permit tumor regrowth. In contrast, anti-PD-1 therapies can induce durable immune surveillance that may persist after limited treatment exposure, consistent with Lodde et al.’s real-world findings.
The role of individualized biomarkers—including PD-L1 expression, BRAF mutation subtype, tumor microenvironment features, and microbiome composition—has become increasingly recognized for guiding treatment selection and sequencing.
Expert Commentary
Lodde et al.’s extensive real-world data reinforce and extend phase 3 trial observations, highlighting that adjuvant targeted therapy may confer superior relapse prevention in BRAF-mutant stage III melanoma, particularly in patients with bulky nodal disease. However, PD-1 monotherapy remains a critical cornerstone given its proven OS benefit, broader applicability (including BRAF wild-type), and potential for immune memory.
The differential impact of treatment duration on outcomes suggests tailored therapeutic strategies may optimize efficacy while minimizing toxicity and cost. Future clinical guidelines should incorporate these real-world insights alongside robust clinical trial data to refine adjuvant melanoma management.
Moreover, the integration of neoadjuvant approaches and microbiome-immune interactions represents an exciting frontier. Stratifying patients by pathologic response and immune correlates offers potential for de-escalation in responders and intensification in high-risk groups.
Limitations include retrospective analyses and potential confounders despite advanced statistical adjustments. Nonetheless, the comprehensive and longitudinal follow-up across multiple centers provides high external validity.
Conclusion
Adjuvant therapy for stage III melanoma has markedly improved outcomes through immune checkpoint inhibition and targeted therapy. Real-world evidence reveals that targeted therapy offers superior relapse control in BRAF-mutant disease, while anti-PD-1 therapy affords durable OS benefits. Treatment decisions should consider disease burden, mutation status, and patient-specific factors, with emerging data supporting the role of treatment duration and neoadjuvant paradigms.
Ongoing research integrating molecular biomarkers, immune profiling, and microbiome dynamics will inform personalized adjuvant strategies, ultimately enhancing long-term survival and quality of life for melanoma patients.
References
- Lodde GC, Hassel JC, von Wasielewski I, et al. Long-Term Follow-Up of Real-World Adjuvant Anti-PD-1 Checkpoint Inhibition and Targeted Therapy in Patients With Stage III Melanoma. J Clin Oncol. 2025 Sep;43(25):2793-2805. doi:10.1200/JCO-24-02776. PMID: 40460331.
- Eggermont AMM, Blank CU, Mandala M, et al. Seven-year analysis of adjuvant pembrolizumab versus placebo in stage III melanoma in the EORTC1325 / KEYNOTE-054 trial. Eur J Cancer. 2024 Nov;211:114327. doi:10.1016/j.ejca.2024.114327. PMID: 39288737.
- Gopalakrishnan V, Vienne M, et al. Neoadjuvant cobimetinib and atezolizumab with or without vemurafenib for stage III melanoma: outcomes and the impact of the microbiome from the NeoACTIVATE trial. J Immunother Cancer. 2025 Apr 15;13(4):e011706. doi:10.1136/jitc-2025-011706. PMID: 40234093.
- Rozeman EA, Hoefsmit EP, Reijers ILM, et al. Survival update of neoadjuvant ipilimumab plus nivolumab in macroscopic stage III melanoma in the OpACIN and OpACIN-neo trials. Ann Oncol. 2023 Apr;34(4):420-430. doi:10.1016/j.annonc.2023.01.004. PMID: 36681299.
