Melanoma Treatment Algorithm for the Community Oncologist
Key Points
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Stage II melanoma carries a significant risk of recurrence, with 1 year of adjuvant immunotherapy using single-agent PD-1 inhibitors as the standard of care.
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Circulating tumor DNA (ctDNA) is emerging as a potential prognostic tool.
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Neoadjuvant immunotherapy is reshaping the management of stage III melanoma, with pathologic complete response serving as a powerful predictor of long-term outcomes.
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In metastatic melanoma, dual immune checkpoint inhibition remains the backbone of first-line therapy.
Current Treatment Landscape of Melanoma
Co-hosts of the Oncology Brothers podcast, Rahul Gosain, MD, MBA, of Wilmot Cancer Institute, and Rohit Gosain, MD, of Roswell Park Comprehensive Cancer Center, spoke with Omid Hamid, MD, of Cedars-Sinai, about the current treatment paradigm for melanoma. The discussion offered expert perspective from early-stage disease to metastatic melanoma with brain metastases.
Advances in immunotherapy, targeted therapy, molecular profiling, and prognostic tools such as ctDNA are moving the field forward, with shared decision-making remaining a crucial part of a patient’s treatment plan.
Treatment of Early-Stage Melanoma
For patients with stage IA to IB melanoma, particularly younger patients with thinner tumors (around 0.75 mm), recent changes in the therapeutic paradigm have focused on the implications of sentinel lymph node positivity, according to Dr. Hamid. While most of these patients are managed surgically, sentinel node findings may influence closer surveillance and future risk discussions.
In stage II disease, particularly stage IIC, the risk of recurrence is significant, eliciting a more aggressive approach that mirrors high-risk stage III management. Patients should undergo comprehensive staging, including whole-body imaging and next-generation sequencing (NGS), said Dr. Hamid.
Unlike stage III disease, there is currently no evidence supporting adjuvant BRAF/MEK inhibitor therapy for BRAF V600-mutant stage II melanoma, said Dr. Hamid. Adjuvant immunotherapy with single-agent PD-1 inhibitors—nivolumab or pembrolizumab—for 1 year is the standard of care.
Discussions around this type of therapy involve the risk for immune-related adverse events, including diabetes, myocarditis, myositis, and adrenal insufficiency. These conversations are especially important for younger and more active patients, as well as female patients who may be considering the effect of treatment on fertility, said Dr. Hamid.
Surveillance strategies involve imaging every 3 months for the first 2 years, then every 6 months for 3 years, followed by annual imaging for up to 10 years, with clinical exams every 6 months.
ctDNA’s Emerging Role
Although many patients visit Dr. Hamid after they’ve had a surgical procedure, he emphasized the importance of ctDNA testing. Assessment prior to surgery and postoperatively can help refine the risk of recurrence. Dr. Hamid explained that persistent or positive ctDNA is associated with worse outcomes. In addition, he stressed that comprehensive NGS remains valuable, as melanoma frequently harbors mutations beyond BRAF, including RAS, ALK, EGFR, and HER alterations.
In his practice, Dr. Hamid splits appointments in half to allow patients time to comprehend the information he shares. The initial visit is a discussion, where patients are sent home with information to review about the treatment. In the following appointment, patients return to discuss treatment options before committing to therapy.
Neoadjuvant Versus Adjuvant Treatment in Stage III Disease
The stage III treatment landscape has shifted significantly with the introduction of neoadjuvant therapy. For patients presenting with clinically evident nodal disease, both neoadjuvant and adjuvant approaches are considered, said Dr. Hamid. Two neoadjuvant immunotherapy regimens are approved (ipilimumab/nivolumab or pembrolizumab), although they have not yet been compared head-to-head.
Compared with adjuvant therapy, randomized trials have demonstrated improved relapse-free survival with neoadjuvant strategies. The strongest evidence supports immunotherapy-based regimens. For instance, SWOG S1801 reinforces neoadjuvant pembrolizumab and NADINA with combination ipilimumab/nivolumab. Both trials showed that if a patient achieves a pathologic complete response (CR), they have a 98% chance of no recurrence. In NADINA specifically, CR was 60% iamong those treated with the regimen. However, dual checkpoint inhibition is associated with increased toxicity, and the impact on long-term overall survival remains under investigation, explained Dr. Hamid.
In BRAF V600K–positive tumors, the use of dabrafenib and trametinib demonstrated no statistically significant advantage over immunotherapy.
Advanced Melanoma With Brain Mets
Dual checkpoint inhibition remains the standard first-line approach for metastatic melanoma. Dr. Hamid explained that workups in advanced disease should always include brain MRI, PET imaging, contrast-enhanced CT scans, and tumor NGS, with BRAF status playing a critical role in sequencing therapy.
While immunotherapy is preferred upfront, patients with rapidly progressive disease may benefit from a “sandwich” approach using short-term BRAF/MEK inhibition followed by immunotherapy (eg, ipilimumab/nivolumab). In cases of brain metastasis, patients are treated aggressively, often with full-dose ipilimumab/nivolumab based on data from CheckMate 204.
In later-line settings, treatment selection depends on prior exposure. Patients progressing on PD-1 therapy may receive CTLA-4–based regimens or newer combinations, like LAG-3/PD-1 inhibitors.
Referral to melanoma centers of excellence is encouraged for access to clinical trials, adoptive T-cell therapies, and emerging strategies, said Dr. Hamid.
Future Outlook
Ongoing clinical trials aim to refine treatment duration and sequencing, including studies evaluating shorter versus longer courses of neoadjuvant and adjuvant immunotherapy, such as the phase 3 international Grand SLAM study. Investigators hope to optimize outcomes while minimizing toxicity for patients with melanoma to move the field forward.