Advances in Systemic Treatments for Melanoma Highlighted

CORONADO, Calif. — Advances in adjuvant and neoadjuvant systemic therapies are continuing to improve recurrence-free and distant metastasis-free survival rates in patients with advanced melanoma.

At the annual Melanoma and Cutaneous Oncology Symposium meeting, Kathryn Bollin, MD, program director in the Division of Hematology and Oncology at Scripps Clinic, La Jolla, California, highlighted key trials that are helping to refine treatment approaches, starting with 4-year data from the phase 3 KEYNOTE-716 study. In this study, 976 patients with stage IIB or IIC melanoma were randomly assigned to pembrolizumab, an immune checkpoint inhibitor targeting the programmed death receptor 1 (PD-1) for the adjuvant treatment of stage IIB or IIC melanoma following complete resection, or placebo. The rate of relapse-free survival (RFS) among patients in the pembrolizumab group vs the placebo group at 4 years was 71% vs 58%, while the rate of distant metastasis-free survival (DMFS) was 81% vs 70%. The number needed to treat before seeing benefit was 5.3 patients for RFS and 7.8 for DMFS.

With treatment, “it is relevant to note that patients suffer grade 3 and 4 toxicities 15%- 20% of the time, and some of these patients would not require adjuvant therapy,” Bollin explained at the meeting, which was hosted by Scripps Cancer Center, San Diego.

In another phase 3 adjuvant immunotherapy trial, CM-76 K, researchers randomly assigned 790 patients with stage IIB or stage IIC completely resected melanoma to receive nivolumab, a PD-1 inhibitor, or placebo. According to an update presented at the 2024 European Society of Clinical Oncology meeting, at 3 years, the RFS rate was 71% in the nivolumab group vs 61% in the placebo group, while the DMFS rate was 79% in the nivolumab group vs 74% in the placebo group.

The study also found that there were fewer distant recurrences in patients who received nivolumab than in those who received placebo (11% vs 17%). Bollin noted that while existing data show a clear benefit of pembrolizumab and nivolumab on RFS and DMFS for some patients with melanoma, “the toxicity is something to keep in mind while also considering the efficacy of treatment and number of patients needing treatment for one patient to experience benefit from therapy,” she said. “We must also consider patterns of recurrence. Sometimes melanoma recurs in a location that may be treated surgically, or if recurrence is unresectable, there still may be highly effective therapies available. Shared decision-making in the clinic is absolutely essential so that patients understand the potential benefit of treatment, potential risks of treatment, risk of recurrence, and how clinicians weigh options when considering available cancer treatments.”

Treatments for Stage III Melanoma

In the field of treatment for stage III melanoma, the COMBI-AD trial randomly assigned 870 patients with resected stage III BRAF V600 melanoma to receive targeted therapies, either dabrafenib, a BRAF inhibitor, and trametinib, a MEK inhibitor, or placebo. Using Kaplan-Meier estimates, the researchers observed that overall survival favored dabrafenib plus trametinib over placebo, although the benefit was not significant (hazard ratio [HR] for death, 0.80; P = .06 by stratified log-rank test). RFS favored dabrafenib plus trametinib over placebo (HR for relapse or death, 0.52), as did distant metastasis-free survival (HR for distant metastasis or death, 0.56).

In the area of adjuvant treatment for stage IIIB-C and resected stage IV melanoma, 5-year data from the phase 3 CheckMate 238 study found that compared with adjuvant ipilimumab (a human cytotoxic T-lymphocyte antigen 4-blocking antibody), adjuvant nivolumab significantly improved RFS (50% vs 39% vs 50%) and DMFS, but overall survival results between the two drugs failed to reach statistical significance (72% vs 77%).

Findings were similar for the EORTC 1325/KEYNOTE-054 study, which evaluated pembrolizumab vs placebo for stage IIIA-C melanoma. At 7 years, RFS was 50% in the pembrolizumab group and 36% in the placebo group, while DMFS was 54% in the pembrolizumab and 42% in the placebo group.

Survival-related findings from studies that combine checkpoint inhibitors also show promise. In the IMMUNED trial, patients with stage IV melanoma with no evidence of disease after surgery or radiotherapy were randomly assigned to either nivolumab plus ipilimumab, nivolumab monotherapy, or matching placebo for up to 1 year. According to the final results of the trial, 4-year RFS was 64.2% in the nivolumab plus ipilimumab group, 31.4% in the nivolumab alone group, and 15% in the placebo group, while 4-year overall survival was 83.8% in the nivolumab plus ipilimumab group, 72.6% in the nivolumab alone group, and 63.1% in the placebo group. However, the rate of grade 3 and 4 toxicity in the nivolumab plus ipilimumab group was 71%, “so this is not prescribed in the adjuvant setting,” Bollin said. “It’s toxic, and we have alternatives that make more sense, as demonstrated in emerging data from neoadjuvant studies.”

The role of neoadjuvant immunotherapy is rapidly advancing. Building on concepts inspired by the PRADO extension of the OpACIN-neo trial, researchers in a phase 2 trial known as the SWOG Cancer Research Network S1801 trial randomly assigned patients with IIIB-IVC melanoma to either neoadjuvant plus adjuvant pembrolizumab or adjuvant pembrolizumab. The 2-year event-free survival was 72% in the neoadjuvant plus adjuvant group vs 49% in the adjuvant-only group. Overall survival data from the trial “are still premature,” said Bollin, who was not involved in the analysis.

In a phase 3 trial known as NADINA, researchers randomly assigned patients with resectable, macroscopic stage III melanoma to two cycles of neoadjuvant ipilimumab plus nivolumab followed by surgery or surgery followed by 12 cycles of adjuvant nivolumab. At a median follow-up of 9.9 months, the estimated 12-month event-free survival was 83.7% in the neoadjuvant group and 57.2% in the adjuvant group. In addition, a major pathologic response was observed in 59% of patients in the neoadjuvant group, “which means that the majority of melanoma is no longer present in the lymph node,” Bollin said. “That is remarkable.”

She noted that while the beauty of prescribing immunotherapy is durable disease control in patients when a response is achieved, “sometimes the toxicities associated with these medications are also durable.” She added that “there can be chronic immune-related adverse events that require permanent immune suppression or hormone supplementation, which impact a person’s quality of life. Patients may require life-long monitoring and a collaborative engagement with subspecialists to keep well in the long term.”

Bollin reported having no financial disclosures.