Melanoma Immunotherapy: 10-Year Survival Data Shows Dramatic Improvement with Checkpoint Inhibitors

How Has Immunotherapy Transformed Advanced Melanoma Survival?

The transformation of advanced melanoma outcomes represents one of the greatest success stories in modern oncology. Before 2011, the only FDA-approved systemic treatments for metastatic melanoma were dacarbazine chemotherapy and high-dose interleukin-2, neither of which improved median overall survival beyond 6-9 months. The five-year survival rate for distant metastatic melanoma was approximately 5%, and a diagnosis of advanced melanoma was considered essentially a death sentence.

The revolution began with ipilimumab (Yervoy), an anti-CTLA-4 antibody approved in 2011 as the first checkpoint inhibitor for any cancer. The pivotal MDX010-20 trial demonstrated that ipilimumab improved median overall survival from 6.4 months with a peptide vaccine to 10.1 months, and approximately 20% of patients achieved durable, long-term survival. While modest by later standards, this was the first drug ever shown to improve survival in metastatic melanoma. The anti-PD-1 antibodies nivolumab (Opdivo, approved 2014) and pembrolizumab (Keytruda, approved 2014) followed, showing superior response rates and survival compared to ipilimumab monotherapy.

The combination of nivolumab plus ipilimumab, targeting both the PD-1 and CTLA-4 immune checkpoints simultaneously, proved to be even more effective. By blocking two distinct inhibitory pathways, the combination unleashes a more potent and sustained anti-tumor immune response. This dual checkpoint blockade has become the foundation of first-line treatment for advanced melanoma, producing response rates and survival outcomes that were unimaginable just 15 years ago.

What Did the CheckMate 067 10-Year Results Show?

CheckMate 067, a three-arm phase 3 trial, randomized 945 patients with previously untreated advanced melanoma to nivolumab plus ipilimumab, nivolumab monotherapy, or ipilimumab monotherapy. The 10-year follow-up data, reported at ASCO 2024 and published in the New England Journal of Medicine, represent the longest follow-up of a randomized checkpoint inhibitor trial in melanoma. The 10-year overall survival rates were 49% for nivolumab plus ipilimumab, 42% for nivolumab alone, and 23% for ipilimumab alone.

The median overall survival was 71.9 months (approximately 6 years) for the combination, 36.9 months for nivolumab alone, and 19.9 months for ipilimumab alone. Remarkably, the survival curves for the combination arm showed a plateau beginning at approximately year 5, suggesting that the majority of patients alive at 5 years will remain alive long-term, consistent with a durable immune memory response against the tumor. Among 10-year survivors in the combination arm, 77% had not received any subsequent systemic therapy, indicating sustained disease control without ongoing treatment.

The durability of responses is particularly noteworthy. Among patients who achieved a complete response (22% of the combination arm), the vast majority remained in remission at 10 years. Grade 3-4 immune-related adverse events occurred in 59% of combination-treated patients, primarily during the induction phase, with immune-mediated colitis, hepatitis, and endocrinopathies being the most common. While many adverse events required immunosuppressive treatment (typically corticosteroids) and some required permanent discontinuation of therapy, the survival benefit was maintained regardless of whether treatment was stopped due to toxicity.

How Are Adjuvant and Neoadjuvant Immunotherapy Extending Benefits to Earlier-Stage Melanoma?

The success of immunotherapy in advanced melanoma has driven its application to earlier disease stages to prevent recurrence after surgical resection. Adjuvant pembrolizumab was evaluated in the KEYNOTE-054 trial, which randomized 1,019 patients with completely resected stage III melanoma to pembrolizumab 200 mg or placebo every 3 weeks for one year. At 5-year follow-up, pembrolizumab reduced the risk of recurrence or death by 35% (HR 0.65), with 5-year recurrence-free survival of 55.4% versus 38.3% with placebo. Adjuvant nivolumab (CheckMate 238) showed similar benefits compared to ipilimumab.

Neoadjuvant immunotherapy, administered before surgery, is an emerging paradigm with compelling early results. The NADINA trial, a phase 3 study presented at ASCO 2024, randomized patients with resectable stage III melanoma to neoadjuvant nivolumab plus ipilimumab (2 cycles before surgery) versus adjuvant nivolumab (12 cycles after surgery). The neoadjuvant arm achieved a major pathological response in 68% and pathological complete response in 59% of patients. At 12 months, event-free survival was 83.7% with neoadjuvant treatment versus 57.2% with adjuvant therapy.

The neoadjuvant approach offers several theoretical advantages: the intact tumor mass may provide a larger source of tumor antigens to prime the immune system, response to treatment can be assessed pathologically to guide further therapy, and patients who achieve a complete pathological response may potentially undergo less extensive surgery. The SWOG S1801 trial further demonstrated that neoadjuvant pembrolizumab (3 cycles before surgery followed by 15 cycles after) improved event-free survival compared to adjuvant pembrolizumab alone (HR 0.58, p=0.004). These results are shifting the treatment paradigm for resectable high-risk melanoma toward neoadjuvant-first strategies.