Neoadjuvant Immunotherapy Shows Promise in Melanoma Treatment: Two Studies Demonstrate Improved Outcomes with Pre-Surgery Approach
Key Insights
The S1801 trial demonstrated that neoadjuvant pembrolizumab before surgery significantly improved event-free survival compared to adjuvant therapy alone, with 72% of patients remaining event-free at 2 years versus 49% in the adjuvant-only group.
A separate study of neoadjuvant relatlimab plus nivolumab achieved a 57% pathologic complete response rate in resectable melanoma patients, with 70% achieving any pathologic response and improved 2-year recurrence-free survival.
Both neoadjuvant approaches showed manageable safety profiles, with the relatlimab-nivolumab combination demonstrating no grade 3/4 immune-related adverse events during the pre-surgical phase.
Two groundbreaking clinical trials are reshaping the treatment landscape for advanced melanoma by demonstrating that immunotherapy administered before surgery can significantly improve patient outcomes compared to traditional post-surgical approaches.
Pembrolizumab Before Surgery Reduces Cancer Recurrence
The phase 2 S1801 trial, conducted by the SWOG Cancer Research Network and presented at the European Society for Medical Oncology (search) meeting, enrolled 313 patients with stage 3 or 4 melanoma. Participants were randomly assigned to receive either surgery followed by 18 doses of pembrolizumab over one year, or three doses of pembrolizumab during the two months before surgery followed by 15 doses over 10 months post-surgery.
The results were striking: at 2 years, 72% of patients in the neoadjuvant therapy group remained alive without disease progression, compared with 49% in the adjuvant-only group. The cancer returned in only 9 of 154 patients who received neoadjuvant treatment, versus 44 of 159 patients in the adjuvant-only group.
"Surgery still has a role for these patients, but the timing of surgery may well change," said lead investigator Dr. Sapna Patel of the University of Texas MD Anderson Cancer Center. Approximately 20% of patients treated with pembrolizumab before surgery experienced complete tumor disappearance.
Dual Checkpoint Blockade Achieves High Response Rates
A separate investigator-initiated trial evaluated the combination of relatlimab and nivolumab in 30 patients with resectable clinical stage III or oligometastatic stage IV melanoma. This study achieved a 57% pathologic complete response rate, with 70% of patients achieving any pathologic response.
The treatment protocol involved two intravenous doses of relatlimab 160 mg with nivolumab 480 mg at 4-week intervals, followed by surgery at 9 weeks and up to 10 additional doses post-surgery. With a median follow-up of 24.4 months, the 2-year recurrence-free survival rates were 92% for patients with any pathologic response compared to 55% for those without response.
Safety Profile Supports Clinical Implementation
Both studies demonstrated manageable safety profiles. The relatlimab-nivolumab combination showed no grade 3/4 immune-related adverse events during the neoadjuvant phase, though 26% of patients experienced grade 3/4 toxicities during adjuvant treatment. The pembrolizumab study reported few serious side effects with no significant difference between treatment groups.
A potential concern with neoadjuvant therapy is disease progression that could preclude surgery. In the pembrolizumab trial, 42 patients showed some cancer progression during neoadjuvant treatment, but 30 were still able to undergo surgery. Only one patient in the relatlimab-nivolumab study developed distant metastases and could not proceed to surgery.
Mechanistic Insights Support Neoadjuvant Approach
The rationale for neoadjuvant immunotherapy centers on exploiting immune cells already present in and around tumors. "The immune system has already recognized the tumor as dangerous," explained Dr. Elad Sharon of NCI's Cancer Therapy Evaluation Program. "The immune response just hasn't been strong enough to destroy the tumor."
By administering immunotherapy while the tumor remains intact, the treatment can dramatically increase tumor-specific T cells. After tumor removal, these activated T cells circulate to target micro-metastases throughout the body.
Correlative studies from the relatlimab-nivolumab trial revealed increased frequencies of memory CD4+ and effector CD8+ T cells in post-treatment tumor specimens of responding patients, along with reduced M2-like macrophages associated with immunosuppression.
Implications for Treatment Guidelines
These findings may prompt revisions to professional oncology treatment guidelines. Dr. Teresa Petrella of the Sunnybrook Odette Cancer Centre (search) noted that the S1801 results "support the idea that neoadjuvant therapy and adjuvant therapy is more effective than adjuvant therapy alone."
The studies also raise important questions about optimizing treatment duration and combinations. Researchers are investigating whether patients achieving complete pathologic responses need full adjuvant therapy courses, and whether combination approaches could further improve outcomes.
Both trials represent a paradigm shift from the standard practice of immediate surgery followed by adjuvant therapy. As Dr. Patel noted, "I think we've shown that leaving the cancer in place, at least for a short time, may be preferable."