Neoadjuvant therapies have the potential to downstage unresectable disease and allow operative resection with a curative intent.
Neoadjuvant therapy for melanoma is systemic treatment administered before surgery, primarily for resectable stage III disease with clinically positive lymph nodes.
This approach has demonstrated improved event-free survival compared to upfront surgery followed by adjuvant therapy.
The primary goal is to induce a pathologic response that correlates with improved outcomes.
Neoadjuvant immunotherapy leads to a greater expansion of T cells in the blood compared with the adjuvant immunotherapy.
Leaving a tumor in place educates the immune system to generate an anti-tumor immune response, better than if the tumor was removed first.
Preoperative therapy may improve the rate of microscopically margin negative resection.
Neoadjuvant therapy means earlier treatment of systemic micrometastatic disease, fewer delays in systemic therapy caused by surgical complications, and a high likelihood of completion of the planned course of multi modality treatment.
Major pathologic response (MPR)—defined as 90% 3-year recurrence-free survival,achieved with a very short course of preoperative therapy (≤3 doses).
Systemic immunotherapy and targeted BRAF/MEK innovation may be more effective in the neoadjuvant management setting: suggesting the presence of tumor biomass may increase the probability of immunologic activation against tumor antigens.
A neoadjuvant approach allows for biologic response assessment to treatment providing information that can indicate prognosis, decision making regarding additional treatment and information about the cellular molecular effects of therapy on the tumor microenvironment.
A pooled analysis of six clinical trials found a pathological complete response rate to neoadjuvant therapy of 40% overall, 47% with targeted therapy, and 33% with immunotherapy: a pathologic complete response, correlated with improved relapse, free, survival, and overall survival, suggesting the use of pathological complete response as an early surrogate endpoint in clinical trials.
Neoadjuvant therapy for melanoma may delay the time to surgical resection and carries a risk that a disease of some patients will progress and become unresectable.
Both targeted therapy and checkpoint blockade are associated with toxicities that could delay surgery, preclude surgery altogether, or complicate the surgical course.
Preferred Regimens:
Pembrolizumab (200 mg every 3 weeks × 3 doses): achieved 72% 2-year event-free survival vs. 49% with adjuvant therapy alone in the SWOG1801 trial .
Nivolumab/ipilimumab (240 mg/80 mg every 3 weeks × 2 doses): achieved 83.7% 12-month event-free survival vs. 57.2% with adjuvant therapy in the NADINA trial .
Other recommended options include nivolumab monotherapy and nivolumab/relatlimab.
For patients with BRAF V600 mutations in whom immunotherapy is contraindicated, dabrafenib/trametinib may be considered for 4-12 weeks preoperatively.
There are high rates of durable responses with neoadjuvant targeted therapy for BRAFV V600 positive melanomas which occurs in approximately 50% of patients.
Neoadjuvant therapy with checkpoint blockers is efficacious in melanoma.
Neoadjuvant checkpoint blockers may be associated with a higher recurrence free rate than adjuvant therapies.
BRAF/MEK plus checkpoint blockade is being evaluated as neoadjuvant melanoma therapy.
The combination of PD-L1 inhibitor Nivolumab plus relatlimab a lymphocyte antigen gene 3 (LAG-3) inhibitor showed improvement in metastatic melanomas vs Nivolumab alone.
Among patients with resectable stage III or IV melanoma, event free survival was significantly longer among those who receives Pembrolizumab, both before, and after surgery than among those who received adjuvant, Pembrolizumab alone (Patel SP).
The effectiveness of treating melanoma neo-adjuvantly has reduced the degree of surgery that is performed on the primary lesion and on lymph nodes.
Among patients with resectable, macroscopic stage III melanoma, neoadjuvant nivolumab and ipilimumab followed by surgery and response driven adjuvant therapy resulted in longer event free survival than surgery followed by adjuvant nivolumab (Blank CU).
Beyond improved survival, neoadjuvant therapy may convert borderline unresectable disease to resectable, potentially allow for more limited lymph node dissection in patients achieving MPR, and enable response-adapted adjuvant therapy decisions.
Overall survival benefit has not yet been demonstrated, and close monitoring is required to detect progression that might prevent curative surgery.
Pathologic response serves as a surrogate endpoint for long-term outcomes.
Pooled analyses show pathologic complete response rates of 33% overall, with 42% for combination immunotherapy and 20% for anti-PD-1 monotherapy.
Pathologic complete response rates of 44-42% and 12-month recurrence-free survival of 94% among responders.
Notably, patients achieving major pathologic response have >90% recurrence-free survival at 2-3 years, often without requiring adjuvant therapy.
The advantage of neoadjuvant therapy lies in activating tumor-resident T-cell clones before surgical resection.
Studies demonstrate that neoadjuvant administration produces larger expansion of tumor-specific T cells compared to postoperative therapy, as these immune effectors remain in circulation to target micrometastatic disease after surgery.
High interferon-γ gene expression and tumor mutational burden independently predict better responses to neoadjuvant immunotherapy.
For BRAF-mutated melanoma, targeted therapy with dabrafenib plus trametinib produces high response rates but demonstrates less durable pathologic responses compared to immunotherapy.
A randomized phase 2 trial showed significantly longer event-free survival with neoadjuvant plus adjuvant BRAF/MEK inhibition versus surgery alone, though cross-trial comparisons suggest immunotherapy may be preferable when feasible.
Current practice often reserves BRAF-targeted therapy for patients with contraindications to immunotherapy or as salvage therapy for immunotherapy non-responders.
Grade ≥3 immune-related adverse events occurring in 9-10% of patients receiving anti-PD-1 monotherapy and 32-72% with combination ipilimumab/nivolumab.
Importantly, 88-86% of patients proceed to planned surgery without delays from treatment-related toxicity.
The risk of disease progression preventing surgery remains low at approximately 6-10% with appropriate patient selection.