BRAF mutations occur in approximately 40% of cutaneous melanomas, often correlating with aggressive early-stage disease and a younger patient population. Significant advancements in melanoma treatment have been achieved with BRAF/MEK-targeted therapies and immune checkpoint inhibitors (ICIs). Targeted therapies, while offering high objective response rates (nearly 70%), typically see most progress within two years. ICIs, though possessing lower initial response rates, demonstrate much less frequent acquired resistance. Preclinical data suggests a synergistic potential between BRAF/MEK inhibitors and ICIs, with BRAF/MEK inhibition shown to create a more favorable tumor immune microenvironment by increasing tumor-infiltrating T cells (CD4+ and CD8+) and PD-L1 expression. This raises the possibility that combining these treatments could amplify antitumor activity. Several trials have explored combining BRAF-targeted therapy and ICIs in advanced melanoma, demonstrating prolonged progression-free survival but also increased toxicity with concurrent administration. Sequential administration strategies have also been investigated. In resectable melanoma, neoadjuvant therapy is a promising area of investigation. Previous studies showed that neoadjuvant BRAF-targeted therapy and neoadjuvant ICI achieved pathological complete response (pCR) in 47% and 33% of patients, respectively, however, the long-term benefits of targeted therapy in this setting remain uncertain. The Neo Trio trial aimed to determine if adding targeted therapy (dabrafenib plus trametinib) enhances the benefits of neoadjuvant anti-PD-1 (pembrolizumab) in resectable BRAF-mutant melanoma.

Existing literature highlights the individual efficacy of both BRAF/MEK inhibitors and immune checkpoint inhibitors in melanoma treatment. Studies demonstrate that BRAF/MEK inhibitors induce a favorable tumor immune microenvironment characterized by increased T-cell infiltration. Conversely, immune checkpoint inhibitors, while having lower response rates, exhibit significantly less acquired resistance. Combining these approaches in advanced melanoma settings has yielded mixed results. Some trials have shown prolonged progression-free survival with combination therapy, but at the cost of increased toxicity. Others have investigated sequencing strategies. For resectable melanoma, the role of neoadjuvant therapy is under investigation, with some studies showing a pCR in a significant portion of patients using either targeted therapy or ICI. However, the long-term benefit and durability of response require further clarification, especially concerning the optimal combination and sequencing of these therapies.

The Neo Trio trial (NCT02858921) was a randomized, open-label, phase II study involving 60 patients with resectable BRAFV600-mutant stage III melanoma. Patients were randomized 1:1:1 to one of three arms: 6 weeks of neoadjuvant pembrolizumab monotherapy, sequential therapy (7 days of dabrafenib/trametinib followed by pembrolizumab), or concurrent triple therapy (dabrafenib/trametinib with pembrolizumab for 6 weeks). All patients underwent surgery after the neoadjuvant phase. The primary endpoint was the pathological response rate (≥5%). Secondary endpoints included radiographic response (RECIST v1.1), recurrence-free survival (RFS), overall survival (OS), surgical outcomes, and safety. Pathological response was assessed by central pathology review. Radiological assessments were conducted using CT scans and FDG-PET scans. Survival outcomes were analyzed using the Kaplan-Meier method. Safety was monitored continuously. A protocol amendment later allowed surgery at 7-12 weeks for some patients.

All three treatment arms achieved a pathological response rate ≥5%, meeting the primary endpoint. Concurrent therapy demonstrated the highest pathological response rate at 80% (16/20, 95% CI 60-97), including ten pCRs. Pembrolizumab monotherapy showed a 55% pathological response rate (11/20, 95% CI 36-83), with six pCRs, while sequential therapy achieved a 50% response rate (10/20, 95% CI 27-73) with three pCRs. Radiographic response rates were also higher with concurrent therapy (70%) compared to pembrolizumab monotherapy (30%) and sequential therapy (50%). At 2 years, event-free survival was 60% with pembrolizumab, 80% with sequential therapy, and 71% with concurrent therapy. Recurrence-free survival rates at 2 years were 66%, 80%, and 75% respectively. Treatment-related adverse events (TRAEs) were frequent across all arms, with the concurrent therapy arm exhibiting the highest rate of grade 3/4 TRAEs (55%) and early discontinuations (40%). Interestingly, recurrences after major pathological response were more frequent in the targeted therapy arms. Overall, the study showed no clear evidence that adding targeted therapy improved outcomes over pembrolizumab alone; in fact, it seemed to reduce the quality of the response and increase toxicity.

The Neo Trio trial investigated the hypothesis that combining BRAF/MEK inhibitors with neoadjuvant anti-PD-1 would enhance the pathological response rate. However, results showed no significant improvement in pathological response rate with the addition of targeted therapy, compared to pembrolizumab alone. The higher pathological response rate observed in the concurrent therapy arm, similar to rates seen with neoadjuvant BRAF-targeted therapy alone, was not associated with superior long-term recurrence-free survival, suggesting that the quality and durability of the response may be compromised. The increased toxicity associated with concurrent therapy, mirroring findings in the advanced setting, raises concerns about the clinical benefit of adding targeted therapy to neoadjuvant ICI. This lack of synergy between targeted therapy and ICI may stem from the non-specific immune response to cell death induced by the targeted therapy, rather than a tumor-specific immune response that would enhance response to ICI. Ongoing translational analysis may provide further insight.

The Neo Trio trial demonstrates that adding BRAF-targeted therapy to neoadjuvant ICI in BRAFV600-mutant melanoma is not recommended, given the higher toxicity and potential reduction in the quality and durability of response. Longer-term follow-up is needed to confirm these findings. Future research should focus on identifying biomarkers to predict response and exploring alternative immune-based approaches to improve outcomes in patients who do not achieve a pathological response to neoadjuvant immunotherapy.

The Neo Trio trial was underpowered to perform formal statistical comparisons between the three treatment arms. The relatively small sample size limits the interpretation of long-term survival and health-related quality of life data. The study was conducted in a specific setting (Australia) and patient population, which may limit the generalizability of findings. The protocol amendment allowed for a variation in the timing of surgery, which could introduce some variability in the results.