In a pooled analysis of 6 clinical trials, neoadjuvant immune checkpoint inhibitor (ICI) strategies show sustained clinical responses, particularly in achieving pathological complete response (pCR) in patients with high-risk resectable melanoma. Regimens with dual ICI were associated with higher pCR odds than anti-PD1 monotherapy; however, they also were associated with increased risk for grade 3 or 4 immune-related adverse events (irAEs).
In terms of neoadjuvant dual ICI treatment with nivolumab and ipilimumab, the alternative-dose regimen was associated with a better adverse event profile than the conventional-dose regimen, with no significant efficacy differences. The findings are published by Dr. Ankit Mangla of the University Hospitals Seidman Cancer Center in Cleveland, OH, US, and colleagues on 28 March 2024 in the JAMA Oncology.
Neoadjuvant approach to the management of patients with high-risk resectable melanoma has gained in interest in the past decade. It is hypothesised that neoadjuvant treatment with ICIs leads to a better immune response due to the delivery of immunomodulators when the tumour is still present in measurable, generally nodal, resectable disease. This, in turn, may lead to increased peripheral T-cell receptor clonal diversity, which may reflect the proliferation and maturation of intratumoural T-cell populations.
Neoadjuvant treatment allows for the assessment of the pathologic response which not only provides information about the immunologic activity of the various interventions but can also have a congruent effect on relapse-free survival, distant metastasis-free survival, and overall survival. However, the optimal neoadjuvant regimen for patients with high-risk resectable melanoma is not known.
In this pooled analysis, the authors have collected data from the published trials of neoadjuvant ICI treatment for patients with high-risk resectable melanoma and analyzed them for safety and efficacy. Phase I, II, or III clinical trials were selected for inclusion if they investigated ICI treatment and being published between January 2018 and March 2023. Participant data included in the analysis were derived from trials evaluating the efficacy and safety of anti-PD1 monotherapy and the combination of anti-CTLA4 with anti-PD1 in the neoadjuvant setting, specifically among patients with high-risk resectable melanoma.
Patients were treated with either anti-PD1 monotherapy, dual ICI with a conventional dose of 3 mg/kg of ipilimumab and 1 mg/kg of nivolumab, or dual ICI with an alternative-dose regimen of 1 mg/kg of ipilimumab and 3 mg/kg of nivolumab. The main outcomes were radiologic complete response (rCR), radiologic overall objective response (rOOR), and radiologic progressive disease. Also, pCR, the proportion of patients undergoing surgical resection, and occurrence of grade 3 or 4 irAEs were considered.
Among 573 patients enrolled in 6 clinical trials, neoadjuvant treatment with dual ICI was associated with higher odds of achieving pCR compared with anti-PD1 monotherapy (odds ratio [OR] 3.16; p < 0.001). Dual ICI was associated with higher odds of grade 3 or 4 irAEs compared with anti-PD1 monotherapy (OR 3.75; p < 0.001).
When comparing the alternative-dose ipilimumab and nivolumab regimen with conventional-dose ipilimumab and nivolumab, no statistically significant difference in rCR, rOOR, radiologic progressive disease, or pCR was noted. However, the conventional-dose ipilimumab and nivolumab regimen was associated with increased grade 3 or 4 irAEs (OR 4.76; p < 0.001).
Conventional-dose ipilimumab and nivolumab was associated with greater odds of achieving improved rOOR (OR 1.95; p = 0.046) and pCR (OR 2.99; p < 0.001) compared with anti-PD1 monotherapy. The alternative dose of ipilimumab and nivolumab also was associated with higher odds of achieving rCR (OR 2.55; p = 0.03) and pCR (OR 3.87; p < 0.001) compared with anti-PD1 monotherapy.
The risk for grade 3 or 4 irAEs is higher with both the conventional-dose (OR 9.59; p < 0.001) and alternative-dose ipilimumab and nivolumab regimens (OR 2.02; p = 0.02) compared with anti-PD1 monotherapy.
The authors commented that translational immunologic assessments of neoadjuvant treatment are needed. Future investigations comparing immunologic outcomes of relatlimab-nivolumab combinations with ipilimumab-nivolumab will be pivotal. While acknowledging the heterogeneity of neoadjuvant treatment arms, these findings have provided a foundation for informed discussions regarding neoadjuvant ICI regimens available for the management of patients with high-risk resectable melanoma. The need for randomisd clinical trials with uniform reporting will be necessary to validate these results in the future.
Reference
Mangla A, Lee C, Mirsky MM, et al. Neoadjuvant Dual Checkpoint Inhibitors vs Anti-PD1 Therapy in High-Risk Resectable Melanoma A Pooled Analysis. JAMA Oncology; Published online 28 March 2024. doi:10.1001/jamaoncol.2023.7333