The International Neoadjuvant Melanoma Consortium reported in an article published on 8 February 2021 in the Nature Medicine the results of a pooled analysis that aimed to determine the relationship between pathological complete response (pCR) and clinical outcomes with neoadjuvant anti-PD1 immunotherapy and BRAF/MEK targeted therapy in patients with clinical stage III melanoma. The findings confirm that pathological response correlates with recurrence-free survival (RFS) and overall survival (OS) with neoadjuvant therapy in stage III melanoma and that immunotherapy, particularly combination immunotherapy, appears more active than targeted therapy. According to Consortium investigators, in contrast to targeted therapy, where attainment of a pCR appears critical, any degree of pathological response with immunotherapy is sufficient to confer excellent survival.
Anti-PD1 and BRAF/MEK therapies have recently been approved for patients with stage III melanoma in the adjuvant setting. Patients with resectable clinical stage III melanoma might benefit from neoadjuvant approaches in multiple ways.
Six melanoma neoadjuvant studies were conducted recently with BRAF/MEK targeted therapy or PD1-based immunotherapy. These studies demonstrated that neoadjuvant therapies achieve high pCR rates and impressive RFS in stage III melanoma. In several other cancer types, the pCR rate to neoadjuvant therapy correlates with survival and, thus, has been used as an endpoint for registration studies for novel drug therapies.
The relationship between pathological response and RFS and OS in stage III melanoma is currently unknown, largely owing to the small number of patients enrolled in the individual studies conducted to date. It prompted the Consortium researchers to conduct this pooled analysis.
The investigators pooled data from six clinical studies of anti-PD1-based immunotherapy or BRAF/MEK targeted therapy. In total, 192 patients were included; 141 received immunotherapy of whom 104 combination of ipilimumab and nivolumab and 37 anti-PD1 monotherapy, while 51 received targeted therapy.
pCR occurred in 40% of patients: 47% with targeted therapy and 33% with immunotherapy (43% combination and 20% monotherapy).
pCR correlated with improved RFS (pCR 2-year 89% vs no pCR 50%, p < 0.001) and OS (pCR 2-year OS 95% versus no pCR 83%, p = 0.027). In patients with pCR, near pCR or partial pathological response with immunotherapy, very few relapses were seen (2-year RFS 96%), and no patient has died from melanoma at time of preparation of the report, whereas, even with pCR from targeted therapy, the 2-year RFS was only 79%, and OS was only 91%.
The study team concluded that pathological response should be considered an early surrogate endpoint for clinical trials and a new benchmark for drug development and approval in melanoma.
The authors acknowledged support from multiple foundations.
Menzies AM, Amaria RN, Rozemans EA, et al. Pathological response and survival with neoadjuvant therapy in melanoma: a pooled analysis from the International Neoadjuvant Melanoma Consortium (INMC). Nature Medicine; Published online 8 February 2021. DOI: https://doi.org/10.1038/s41591-020-01188-3.