Predictors of response to neoadjuvant therapy in melanoma

Clinical stage III melanoma, defined as patients with RECIST measurable, clinically detected nodal disease with or without in-transit metastases, represents a high-risk population with poor outcomes. Despite recent advances in adjuvant medical therapy, only 40% of clinical stage III BRAFV600E/K mutant melanoma patients treated with adjuvant dabrafenib and trametinib (DT) are relapse-free at 3 years. Thus, there is a strong need for new, more effective therapies for these high-risk patients.

Lay Abstract

Clinical stage III melanoma patients have poor outcomes when treated with upfront surgery and adjuvant therapy. Neoadjuvant, or pre-operative therapy, can potentially improve outcomes for this high-risk patient population. Researchers at MD Anderson Cancer Center and the Melanoma Institute of Australia have recently reported that approximately 50% of clinical stage III melanoma patients with BRAF V600 mutated disease achieve a pathologic complete response (pCR) or complete melanoma death, after exposure to neoadjuvant dabrafenib and trametinib (DT) treatment. Patients who do have pCR have improved survival outcomes compared to those that do not have a pCR. We do not understand which features will predict development of pCR but have identified preliminary molecular, immunological and pathologic data in pre-treatment tumors we believe may be predictive of long-term outcomes. Additionally, while pCR patients are less likely to develop relapse than non-pCR patients, there are still some pCR patients who relapse, and we believe there are distinct features in these patient’s surgical samples that determine subsequent relapse risk. Finally, patients who do not achieve a pCR are at higher risk of developing CNS metastases at time of relapse. We believe there are features in their tumor specimens which evolve over the course of therapy and identification of these factors will predict the risk of CNS relapse. Together, these studies aim to inform mechanisms of treatment response and resistance to BRAF targeted therapy, will enhance the field of neoadjuvant therapy, identify risk of CNS metastasis formation and ultimately improve melanoma patient outcomes.