KEYNOTE - D36: personalized immunotherapy with a neoepitope vaccine, EVX-01 and pembrolizumab in advanced melanoma.

Despite improvements made with checkpoint inhibitor (CPI) therapy, a need for new approaches to improve outcomes for patients with unresectable or metastatic melanoma remains. EVX-01, a personalized neoepitope vaccine, combined with pembrolizumab treatment, holds the potential to fulfill this need. Here we present the rationale and novel design behind the KEYNOTE - D36 trial: an open label, single arm, phase II trial aiming to establish the clinical proof of concept and evaluate the safety of EVX-01 in combination with pembrolizumab in CPI naive patients with unresectable or metastatic melanoma. The primary objective is to evaluate if EVX-01 improves best overall response after initial stable disease or partial response to pembrolizumab treatment, in patients with advanced melanoma. The novel end points ensure a decisive readout which may prove helpful before making major investments in phase III trials with limited phase I data. Clinical Trial Registration: NCT05309421 (ClinicalTrials.gov).

Drugs targeting the immune system have improved the outcomes for patients with advanced melanoma. However, a significant proportion of patients do not benefit and there is a need for better therapeutic agents to be used alone or in combination with immune modulating agents. This article summarizes the rationale and design of a new trial with a personalized vaccine (EVX-01) that may improve outcomes for patients with advanced melanoma (unresectable stage III or IV melanoma). The EVX-01 vaccine aims to stimulate the patient's immune system to generate T cells that target specific molecules that can only be found on the surface of the individual patients' cancer cells (i.e. neoepitopes), resulting in cancer cell death. The trial will investigate if the personalized EVX-01 vaccine together with checkpoint inhibitor therapy works better for patients with advanced melanoma, than checkpoint inhibitor therapy alone.

Kinase inhibitors and immune check-point blockade for the treatment of metastatic melanoma and advanced cancer: synergistic or antagonistic?

In recent years, therapeutic approaches for many tumors have broadened or even shifted entirely from cytotoxic chemotherapy to specific targeting of dysregulated proteins (predominately kinases), and more recently, harnessing of the anti-tumor immune response. The most prominent example of this shift is the management of metastatic melanoma, where BRAF and MEK inhibition and CLTA-4 blockade have established an entirely new standard of care in the last 3 years. Targeted kinase inhibition and immune checkpoint blockade have different strengths and weaknesses. Kinase inhibitors generally have rapid and impressive response rates but modest progression-free survival while immunotherapy can achieve durable tumor control, but is often associated with lower response rates and slower time to clinical benefit. These approaches would seem to be complementary however the results of early combination studies suggest that caution is advised when combining targeted kinase inhibition with immunotherapy. In this context, rigorous biomarker driven clinical trials are needed to further elucidate mechanisms of both benefit and toxicity. Depending on disease specific biology, it seems likely that both combination and sequential approaches of kinase inhibitors with immunotherapy will be required in order to harness the full potential of these approaches.