KEYNOTE – D36: Personalized Immunotherapy with a Neoepitope Vaccine, EVX-01 and Pembrolizumab in Advanced Melanoma

Abstract

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)

Plain language summary

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.

Keywords::

• AI-guided cancer vaccine design
• checkpoint inhibitor
• EVX-01
• immunotherapy
• melanoma
• neoantigen
• PD-1
• PD-L1
• pembrolizumab
• personalized neoepitope vaccine

Author contributions

All authors fulfil the four authorship criteria.

Financial & competing interests disclosure

GV Long: consultant advisor for Agenus, Amgen, Array Biopharma, Boehringer Ingelheim, Bristol–Myers Squibb, Evaxion, Hexal AG (Sandoz Company), Highlight Therapeutics, Innovent Biologics, MSD, Novartis, OncoSec, Pierre Fabre, Provectus, Qbiotics, Regeneron. PF Ferrucci: advisory role for BMS, Novartis, MSD, Pierre Fabre and Roche. Research fund from BMS. A Khattak: no disclosures. TM Meniawy: advisory role for GlaxoSmithKline, AstraZeneca, Takeda, Novartis, Bristol–Myers Squibb and consultant for Eisai. PA Ott: research funding from and advisory role for Neon Therapeutics, Bristol–Myers Squibb, Merck Sharpe & Dohme, CytomX, Pfizer, Novartis, Celldex, Amgen, Array, AstraZeneca/MedImmune, Armo BioSciences, Xencor, Oncorus, Evaxion, Phio, and Roche/Genentech. M Chisamore: is an employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway (NJ, USA) and owns stock in Merck & Co., Inc., Rahway (NJ, USA). A Hyseni, T Trolle and E Heegard are employees of Evaxion Biotech A/S and own stock options in Evaxion Biotech A/S.

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Medical writing assistance was provided by LS Schmidt from Pharma IT Aps, funded by Evaxion Biotech A/S.

Ethical conduct of research

The authors state that this trial is being performed in accordance with the requirements of applicable local regulatory authorities and the International Council of Harmonisation GCP guidelines. Institutional review board/independent ethics committee approval of the protocol and all amendments is required prior to implementation.

Notes

AE: Adverse event; BOR: Best overall response; CR: Complete response; OS: Overall survival; PFS: Progression-free survival; PR: Partial response; RECIST: Response evaluation criteria in solid tumors; SAE: Serious adverse event; SD: Stable disease.

AJCC: American Joint Committee on Cancer; CNS: Central nervous system; CPI: Checkpoint inhibitor; ECOG: Eastern Cooperative Oncology Group; LDH: Lactate dehydrogenase; RECIST: Response evaluation criteria in solid tumors; ULN: Upper limit of normal.