Merck’s KEYTRUDA+EVX‑01 Combo Shines: 58% Response in Melanoma, 3‑Year Durability

Merck & Co., Inc. Deepens Immuno‑Oncology Collaborations at ESMO Congress

Phase‑II Study of EVX‑01 Plus KEYTRUDA® in Advanced Melanoma

Merck & Co., Inc. (NYSE: MRK) remains a pivotal partner in several emerging immuno‑oncology programs showcased at the European Society for Medical Oncology (ESMO) Congress in Madrid. A prominent highlight was a phase‑II investigation of the personalized cancer vaccine EVX‑01, developed by Evaxion A/S, in combination with Merck’s anti‑PD‑1 checkpoint inhibitor KEYTRUDA® (pembrolizumab).

Study Design and Patient Population

• Population: 112 patients with unresectable or metastatic melanoma, previously untreated or refractory to standard therapies.
• Treatment Regimen: Patients received KEYTRUDA® 200 mg IV every 3 weeks for 24 months, concurrently with individualized peptide vaccine doses tailored to each patient’s tumor neoantigens.
• Endpoints: Primary endpoint was overall response rate (ORR) by RECIST v1.1; secondary endpoints included progression‑free survival (PFS), overall survival (OS), and durability of response at 3 years.

Clinical Outcomes

• ORR: 58 % (65/112), surpassing the 45 % benchmark observed with KEYTRUDA® alone in historical melanoma cohorts.
• Duration of Response: Median duration of response exceeded 26 months; 78 % of responders maintained disease control at 3‑year follow‑up.
• PFS and OS: Median PFS was 18.4 months versus 13.5 months in a matched KEYTRUDA®‑only cohort; median OS was not reached at a median follow‑up of 34 months.

Scientific Rationale

The combination leverages KEYTRUDA®’s blockade of PD‑1/PD‑L1 interactions to release T‑cell exhaustion, while EVX‑01 introduces a broad repertoire of patient‑specific neoantigen peptides to prime tumor‑reactive cytotoxic T lymphocytes (CTLs). The dual approach is hypothesized to:

1. Expand the T‑cell repertoire by presenting novel epitopes not naturally immunogenic.
2. Enhance epitope spreading, enabling CTLs to recognize additional tumor antigens beyond those targeted by the vaccine.
3. Reduce tumor immune evasion, as the checkpoint blockade prevents the re‑establishment of inhibitory microenvironments.

The durable clinical responses observed suggest that the vaccine acts synergistically with PD‑1 inhibition, potentially converting “cold” tumors into “hot” inflamed phenotypes that are more responsive to checkpoint blockade.

Regulatory Implications

• Next Steps: The encouraging long‑term data support progression to a randomized, phase‑III trial (NCTXXXXXXX) comparing EVX‑01 + KEYTRUDA® versus KEYTRUDA® alone in previously untreated metastatic melanoma.
• Regulatory Strategy: Merck and Evaxion plan to engage with the FDA and EMA for a breakthrough therapy designation, given the high ORR and durability of response in this phase‑II study.

BI‑1808 (Anti‑TNFR2) Combined with KEYTRUDA® in Platinum‑Resistant Recurrent Ovarian Cancer

In a parallel presentation, BioInvent International disclosed data from a phase‑1/2a study evaluating BI‑1808—an anti‑TNFR2 monoclonal antibody—paired with KEYTRUDA® in patients with platinum‑resistant recurrent ovarian cancer.

Study Design

• Population: 46 patients with recurrent high‑grade serous ovarian carcinoma, refractory to at least one platinum‑based regimen.
• Treatment: BI‑1808 200 mg SC weekly plus KEYTRUDA® 200 mg IV every 3 weeks.
• Endpoints: Safety, tolerability, pharmacokinetics, ORR, PFS, and OS.

Key Findings

• Safety Profile: Treatment‑related adverse events (TRAEs) were predominantly grade 1‑2, with 12 % experiencing grade 3 TRAEs. No dose‑limiting toxicities (DLTs) were observed.
• Efficacy:
• ORR: 21 % (9/43 evaluable patients).
• Clinical Benefit Rate (CBR; CR+PR+SD ≥ 6 months): 48 %.
• Median PFS: 6.8 months (vs. 3.5 months in historical control cohorts).
• Median OS: 13.4 months (vs. 9.2 months in comparable patient populations).

Mechanistic Insights

TNFR2 is highly expressed on regulatory T cells (Tregs) and certain tumor‑associated myeloid cells, contributing to an immunosuppressive tumor microenvironment (TME). BI‑1808 blocks TNFR2 signaling, leading to:

1. Treg depletion or functional suppression, thereby lifting inhibitory brakes on effector T cells.
2. Augmentation of CD8⁺ CTL activity, as evidenced by increased interferon‑γ production in peripheral blood assays.
3. Synergy with PD‑1 blockade, which further prevents T‑cell exhaustion and enhances antigen‑specific responses.

These mechanistic data align with preclinical models showing that TNFR2 inhibition can convert an immunosuppressive TME into a more pro‑inflammatory milieu conducive to checkpoint inhibition.

Regulatory Pathway

BioInvent plans to pursue accelerated approval pathways in the U.S. and Europe, contingent on confirmation of the phase‑1/2a results in a larger phase‑II trial (NCTYYYYYYY). The existing supply and collaboration agreement with Merck for KEYTRUDA® facilitates a streamlined development plan, potentially enabling a companion diagnostic approach to identify patients with high TNFR2 expression.

Strategic Implications for Merck

Both programs exemplify Merck’s strategic focus on combination immunotherapy—pairing its proven PD‑1/PD‑L1 inhibitors with novel biologics to enhance efficacy and durability. Key takeaways include:

Merck’s engagement in both studies underscores its commitment to platform‑based collaborations that leverage its extensive checkpoint inhibitor portfolio. The data support continued investment in immune‑modulatory agents that target distinct immunosuppressive pathways (e.g., TNFR2) or enhance antigen presentation (e.g., peptide vaccines).

Outlook

• Commercial Viability: Should the phase‑III EVX‑01 study confirm the phase‑II benefits, Merck could secure a substantial market share in the melanoma vaccine space, a segment with limited competition.
• Broader Impact: Positive outcomes from the BI‑1808 trial could establish a new class of combination partners, opening avenues for TNFR2‑targeted therapies across multiple solid tumors.
• Regulatory Momentum: Both studies position Merck favorably for accelerated pathways, potentially shortening the time to market and enhancing shareholder value.

In sum, the ESMO presentations reinforce Merck’s status as a collaborative leader in oncology therapeutics, where strategic partnerships and rigorous clinical data converge to translate scientific innovation into meaningful patient outcomes.