Merck Submits Clinical Application for TIGIT + Pembrolizumab Fixed-Dose Combination MK-7684A

On March 10, the CDE website indicated that the clinical trial application for MSD’s MK-7684A injection had been accepted by the Center for Drug Evaluation (CDE). According to available information, MK-7684A is a fixed-dose combination formulation composed of vibostolimab and pembrolizumab developed by MSD.

Vibostolimab, a component of the combination formulation, is a monoclonal antibody targeting the immune cell protein receptor TIGIT, developed by MSD. Pembrolizumab is an anti-PD-1 monoclonal antibody. TIGIT is expressed on various immune cells, including CD8+ T cells, CD4+ T cells, and NK cells, and serves as a specific negative regulator of the CD226 co-stimulatory receptor. CD155, highly expressed on the surface of tumor cells, is a high-affinity ligand for TIGIT. Upon binding to TIGIT on NK and T cells, it inhibits the cytotoxic activity of T cells against tumor cells. Therefore, dual blockade of TIGIT and the PD-1/PD-L1 pathway can theoretically more effectively relieve immune suppression, thereby enhancing the immune system’s cytotoxic response.

At the virtual ESMO Congress held in September 2020, MSD announced data from Part B of its first-in-human, open-label, Phase I study (NCT02964013). This part of the study evaluated the safety and efficacy of vibostolimab in combination with KEYTRUDA for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) who had not previously received PD-1/PD-L1 therapy but had received at least one other prior therapy (73%, n=30/41). All patients received vibostolimab (200 or 210 mg) combined with KEYTRUDA (200 mg) every three weeks for a total of 35 cycles.

Study results demonstrated that vibostolimab in combination with KEYTRUDA exhibited a manageable safety profile and showed potential antitumor activity. In the combination therapy group, 34 patients (83%) experienced treatment-related adverse events (TRAEs), 6 patients (15%) experienced Grade 3–5 TRAEs, and there were no deaths attributable to TRAEs.

Among all enrolled patients, the objective response rate (ORR) for vibostolimab in combination with KEYTRUDA was 29%, with a median progression-free survival (PFS) of 5.4 months. The median duration of response (DOR) was not reached. In 13 patients with PD-L1 expression and a tumor proportion score (TPS) ≥1%, the ORR was 46%, with a median PFS of 8.4 months. In 12 patients with PD-L1 expression and a TPS <1%, the ORR was 25%, with a median PFS of 4.1 months.

Additionally, a separate cohort in this study evaluated the efficacy of vibostolimab monotherapy (n=41) or in combination with KEYTRUDA (n=38) in patients with metastatic NSCLC who had experienced disease progression after prior anti-PD-1/PD-L1 therapy. 78% of patients had previously received two or more lines of treatment. Patients received vibostolimab monotherapy (200 or 210 mg) or vibostolimab in combination with KEYTRUDA (200 mg), with each cycle lasting three weeks, for a total of 35 cycles.

Study results demonstrated that vibostolimab monotherapy and combination therapy with KEYTRUDA exhibited a manageable safety profile and showed antitumor activity in patients refractory to PD-1/PD-L1 inhibitors. The incidence of grade 3–5 treatment-related adverse events (TRAEs) was 15% in the vibostolimab monotherapy group and 13% in the combination therapy group; one patient in the combination group died from treatment-related pneumonitis. The objective response rate (ORR) was 7% in the vibostolimab monotherapy group and 5% in the combination group. The median duration of response (DOR) was 9 months in the vibostolimab monotherapy group and 13 months in the combination therapy group.

In the NCT02964013 study, MSD also conducted safety and pharmacokinetic (PK) trials comparing the fixed-dose combination formulation of vibostolimab plus pembrolizumab (MK-7684A) with separate intravenous infusions of vibostolimab and pembrolizumab.