Merck Halts Dosing of Anti-TIGIT Antibody in KeyVibe-010 Melanoma Study

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Merck has announced the cessation of dosing its anti-TIGIT antibody, vibostolimab, coformulated with pembrolizumab (Keytruda) in a phase III clinical trial for high-risk melanoma patients. The decision comes after a pre-planned analysis indicated that the coformulation, known as MK-7684A, was "highly unlikely" to demonstrate a benefit in recurrence-free survival (RFS), the study's primary endpoint. In a press release, the company wrote, “Data analysis from this study is ongoing. Results will be shared with the scientific community and communicated to regulatory agencies.”¹

Background

In the US, pembrolizumab is approved for 2 indications in melanoma: for the treatment of patients with unresectable or metastatic melanoma, and as adjuvant therapy for adult and pediatric (12 years and older) patients with Stage IIB, IIC, or III melanoma following complete resection.

Vibostolimab is Merck’s investigational anti-TIGIT antibody, designed to restore antitumor activity by blocking the TIGIT receptor from binding to its ligands (CD112 and CD155), thereby activating T lymphocytes to help destroy tumor cells. Merck's extensive clinical development program is evaluating the safety and efficacy of the vibostolimab and pembrolizumab coformulation alone and in combination with other agents in more than 3000 patients.

Adverse Experiences Reported

The KeyVibe-010 (NCT05665595)randomized, double-blind, active comparator-controlledtrialevaluated the efficacy of MK-7684A versus pembrolizumab alone as an adjuvant treatment in 1594 patients with resected high-risk Stage IIB-IV melanoma. The trial’s primary endpoint was recurrence-free survival (RFS). Key secondary endpoints included distant metastasis-free survival (DMFS) and overall survival (OS). The study participants were randomly assigned (1:1) to receive 1 of the following treatments:

1. Vibostolimab/pembrolizumab coformulation (pembrolizumab 200 mg/20 mL and vibostolimab 200 mg intravenously [IV] every three weeks [Q3W] for up to 17 cycles); or

2. Pembrolizumab (adult patients received 200 mg and adolescent patients ≥40 kg received 2 mg/kg [up to a maximum of 200 mg] IV Q3W for up to 17 cycles).

The analysis revealed a higher rate of discontinuations in the MK-7684A arm compared to the pembrolizumab monotherapy arm, primarily due to immune-mediated adverse experiences.Marjorie Green, MD, head of oncology, global clinical development at Merck Research Laboratories, commented on the findings in a press release, stating, "Through our clinical development program, we continue to ask the tough questions." The independent data monitoring committee overseeing the trial has recommended unblinding the study, allowing patients on the coformulation to switch to pembrolizumab monotherapy.

Looking Forward

Despite this setback, Merck said it continues to investigate vibostolimab in combination with pembrolizumab in other phase III trials targeting lung cancer, including KeyVibe-003, KeyVibe-006, KeyVibe-007, and KeyVibe-008.Vibostolimab has encountered previous clinical challenges. Last year, Merck revealed that combining vibostolimab with pembrolizumab did not demonstrate any benefit over standard care with docetaxel in progression-free survival (PFS) among previously treated non-small-cell lung cancer (NSCLC) patients. Additionally, the coformulation did not show significant benefit when added to docetaxel. These results were observed in the phase II KeyVibe-002 trial.

Other Recent Pembrolizumab News

The Lancet Oncology recently published phase 3 KEYNOTE-412 trial (NCT03040999) data, evaluating pembrolizumab in combination with chemoradiotherapy for locally advanced head and neck squamous cell carcinoma (HNSCC). Overall, the addition of pembrolizumab did not significantly improve event-free survival compared to chemoradiotherapy alone. Of the 804 patients, median event-free survival was not reached in the pembrolizumab group versus 46.6 months in the placebo group. Adverse events were common in both groups, with serious adverse events more frequent in the pembrolizumab group. While no new safety concerns arose, the study highlights the ongoing challenge of treating locally advanced HNSCC, emphasizing the need for improved therapeutic strategies, according to Machiels et al.²

References

1. Merck provides update on phase 3 KeyVibe-010 trial evaluating an investigational coformulation of vibostolimab and pembrolizumab as adjuvant treatment for patients with resected high-risk melanoma. News Release. Merck. May 13, 2024. Access May 14, 2024. https://www.merck.com/news/merck-provides-update-on-phase-3-keyvibe-010-trial-evaluating-an-investigational-coformulation-of-vibostolimab-and-pembrolizumab-as-adjuvant-treatment-for-patients-with-resected-high-risk-melanoma/
2. Machiels JP, Tao Y, Licitra L, et al. Pembrolizumab plus concurrent chemoradiotherapy versus placebo plus concurrent chemoradiotherapy in patients with locally advanced squamous cell carcinoma of the head and neck (KEYNOTE-412): a randomised, double-blind, phase 3 trial. Lancet Oncol. 2024;25(5):572-587. doi:10.1016/S1470-2045(24)00100-1