Adverse events halt Merck's TIGIT, Keytruda melanoma study

ASCO Daily Digest, the premier source for critical updates from the American Society of Clinical Oncology (ASCO) annual meeting, has announced some significant developments. Merck & Co. has decided to halt the administration of a coformulation of its anti-TIGIT antibody, vibostolimab, and Keytruda (pembrolizumab) in a Phase III trial involving patients with high-risk melanoma. This decision comes after observing a higher rate of discontinuations in this treatment arm.

The KeyVibe-010 trial was designed to test the coformulation, known as MK-7684A, against Keytruda alone as an adjuvant treatment for 1594 patients who have undergone surgery for high-risk Stage IIB-IV melanoma. Merck revealed that a pre-planned analysis showed the study was "highly unlikely" to demonstrate a significant benefit in terms of recurrence-free survival (RFS), the primary endpoint.

The higher dropout rate in the coformulation group was primarily attributed to immune-mediated adverse experiences, according to Merck. Following recommendations from an independent data monitoring committee, Merck has decided to unblind the study and offer patients in the coformulation arm the option to receive Keytruda monotherapy instead.

Marjorie Green, who heads oncology global clinical development at Merck Research Laboratories, stated, "Through our clinical development programme, we continue to ask the tough questions." Despite this setback, Merck is continuing with other Phase III studies of vibostolimab coformulated with Keytruda in lung cancer, including the KeyVibe-003, KeyVibe-006, KeyVibe-007, and KeyVibe-008 trials.

Vibostolimab has faced challenges in the clinical setting before. Last year, Merck reported that combining vibostolimab with Keytruda did not show a benefit over standard care with docetaxel in terms of progression-free survival (PFS) for previously treated patients with non-small-cell lung cancer (NSCLC). Additionally, the combination did not significantly improve outcomes when added to docetaxel in the Phase II KeyVibe-002 trial.

Despite the recent setback, Morgan Stanley analysts have termed it as "an incremental negative" for vibostolimab. They noted that the lung cancer program, which presents a larger market opportunity, is still ongoing. The full data from the melanoma trial are awaited with anticipation.

TIGIT inhibition has shown mixed results historically. Roche's anti-TIGIT antibody tiragolumab failed in two major lung cancer trials, yet interim data from the Phase III SKYSCRAPER-01 study indicated promising overall survival benefits in NSCLC patients treated with tiragolumab and Roche's PD-L1 drug, Tecentriq (atezolizumab).

Morgan Stanley analysts emphasize that not all TIGIT antibodies are created equal. Gilead Sciences and Arcus Biosciences’ domvanalimab could offer a better toxicity profile due to its Fc-silent structure, unlike Merck's TIGIT, which has an intact Fc domain. Analysts believe that despite the current challenges, vibostolimab could potentially generate $4.6 billion in sales by 2033, about five years after Keytruda's key patents expire.

Merck's future strategies, particularly post-exclusivity on Keytruda, remain a topic of significant interest. The company continues to explore new avenues and potential treatments, including the promising Winrevair approval, which could help Merck navigate the challenges associated with Keytruda's patent expiration.