Adverse events scupper melanoma study of Merck & Co.'s TIGIT, Keytruda combo
13 May 2024
Phase 3Clinical ResultASCOPhase 2Immunotherapy
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Merck & Co. will stop dosing a coformulation of its anti-TIGIT antibody vibostolimab with Keytruda (pembrolizumab) in a Phase III study of patients with high-risk melanoma due to a higher rate of discontinuations observed in that arm of the study.
The KeyVibe-010 trial is evaluating the coformulation, dubbed MK-7684A, versus Keytruda alone as adjuvant treatment in 1594 patients with resected high-risk Stage IIB-IV melanoma. According to Merck, a pre-planned analysis indicated that the study was "highly unlikely" to show a treatment benefit on the primary endpoint of recurrence-free survival (RFS).
Immune-mediated AEs
Compared to Keytruda alone, Merck said there was a higher dropout rate in the coformulation arm, primarily due to immune-mediated adverse experiences. An independent data monitoring committee has recommended that Merck unblind the study and allow patients in the coformulation arm to receive Keytruda monotherapy.
"Through our clinical development programme, we continue to ask the tough questions," remarked Marjorie Green, head of oncology, global clinical development at Merck Research Laboratories. The company's other ongoing Phase III studies of vibostolimab coformulated with Keytruda in lung cancer include KeyVibe-003, KeyVibe-006, KeyVibe-007 and KeyVibe-008.
Vibostolimab has faced clinical setbacks before. Last year, Merck disclosed that when combined with Keytruda, vibostolimab showed no benefit compared to standard care with docetaxel in terms of progression-free survival (PFS) in previously treated patients with non-small-cell lung cancer (NSCLC), nor did it show a significant benefit when the coformulation was added to docetaxel. Those findings were from the Phase II KeyVibe-002 trial.
Bigger opportunity in lung cancer
In a note to clients Monday, Morgan Stanley called the setback "an incremental negative" for vibostolimab, "but acknowledge that the lung programme is ongoing, which represents the more significant market opportunity and we await release of the full data from [the drug] in melanoma."
Despite some renewed hope around TIGIT inhibition, the target's track record has been underwhelming, marked by some high-profile fails, most notably Roche's Fc-intact anti-TIGIT antibody tiragolumab missing the mark in two critical lung cancer trials. But interim data from the Phase III SKYSCRAPER-01 study released last year showed promising overall survival in NSCLC patients given tiragolumab on top of Roche's PD-L1 drug Tecentriq (atezoluzumab).
Meanwhile, the analysts at Morgan Stanley point out that "not every TIGIT antibody is the same," with Gilead Sciences and Arcus Biosciences’ domvanalimab potentially offering an improved toxicity profile due to its Fc-silent structure. The analysts note that, like tiragolumab, Merck's TIGIT also has an intact Fc domain. They estimate that vibostolimab could generate sales of $4.6 billion in 2033, which is about five years after key patents on Keytruda are set to expire.
For more on how Merck is plotting its course after exclusivity on the immunotherapy runs out, see Spotlight On: Winrevair approval could help Merck & Co. overcome its Keytruda issues.
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