Merck Halts Phase 3 KeyVibe Trials for NSCLC with Vibostolimab FDCs

Merck, known as MSD outside of the United States and Canada, announced the discontinuation of the clinical development programmes for vibostolimab, an anti-TIGIT antibody, and favezelimab, an anti-LAG-3 antibody. Vibostolimab is being evaluated as an investigational fixed-dose combination with pembrolizumab (Keytruda) in the KeyVibe programme. Favezelimab is being evaluated as an investigational fixed-dose combination with pembrolizumab in the KEYFORM programme.

Merck is discontinuing the phase 3 KeyVibe-003 and KeyVibe-007 trials, which are evaluating the fixed-dose combination of vibostolimab and pembrolizumab in certain patients with non-small cell lung cancer (NSCLC), based on the recommendation of an independent Data Monitoring Committee (DMC). In a pre-planned analysis, both trials met the pre-specified futility criteria for the primary endpoint of overall survival. In these studies, the safety profile of vibostolimab/pembrolizumab was consistent with that observed for vibostolimab and pembrolizumab in previously reported studies, with no new safety signals identified. As expected with dual checkpoint inhibitor therapy, more immune-related adverse events were observed with the fixed-dose combination than with pembrolizumab. Considering the totality of data from the phase 3 KeyVibe studies, including the efficacy outcomes from KeyVibe-003 and KeyVibe-007, the company has decided to discontinue the phase 3 KeyVibe-006 trial and other vibostolimab studies.

Separately, Merck has decided to end the favezelimab clinical development programme, and will stop enrollment in the phase 3 KEYFORM-008 trial evaluating the fixed-dose combination of favezelimab and pembrolizumab in patients with relapsed or refractory classical Hodgkin lymphoma (cHL) whose disease has progressed following prior anti-PD-1 therapy. Patients currently in this trial may continue on therapy until study completion. KEYFORM-008 is the only phase 3 study in the KEYFORM clinical development programme for which results are not available. The company has made this decision after a thorough evaluation of data from the favezelimab clinical programme and will prioritize the development of other candidates in its comprehensive and diversified oncology pipeline. This decision is not based on any concerns about the safety of this fixed-dose combination.

Merck is informing study investigators for these clinical trials and advises patients to speak to their study team and physician regarding next steps and treatment options. Data analyses for the phase 3 trials are ongoing, and the results will be shared with the scientific community.

""Following a careful analysis of the data, the decision has been made to discontinue development of these candidates to prioritize other ongoing programmes. We are grateful to all the patients, caregivers and investigators for their many contributions that made these studies possible,"" said Dr. Marjorie Green, senior vice president and head of oncology, global clinical development, Merck Research Laboratories. ""We continue to pursue the most promising science with a focus on agents with the greatest potential to improve outcomes for more patients with cancer.""

KeyVibe-003 is a randomized, double-blind phase 3 trial (ClinicalTrials.gov, NCT04738487 ) evaluating the fixed-dose combination of vibostolimab and pembrolizumab (MK-7684A) versus pembrolizumab monotherapy, as a first-line treatment for patients with PD-L1 positive metastatic NSCLC. The primary endpoint is overall survival (OS) in participants with PD-L1 TPS =50%. Secondary endpoints include OS in participants with PD-L1 TPS =1% and TPS 1-49%, progression-free survival (PFS), overall response rate (ORR), duration of response (DOR), safety and quality of life.

The trial enrolled 1,264 patients who were randomized (1:1) to receive: Vibostolimab/pembrolizumab fixed-dose combination (pembrolizumab 200 mg and vibostolimab 200 mg intravenously [IV] every three weeks [Q3W] for up to 35 administrations); or Pembrolizumab (200 mg IV Q3W for up to 35 administrations).

KeyVibe-007 is a randomized, double-blind phase 3 trial (ClinicalTrials.gov, NCT05226598 ) evaluating the fixed-dose combination of vibostolimab and pembrolizumab with chemotherapy in treatment-naïve patients with metastatic NSCLC. The primary endpoint is OS in participants with PD-L1 TPS =1%. Secondary endpoints include OS in all participants, PFS, ORR and DOR in TPS = 1% and all participants, safety and patient reported outcomes.

The trial enrolled 739 patients who were randomized (1:1) to receive: Vibostolimab/pembrolizumab fixed-dose combination (pembrolizumab 200mg and vibostolimab 200 mg IV) plus platinum doublet chemotherapy (Q3W for 4 cycles); then vibostolimab/pembrolizumab (200mg/200mg IV) for up to 31 cycles? (plus pemetrexed 500mg/m2 Q3W maintenance for nonsquamous histology); Pembrolizumab (200 mg IV) plus platinum doublet chemotherapy (Q3W for 4 cycles); then pembrolizumab (200mg IV) for up to 31 cycles (plus pemetrexed 500mg/m2 Q3W maintenance for nonsquamous histology).

KeyVibe-006 is a randomized, open-label phase 3 trial (ClincialTrials.gov, NCT05298423 ) evaluating the fixed-dose combination of vibostolimab and pembrolizumab with concurrent chemoradiotherapy followed by vibostolimab and pembrolizumab versus concurrent chemoradiotherapy followed by durvalumab in patients with stage III NSCLC. The primary endpoints are PFS and OS for all participants and for participants with TPS = 1%. The secondary endpoints are ORR, DOR, safety and patient reported outcomes.

The trial enrolled approximately 580 patients who were randomized (1:1) to receive: Vibostolimab/pembrolizumab (200mg/200mg IV) plus platinum doublet (1 cycle); then platinum doublet plus vibostolimab/pembrolizumab (2 cycles) plus thoracic radiotherapy; then vibostolimab/pembrolizumab (200mg/200mg IV Q3W for 17 cycles); or Platinum doublet (1 cycle); then platinum doublet (2 cycles) plus thoracic radiotherapy; then durvalumab (10 mg/kg Q2W for 26 cycles).

KEYFORM-008 is a randomized, open-label phase 3 trial (ClinicalTrials.gov, NCT05508867 ) evaluating the fixed-dose combination of favezelimab and pembrolizumab (MK-4280A) versus physician's choice chemotherapy for the treatment of patients with PD-1 relapsed or refractory classical Hodgkin lymphoma. The primary endpoint is PFS per Lugano Response Criteria as assessed by Blinded Independent Central Review (BICR). The secondary endpoints are OS, ORR, DOR and safety.

The trial enrolled 169 patients who were randomized (1:1) to receive: Favezelimab/pembrolizumab (800 mg/200 mg IV on day 1, then Q3W for up to 35 infusions); or Physician's choice of either bendamustine (between 90-120 mg/m2 IV on day 1 and day 2 of either a 3- or 4-week cycle for up to 6 cycles); or gemcitabine (between 800-1,200 mg/m2 IV on day 1 and day 8 of a Q3W cycle for up to 6 cycles).

Vibostolimab (MK-7684) is an investigational humanized anti-TIGIT antibody discovered and developed by Merck. Vibostolimab restores antitumor activity by blocking the TIGIT receptor from binding to its ligands (CD112 and CD155), thereby activating T lymphocytes that help destroy tumour cells.

Favezelimab (MK-4280) is an investigational anti-lymphocyte activation gene-3 (LAG-3) antibody. LAG-3 is a cell surface immunomodulatory receptor expressed on various immune cells that down-regulates T cell proliferation and activation. Favezelimab aims to restore T cell effector function by preventing LAG-3 from binding to its primary ligand, major histocompatibility complex (MHC) class II molecules.

Keytruda is an anti-programmed death receptor-1 (PD-1) therapy that works by increasing the ability of the body’s immune system to help detect and fight tumour cells. Keytruda is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD- L1 and PD-L2, thereby activating T lymphocytes which may affect both tumour cells and healthy cells.

Merck has the industry’s largest immuno-oncology clinical research programme. There are currently more than 1,600 trials studying Keytruda across a wide variety of cancers and treatment settings. The Keytruda clinical programme seeks to understand the role of Keytruda across cancers and the factors that may predict a patient's likelihood of benefitting from treatment with Keytruda, including exploring several different biomarkers.

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