Cotellic (cobimetinib)

P1, N=65, Active, not recruiting, Genentech, Inc. | Trial completion date: Jun 2027 --> Dec 2026 | Trial primary completion date: Jun 2027 --> Dec 2026

The combinations of atezolizumab and varlilumab with/without cobimetinib were safe but neither meaningfully improved outcomes in BTC treated in the later lines. Correlative tissue studies validated preclinical work that MEK inhibition increases CD8+TILs.

P2, N=29, Active, not recruiting, M.D. Anderson Cancer Center | Trial completion date: Jun 2026 --> Jun 2028 | Trial primary completion date: Jun 2026 --> Jun 2028

P2, N=25, Recruiting, University Health Network, Toronto | Not yet recruiting --> Recruiting

Although recent advances have led to covalent inhibitors such as Sotorasib and Adagrasib for the KRAS G12C mutation, effective therapies for other common variants, particularly KRAS G12D, which is highly prevalent in aggressive pancreatic cancers, remain limited...To further validate the predictive capability of the models, two compounds identified as high-confidence candidates, Cobimetinib and Etrasimod, were selected for experimental evaluation...While additional biochemical and pathway-level studies are required to confirm direct target engagement, these results support the model's utility in prioritizing candidate compounds with allele-specific activity profiles. Overall, this study provides a data-driven framework for identifying potential KRAS-targeted therapies and highlights the value of integrating machine learning predictions with experimental validation.

P2, N=64, Completed, University of Sydney | Active, not recruiting --> Completed

Lonafarnib effectively suppresses the malignant progression of anaplastic thyroid carcinoma both in ATC cell lines and in a BALB/c nude mouse xenograft model. The mechanism involves inhibition of Ras farnesylation and the downstream ERK signaling pathway, leading to activation of Caspase-3/PARP-mediated apoptosis and GSDME-mediated pyroptosis.

P1/2, N=1000, Recruiting, Oslo University Hospital HF | N=6000 --> 1000

Notably, we observed differential immunomodulatory effects of cobimetinib in tumor-bearing mice compared to non-tumor-bearing immunocompetent mice. Our findings indicate that MEK inhibition is associated with ICD-related molecular alterations, and that cobimetinib may contribute to immune modulation in TNBC.

Building on this insight, we developed cobimetinib analogs with enhanced sensitization properties. Together, our findings provide a mechanistic framework for understanding the cellular determinants of DFG-out-stabilizing inhibitor sensitivity and offer strategies for optimizing synergistic RAF-MEK inhibitor combinations.

P1/2, N=314, Terminated, Hoffmann-La Roche | Completed --> Terminated; Study was closed early as the sponsor decided not to continue development of certain treatment combinations.

Human and murine models resistant to combined belvarafenib and cobimetinib exhibited elevated levels of ATF4 and MTHFD2 and were sensitive to sapanisertib. This study provides promising treatment opportunities for patients with non-BRAF-mutant melanomas, or those who relapse following belvarafenib and cobimetinib combination therapy.