avutometinib (VS-6766)

P2, N=40, Recruiting, Memorial Sloan Kettering Cancer Center | N=20 --> 40

P2, N=15, Recruiting, Verastem, Inc.

P1/2, N=85, Active, not recruiting, Verastem, Inc. | Recruiting --> Active, not recruiting | Trial primary completion date: Jul 2024 --> Dec 2024

MEK inhibition with avutometinib abrogates the adaptive rebound in ERK signaling, but the antitumor effects are limited...In contrast to the NF1-deficient setting, concurrent SOS1 and SOS2 depletion is required to completely inhibit RAS signaling in NF1 wild-type cells. In sum, our data provide a mechanistic rationale for enhancing the therapeutic efficacy of MEK inhibitors by exploiting the lower residual SOS activity in NF1-null tumor cells.

Concomitant inhibition of both FAK (with VS-4718) and rapidly accelerated fibrosarcoma and MAPK kinase (RAF-MEK) (with avutometinib) induced tumor growth inhibition and increased survival across multiple PDAC mouse models. Combination of FAK and RAF-MEK inhibition alone improved antitumor immunity and priming of T cell responses in response to chemotherapy. These findings provided the rationale for an ongoing clinical trial evaluating the efficacy of avutometinib and defactinib in combination with gemcitabine and nab-paclitaxel in patients with PDAC and may suggest further paths for combined stromal and tumor-targeting therapies.

P1/2, N=182, Recruiting, Institute of Cancer Research, United Kingdom

The estimated primary completion date of RAMP 301 is 2028, and the estimated study completion date is 2031. ClinicalTrials.gov NCT06072781.

Avutometinib, defactinib, and to a larger extent their combinations, demonstrated promising in vitro and in vivo activity against EAC cell lines and xenografts. These preclinical data support the potential clinical evaluation of this combination in high-grade EAC patients.

P1, N=12, Recruiting, Emory University | Trial completion date: Oct 2025 --> Oct 2026 | Trial primary completion date: Oct 2024 --> Oct 2025

P2, N=50, Recruiting, Emory University | Not yet recruiting --> Recruiting

In this study, we explored the suppression mechanism of the phosphorylation process in the presence of MEK allosteric inhibitors, such as selumetinib, trametinib, cobimetinib, and CH5126766, by employing molecular dynamics simulations accompanied by principal component analysis. The results conclude that a strong interaction of allosteric inhibitors with the activation loop restricts the movement of Ser222 toward Mg-ATP, which could be the dominant factor for the suppression of phosphorylation in MEK1. This research will provide novel insights to design effective anticancer therapeutics for targeting MEK1 in the future.

P1, N=15, Completed, Memorial Sloan Kettering Cancer Center | Active, not recruiting --> Completed

P2, N=50, Not yet recruiting, Emory University

P2, N=27, Recruiting, Ryan H. Moy, MD, PhD

CH5126766 (CKI27) is an inhibitor that binds to MEK and prevents release of RAF, reducing the relief of negative feedback commonly observed with other MEKis...Moreover, this triple combination increased CD8+ and CD4+ T-cell proliferation, activation, and effector/memory subsets in the tumor draining lymph nodes and tumors and led to intratumoral regulatory T cell (Treg) destabilization. These data, collectively, will allow for more informed decisions when optimizing combination regimens by overcoming resistance, reducing toxicity, and generating long-term immune responses.

These results demonstrate that the epithelial-mesenchymal transition status may be a promising biomarker for the efficacy of combination therapy with avutometinib and defactinib in KRAS-mutated NSCLC.

The combination of avutometinib and defactinib demonstrates promising in vitro and in vivo anti-tumor activity against primary UCS cell lines and xenografts.

P1/2, N=53, Recruiting, University of Chicago | Trial completion date: Apr 2024 --> Aug 2025 | Trial primary completion date: Apr 2024 --> Aug 2025

P2, N=20, Recruiting, Memorial Sloan Kettering Cancer Center

P2, N=33, Not yet recruiting, M.D. Anderson Cancer Center

Avutometinib, and to a larger extent its combination with FAK inhibitor VS-4718, demonstrated promising in vivo activity against a KRAS wild-type LGSOC-PDX. These data support the ongoing registration-directed study (RAMP201/NCT04625270).

P2, N=225, Active, not recruiting, Verastem, Inc. | Recruiting --> Active, not recruiting

P1/2, N=33, Recruiting, University of Utah | Not yet recruiting --> Recruiting

P1/2, N=153, Recruiting, Verastem, Inc. | N=53 --> 153 | Trial completion date: Sep 2025 --> Apr 2027

P1/2, N=53, Recruiting, University of Chicago | Phase classification: P1b/2 --> P1/2

P2, N=90, Completed, Verastem, Inc. | Recruiting --> Completed | Trial completion date: Dec 2025 --> Dec 2023 | Trial primary completion date: Mar 2023 --> Aug 2023

P1/2, N=33, Not yet recruiting, University of Utah

P2, N=20, Recruiting, Memorial Sloan Kettering Cancer Center

P1/2, N=53, Recruiting, Verastem, Inc. | Trial primary completion date: Dec 2023 --> Jul 2025

P3, N=270, Recruiting, Verastem, Inc. | Not yet recruiting --> Recruiting

P2, N=55, Recruiting, University of Oklahoma

P1/2, N=40, Recruiting, Verastem, Inc. | Phase classification: P1b/2a --> P1/2

In vitro, cell viability and proliferation assays were used to test abemaciclib (CDK4/6 inhibitor), defactinib (FAK inhibitor) and VS-6766 (RAF/MEK inhibitor) as monotherapy and in combination...The efficacy of VS-4718 (in vivo formulation of defactinib) and abemaciclib were evaluated in a subcutaneous IOMM-lee meningioma model (having CDKN2A loss) in nude mice... Abemaciclib showed promising efficacy in preclinical meningioma xenografts with CDKN2A loss. Studies to evaluate these therapies in other orthotopic models are underway.

P1, N=24, Recruiting, Memorial Sloan Kettering Cancer Center

P2, N=13, Active, not recruiting, Thomas Jefferson University | Recruiting --> Active, not recruiting | Trial completion date: Jul 2024 --> Jan 2025 | Trial primary completion date: Oct 2023 --> Apr 2024

P3, N=270, Not yet recruiting, Verastem, Inc.

P1, N=15, Active, not recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: Sep 2023 --> Sep 2024 | Trial primary completion date: Sep 2023 --> Sep 2024

No abstract available

P2, N=30, Recruiting, Memorial Sloan Kettering Cancer Center

Most treatment-related adverse events (AEs) for combo (n=81) were grade 1-2, with a low proportion of dose reductions (17%) and discontinuations due to AEs (12.3%) in the combo arm.Conclusion Interim data support avutometinib + defactinib as an active go-forward regimen in heavily-pretreated recurrent LGSOC, regardless of KRAS status. No new safety signals were observed; most AEs were mild to moderate.

P1, N=104, Recruiting, Royal Marsden NHS Foundation Trust | Trial completion date: Feb 2023 --> May 2024 | Trial primary completion date: Feb 2023 --> May 2024

P1, N=87, Active, not recruiting, Institute of Cancer Research, United Kingdom | Recruiting --> Active, not recruiting | Trial completion date: Mar 2023 --> Oct 2023 | Trial primary completion date: Sep 2022 --> Apr 2023