avutometinib (VS-6766)

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

Patients received up to 5 lines of prior systemic therapy (median 2), including prior platinum-based chemotherapy, ICIs, and bevacizumab. In this heavily pretreated population of patients with KRAS G12V mt NSCLC, limited clinical activity was observed with combination therapy. While no new safety signals were identified, criteria to proceed to part B were not met, and further evaluation of avutometinib ± defactinib in KRAS G12V mt NSCLC will not be pursued. Additional trials evaluating rational avutometinib combinations (sotorasib, adagrasib, everolimus) are ongoing in patients with KRAS mt NSCLC.

P2, N=184, Recruiting, Verastem, Inc. | N=100 --> 184

Interestingly, all these pro-immune changes observed with avuto were stronger than those observed with an equivalent dose level of the MEK-only inhibitor trametinib. Furthermore, all complete responders in the avuto + anti-PD-1 group were able to reject a re-challenge with CT26 tumor cells and showed increased CD8 and CD4 effector memory T cells relative to untreated naïve control mice, indicating that avuto + anti-PD-1 treatment induces durable immune memory. These results support clinical evaluation of avutometinib in combination with an anti-PD-1 antibody for treatment of patients with solid tumors harboring MAPK pathway alterations such as KRAS or BRAF mutations.

The combination of avutometinib and everolimus overcomes the activation of the PI3K/AKT/mTOR pathway which is an adaptive resistance mechanism to MAPK pathway inhibition. We have shown that avutometinib and everolimus induce synergistic anti-tumor effects preclinically, and preliminary data suggest clinically meaningful ORR and PFS in patients with KRAS mt NSCLC including non-G12C variants.

VS-4718 is a focal adhesion kinase (FAK) inhibitor that has shown synergistic anti-tumor activity with avutometinib in other cancer models, as it blocks the potential of FAK to function as an adaptive resistance mechanism to RAF/MEK inhibition. Combination of avutometinib with FAK inhibition showed improved in vivo preclinical anti-tumor efficacy relative to either agent alone in an LGSC PDX model with wildtype KRAS and with a RAF1 mutation. These data support an ongoing registration-directed study with avutometinib ± the FAK inhibitor defactinib for patients with recurrent LGSC (NCT04625270).

When combined with inhibitors against mitogen-activated protein kinase kinase (MEK) [trametinib and selumetinib], mammalian target of rapamycin (mTOR) [rapamycin], focal adhesion kinase (FAK) [defactinib and Ascentage’s APG-2449, which targets FAK/ALK/ROS1], and MEK/rapidly accelerated fibrosarcoma [RAF] [VS-6766], alrizomadlin demonstrated enhanced antiproliferative activity. Combining MEK and FAK inhibitors also markedly augmented caspase-3 and poly (ADP-ribose) polymerase 1 (PARP-1) cleavage (apoptosis hallmarks) and enhanced observed antitumor effects. In conclusion, our results demonstrate the potential utility of combining alrizomadlin with MAPK pathway inhibitors to treat patients with UM.

Mice bearing PDX tumors were randomized into groups of 6 mice treated with avuto alone or in combination with panitumumab for 21 days with tumor volume measured twice weekly.Results In 3D proliferation assays with a panel of KRAS mt CRC cell lines (including G12D, G12V and G13D mutations), the EGFR/ErbB family inhibitor afatinib showed the strongest synergy score with avuto relative to inhibitors of SHP2, ERK1/2, mTOR or CDK4/6. The combination of avuto and panitumumab showed significant anti-tumor activity in a CRC PDX model harboring KRASG12V with less tumor regression observed in a KRASG12D PDX model or in a KRASG12V PDX model with concurrent PIK3CA mutation. These results support the ongoing clinical evaluation of avutometinib in combination with the anti-EGFR antibody cetuximab for treatment of KRAS mt CRC (NCT05200442).

P2, N=55, Recruiting, University of Oklahoma | Not yet recruiting --> Recruiting

P1/2, N=63, Recruiting, Adrienne G. Waks | Not yet recruiting --> Recruiting

P1/2, N=63, Not yet recruiting, Adrienne G. Waks

P1b/2, N=53, Recruiting, University of Chicago | Not yet recruiting --> Recruiting | Initiation date: Apr 2022 --> Aug 2022

We used CellTiter-Glo assay to assess the anti-tumor effects of CDK4/6 inhibitor abemaciclib, FAK inhibitor defactinib (VS-6063) and dual RAF/MEK inhibitor RO5126766 (VS-6766) in BEN-MEN-1 (WHO Grade I, NF2-mutant), CH157-MN (WHO Unknown, NF2-mutant), and IOMM-Lee (WHO Grade III, CDKN2A loss) cell lines. Selective inhibitors of CDK4/6, FAK, and RAF/MEK showed anti-meningioma activity against traditional and patient-derived cell models in vitro. Molecular characterization and establishment of patient-derived models that encompass the diversity of clinical meningiomas are ongoing.

P2, N=55, Not yet recruiting, University of Oklahoma

P1/2, N=85, Recruiting, Verastem, Inc. | Not yet recruiting --> Recruiting

Using the screening systems for agents that up-regulate the expression of p15, p27, and p21, we discovered the novel MEK inhibitor trametinib, the novel RAF/MEK inhibitor CH5126766/RO5126766/VS-6766, and the histone deacetylase inhibitor YM753/OBP-801, respectively...The combination of trametinib and the BRAF inhibitor dabrafenib was approved for advanced BRAF mutant melanoma in the USA, EU, Japan, and many other countries...In 2018, this combination was also approved for locally advanced or metastatic BRAF V600-mutant anaplastic thyroid cancer in the USA after it had been granted Breakthrough Therapy Designation by the FDA. I describe here the characterization of our original screening system, RB-reactivator screening, by which these three molecular-targeting agents that advanced into clinical trials were identified.

P1/2, N=85, Not yet recruiting, Verastem, Inc.

P1, N=104, Recruiting, Royal Marsden NHS Foundation Trust | Trial completion date: Dec 2021 --> Feb 2023 | Trial primary completion date: Dec 2021 --> Feb 2023