Avmapki (avutometinib)

Avutometinib plus defactinib represents a promising targeted therapeutic strategy for recurrent LGSOC, particularly in patients with KRAS-mutant tumors. If confirmed in phase III trials, this combination may establish a molecularly informed disease-specific treatment paradigm with the potential for more durable disease control than existing therapies.

The authors discuss adverse event management and the implications for integration into routine clinical practice. Clinicians caring for patients with low-grade serous ovarian carcinoma can use the drug knowledge and evidence outlined in this review to assist with implementing avutometinib and defactinib therapy.

P2, N=36, Recruiting, Washington University School of Medicine | Not yet recruiting --> Recruiting

P2, N=50, Recruiting, Emory University | Trial completion date: Sep 2028 --> Sep 2029 | Trial primary completion date: Mar 2028 --> Mar 2029

P1, N=87, Active, not recruiting, Institute of Cancer Research, United Kingdom | Trial completion date: Oct 2023 --> Oct 2026

The FDA recently granted accelerated approval of the small-molecule focal adhesion kinase (FAK) inhibitor (FAKi, defactinib) in combination with a RAF-MEK clamp inhibitor (avutometinib) for KRAS-mutated low-grade serous ovarian cancer developed by Verastem Inc. In this study, we review a short history of FAK, summarize ongoing combinatorial clinical trials, discuss potential mechanisms of action, and highlight studies showing that FAK activation is a chemo- and mechano-sensitive signaling hub driving tumor adaptive changes. Targeting FAK disarms tumor resistance through multiple mechanisms, which supports new biological insights and future clinical combinations.

P2, N=33, Recruiting, M.D. Anderson Cancer Center | Trial completion date: Feb 2028 --> Feb 2029 | Trial primary completion date: Feb 2026 --> Feb 2029

P1, N=104, Completed, Royal Marsden NHS Foundation Trust | Active, not recruiting --> Completed | Trial completion date: Jun 2025 --> Oct 2025 | Trial primary completion date: Jun 2025 --> Oct 2025

P2, N=40, Recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: Mar 2026 --> Mar 2027 | Trial primary completion date: Mar 2026 --> Mar 2027

The following ten drugs received FDA approval in 2025 - avutometinib (inhibiting MEK1/2 in serous ovarian carcinomas), defactinib (blocking FAK in low grade serous ovarian carcinomas), delgocitinib (antagonizing the JAK family in hand eczema), mirdametinib (inhibiting MEK1/2 in type I neurofibromatosis), remibrutinib (blocking BTK in chronic spontaneous urticaria), rilzabrutinib (antagonizing BTK in chronic immune thrombocytopenia), sunvozertinib (blocking mutant exon 21 insertion EGFR NSCLC), taletrectinib (inhibiting mutant ROS1 in NSCLC), vimseltinib (blocking CSF1R in tenosynovial giant cell tumors), and zongertinib (antagonizing mutant HER2 in NSCLC). This article summarizes the physicochemical properties of all 94 FDA-approved small molecule protein kinase inhibitors including the molecular weight, number of hydrogen bond donors/acceptors, ligand efficiency, lipophilic efficiency, polar surface area, and solubility. A total of 45 of the 94 FDA-approved drugs have a least one Lipinski rule of five violation.