P1, N=3, Active, not recruiting, Memorial Sloan Kettering Cancer Center | Recruiting --> Active, not recruiting | N=23 --> 3

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

Notably, these findings were recapitulated through pharmacological inhibition of FAK signaling using Defactinib, an FAK-specific inhibitor. Taken together, our findings reveal that bone-marrow ssDNA may represent a bone microenvironment factor that captures and promotes PCa homing to bone, further suggesting a potential therapeutic strategy for mitigating bone metastasis.

In this study, we identified defactinib, a specific inhibitor of FAK as a novel ferroptosis suppressors...Notably, elevated FAK/SRC-JNK signaling sensitizes cancer cells to ferroptosis-inducing therapies, while inhibition of the FAK/SRC-JNK signaling pathway protects against acute pancreatitis by suppressing ferroptosis. These findings highlight the central role of FAK/ SRC-JNK signaling in controlling ferroptotic cell death and underscore the therapeutic potential of targeting FAK/ SRC-JNK mediated ferroptosis, offering new avenues for the treatment of cancer and acute pancreatitis.

We present a patient with Anaplastic lymphoma kinase (ALK) fusion lung adenocarcinoma who received sequential treatment with ALK tyrosine kinase inhibitor (TKI) (crizotinib, PFS:32.3 months and then conteltinib, PFS: 29 months). Subsequently, the patient switched to third generation EGFR-TKI treatment with almonertinib. This case suggests EGFR mutation is one of the mechanisms of ALK-TKI resistance, highlights the value of re-biopsy in identifying potentially targetable resistance mechanisms and underscores the spatiotemporal heterogeneity of tumors under the selective pressure of ALK-TKI.

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=35, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Dec 2025 --> Jan 2027