Discussing a Phase 2 Defactinib/Avutometinib Trial in Diffuse Gastric Cancer

The identification of targetable pathways for diffuse histologic gastric cancers is a huge unmet need for patients, according to Ryan H. Moy, MD, PhD. There are several reasons for this, but Moy highlighted that diffuse disease is poorly differentiated and excludes immune cells. As a result, patients with diffuse type gastric cancers are more resistant to standard chemotherapy and immunotherapy.

A recent hypothesis proposed that cotargeting the FAK and MAP kinase pathways might lead to synergistic effects that result in greater tumor growth inhibition. Moy has since become the principal investigator of a landmark phase 2 trial (NCT06487221) evaluating defactinib and avutometinib (Avmapki Fakzynja Co-pack) in patients with diffuse-type gastric cancer. He shared information on this in a trials in progress poster at the 2025 ASCO GI Cancers Symposium.¹

The trial is enrolling patients with histologic evidence of gastric/gastroesophageal junction carcinoma, classified as diffuse type, poorly cohesive, signet ring cell, or mixed type, and those with CDH1 or RHOA mutations will be allowed regardless of history. Patients are also required to have received at least 1 line of therapy for unresectable or metastatic disease, including platinum-based chemotherapy and fluoropyrimidine.

Treatment with avutometinib will be administered at 3.2 mg twice weekly and defactinib at 200 mg twice daily, both on a 3-weeks-on, 1-week-off schedule, with cycles lasting 28 days. The primary end point is to evaluate the 6-month progression-free survival rate with the combination in patients with metastatic diffuse gastric cancer.

Moy highlighted that, as of March 2026, no new safety signals had been observed in the trial.

CancerNetwork® spoke with Moy, an assistant professor of medicine at Columbia University Irving Medical Center, during a site visit to Columbia University.

Transcript:

CancerNetwork: What is the rationale for your study evaluating defactinib and avutometinib in diffuse gastric cancer?

Moy: There are 2 main histologic types of gastric cancer by the Lawrence classification system: the diffuse type and intestinal type. Diffuse type gastric cancers tend to be a more aggressive phenotype. They're poorly differentiated, highly invasive, frequently have signet ring cells, and tend to metastasize to the peritoneum. In addition, they are characterized by a very dense, fibrotic, stromal-rich tumor microenvironment, and this leads to exclusion of immune cells, like T cells, and is correlated with what's known as an immune cold phenotype. Moreover, diffuse type tumors tend to be genomically stable and lack easily targetable alterations. This leads to greater resistance to standard chemotherapy, as well as immunotherapy. There's a large unmet need to identify targetable pathways for this diffuse histologic type.

In preclinical models using patient tumors, diffuse gastric cancer cell lines, and genetic mouse models of diffuse gastric cancer with mutations in CDH1 and RHOA—common mutations in diffuse gastric cancer—recent studies have shown that there's activation of the focal adhesion kinase, or FAC, pathway. Inhibiting this pathway leads to tumor growth inhibition, but there can also be compensatory activation of MAP kinase signaling, which can lead to treatment resistance. It was hypothesized that co-targeting the FAK and MAP kinase pathways together could lead to synergistic effects and greater tumor growth inhibition, which is what we saw in the preclinical models. Clinically, targeting these pathways is feasible. Recently, the drugs defactinib, a FAK inhibitor, and avutometinib, a RAF/MEK clamp, were approved for treatment in patients with low grade serous ovarian cancer.² We proposed a phase 2 clinical trial to look at this combination in patients with advanced diffuse gastric cancer that's refractory to standard treatments. This trial is currently enrolling.

What has the trial found?

We're still recruiting additional patients, so I don't have any of those data to share…in terms of efficacy. I can say that the regimen appears to be tolerable, [with] no new safety signals from patients who have been treated so far. Diffuse gastric cancer is an aggressive disease, and patients can progress quite quickly. Interestingly, there are data in other tumor types, such as pancreatic cancer, to combine defactinib and avutometinib with chemotherapy, such as gemcitabine and nab-paclitaxel, so we are planning to add a combination cohort combining defactinib and avutometinib with paclitaxel for diffuse gastric cancer.

References

1. Moy RH, Wu LW, Cho H, et al. Phase 2 trial of defactinib in combination with avutometinib in patients with advanced diffuse-type gastric cancer. J Clin Oncol. 2025;43(suppl_4):TPS505. doi:10.1200/JCO.2025.43.4_suppl.TPS505
2. FDA grants accelerated approval to the combination of avutometinib and defactinib for KRAS-mutated recurrent low-grade serous ovarian cancer. News release. FDA. May 8, 2025. Accessed April 1, 2026. https://tinyurl.com/ywyd4ps3