Taking a Look At FAK Inhibitors

A drug called a focal adhesion kinase (FAK) inhibitor may improve the response to chemotherapy and immunotherapy for some pancreatic cancer patients.

FAK is a protein found in our cells. It serves as a kind of interface between the inside of a cell and the exterior. FAK has a number of jobs. It regulates how cells bond with each other to create larger structures, how cells move from one location to another using energy, cell growth and cell division (proliferation), and the survival of cells. In cancer, FAK promotes cancer progression and metastasis.

Solid tumors like breast, lung, and pancreatic cancer, as well as others, are dependent on FAK signaling. FAKs are also known to play a role in the development of fibrous tissue in cancer and a number of other diseases. Fibrous tissue protects cancer cells by preventing the immune system from attacking them. This stops the cancer cells from entering the bloodstream, which reduces their exposure to chemotherapy. Now researchers are looking at ways to target FAK to shut down that process.

“The research is ongoing and scientists are learning that FAK alone doesn’t show a lot of efficacy as a single agent, according to some of the trial results,” explains physician–scientist Conan Kinsey, M.D., Ph.D., of the University of Utah Huntsman Cancer Institute, Salt Lake City. “But there are some trials now that are looking at combining a FAK inhibitor with another agent. So we have to wait and see where those end up.”

What is clear to Kinsey and all pancreatic cancer physician–scientists is there is an urgent need to develop more effective drug treatments for pancreatic cancer patients with advanced disease.  

For those patients, drug therapy remains the backbone of treatment. One significant area of research is the so-called RAS signaling pathway. When operating normally, RAS signaling is vital to the regulation of signaling networks for cell proliferation, growth, and survival, explains Kinsey, who has published research combining MEK1/2 and autophagy inhibitors in RAS/RAF mutated cancers and is the primary investigator in two trials for pancreatic and gastrointestinal cancers resulting from this work.

But, like other cell signaling networks, things can go wrong with RAS. Mutations in the RAS gene, or in upstream or downstream regulators, can morph the pathway into inducing cancer. “We’re learning more but there are still many unanswered questions when it comes to inhibiting this whole process,” Kinsey says. “With innovative research into combining agents along with well-designed clinical trials, we will make progress.”

A New Trial

In 2022, patient advocacy group PanCAN awarded the inaugural Therapeutic Accelerator Award to Verastem Oncology to evaluate their investigational treatments VS-6766 and the FAK inhibitor defactinib. The award includes funding to conduct a phase Ib/II clinical trial for these treatments.

Defactinib, given orally, is a small-molecule FAK inhibitor that may prevent the integrin-mediated activation of several downstream signal transduction pathways. These pathways include those involving RAS/MEK/ERK and PI3K/Akt that would, in turn, inhibit tumor cell migration, proliferation, survival, and the formation of new blood vessels (tumor angiogenesis). 

KRAS is mutated in more than 95 percent of pancreatic cancers and Verastem’s RAF/MEK clamp VS-6766 blocks tumorigenic signaling downstream of mutant KRAS. Verastem’s selective FAK inhibitor, defactinib, is included because FAK has been identified in lab studies and studies in humans as a potential resistance mechanism to RAF and MEK inhibition.

The new study is designed to evaluate the safety, tolerability, and efficacy of avutometinib (VS-6766) and defactinib in combination with gemcitabine and nab-paclitaxel in patients with previously untreated metastatic pancreatic cancer. Also known as RAMP205, the study has an estimated enrollment of 40 patients and is open in three locations in the U.S.

If the results of this early-phase clinical trial are positive, the hope is that the investigational treatment combination will be incorporated into the PanCAN Precision Promise adaptive clinical trial.

A Lens on FAK Inhibitors

Although immunotherapy, including immune checkpoint inhibitors, has had remarkable success in the treatment of some cancer types, it has had much less success in treating pancreatic cancer. Researchers are looking at how FAK inhibitors can be used in combination with immune checkpoint agents and chemotherapy to potentially delay disease progression.

In a meeting abstract presented at the 2022 ASCO Annual Meeting, researchers showed findings from a multicenter, open-label, phase I study with dose escalation and expansion phases. The study was designed to evaluate the safety and recommended phase II dose of defactinib in combination with pembrolizumab (brand name Keytruda) and gemcitabine for pancreatic cancer patients.

The triple drug combination was well-tolerated with no dose-limiting toxicities. Among 17 treated patients with refractory disease, the disease control rate was 58.8%, with one partial response and nine with stable disease. The median progression-free survival and overall survival were 4.2 months and 9.1 months, respectively. Among the evaluable patients in the maintenance cohort, the disease control rate was 63.6%, with one partial response and six with stable disease. Three patients with stable disease came off study due to treatment- or disease-related complications. The median progression-free survival and overall survival were 5.0 months and 8.3 months, respectively. 

The researchers concluded the combination of defactinib, pembrolizumab, and gemcitabine was well-tolerated, had promising preliminary efficacy, and showed increased infiltrative T lymphocytes in post-treatment tumor biopsies. The researchers believe a more potent chemotherapy backbone should be considered in future trial designs.