Defactinib is an oral small molecule inhibitor of FAK and PYK2 that is currently being evaluated as a potential combination therapy for various solid tumors. Defactinib has received orphan drug designation in ovarian cancer and mesothelioma in the US, EU and Australia

Clinical Development in Advanced Cancers

Defactinib has been studied in over 300 patients and has shown a well-tolerated safety profile to date. Initial signs of activity has been observed in clinical studies as a monotherapy in KRAS mt (mutation) NSCLC and in relapsed ovarian cancer in combination with paclitaxel have been observed.

Clinical Investigation of Defactinib Combinations

Research by Verastem Oncology scientists and collaborators at world-renowned academic institutions has described the effect of focal adhesion kinase (FAK) inhibition to enhance immune response by decreasing immuno-suppressive cells, increasing cytotoxic T cells, and reducing stromal density, which allows tumor-killing immune cells to enter the tumor.

Preclinical models of KRAS mutant solid tumors treated with defactinib + CH5126766 show the combination to be synergistic in a variety of KRAS mutant tumors. A clinical trial of patients with KRAS mutant advanced solid tumors including low grade serious ovarian cancer (LGSOC), non-small cell lung cancer (NSCLC) colorectal cancer (CRC) in addition to other tumor types is in progress, with encouraging initial results.

Ongoing defactinib clinical trials

  1. Phase 1b study in combination with Merck & Co.’s PD-1 inhibitor pembrolizumab and gemcitabine in patients with advanced pancreatic cancer.
  2. Phase 1/2 collaboration with Merck & Co. and Cancer Research UK to evaluate combination therapy with pembrolizumab. Following dose escalation, three expansion arms are planned in NSCLC, relapsed pancreatic cancer and mesothelioma.
  3. Phase 1b study in combination with Merck & Co.’s PD-1 inhibitor pembrolizumab in patients with resectable pancreatic ductal adenocarcinoma.
  4. Phase 1b study in combination with CH5126766 in patients with advanced solid tumors.
  5. Phase 1b study in combination with platinum and taxane in patients with carboplatin resistant ovarian cancer.