2022 Grantee: Louis Denis, MD
Research Project: Phase 1/2 Trial of VS-6766 + Defactinib and GEM + Nab-P in Metastatic PDAC
Award: 2022 Pancreatic Cancer Action Network Therapeutic Accelerator Award supported by the 1440 Foundation and the Gail V. Coleman-Kenneth M. Bruntel Research Fund
Award Period: July 1, 2022 – June 30, 2024
Dr. Denis was appointed Chief Medical Officer of Verastem Oncology in September 2021. Dr. Denis is a medical oncologist and brings to Verastem more than 25 years of academic and industry experience in clinical cancer drug development. Prior to joining Verastem, Dr. Denis was the Chief Medical Officer of Asana BioSciences where he provided strategic direction as well as medical and safety oversight to Asana’s portfolio of oncology and immunology assets. Previously, Dr. Denis held various leadership roles in Oncology clinical development and medical affairs at Boehringer Ingelheim and Pfizer. Dr. Denis received his MD from Vrije Universiteit Brussel Medical School, Belgium, and did his post-doctoral fellowships in Internal Medicine/Medical Oncology at Middelheim Hospital, Antwerp; the Rotterdam Cancer Institute, The Netherlands; and the Institute for Drug Development, Cancer Therapy and Research Center, San Antonio, Texas.
The standard-of-care treatments for patients with metastatic pancreatic cancer, which includes gemcitabine and nab-paclitaxel, do not offer significant improvement in overall survival. Therefore, additional combination agents may be needed to address the unique challenges of pancreatic cancer. Up to 98% of pancreatic cancer patients’ tumors express a mutated version of a protein called KRAS, which is thought to be the main oncogenic driver (causes healthy cells to become – and stay – cancerous). There are currently no approved drugs that target the KRAS mutations most typically found in pancreatic tumors.
In addition, pancreatic tumors are characterized by a high stromal density, which means the tumor and its surroundings are densely populated with a variety of cell types. The pancreatic cancer stroma is made up of fibroblasts and dense extracellular matrix, which are thought to limit the penetration of cancer-fighting drugs and T-cells, which may elicit an immune attack, from the tumor.
Dr. Denis’ proposed project will evaluate the addition of two investigational agents, VS-6766 and defactinib, to the standard gemcitabine/nab-paclitaxel regimen with the objective of increasing response rate and survival.
VS-6766 is a unique RAF/MEK clamp with demonstrated preclinical and clinical anti-tumor efficacy against KRAS mutant cancers. RAF and MEK are two proteins “downstream” of KRAS, which means they get activated as a result of KRAS activation.
Defactinib is a selective inhibitor of focal adhesion kinase (FAK), which reduces stromal density in preclinical pancreatic cancer models and in liver metastases from pancreatic cancer patients. FAK gets activated alongside KRAS and can compensate for the absence of KRAS signaling via RAF/MEK inhibitor. Therefore, targeting FAK in combination with the RAF/MEK inhibitor may block a key resistance pathway to RAF/MEK inhibition.
The combination of VS-6766 with defactinib has shown clinical benefit with good tolerability for patients with KRAS mutant lung and ovarian cancers and has received FDA Breakthrough Therapy Designation for treatment of patients with low-grade serous ovarian cancer. Since the combination of VS-6766, defactinib, gemcitabine and nab-paclitaxel has not been tested in patients, the first step of the clinical trial that Dr. Denis and his team will conduct will be a “dose escalation” phase, which will enroll up to 12 patients to seek to establish tolerability and a recommended phase 2 dose. Once a recommended phase 2 dose is established, an expansion cohort will test the clinical activity of this combination in patients with metastatic pancreatic cancer. The research team will also assess whether patients whose tumors have specific KRAS mutations, G12V and G12R (which make up around 33% of pancreatic cancer cases), may be especially responsive to the treatment combination as suggested by preclinical and clinical data. Pending results of the phase 2 clinical trial supported by this grant, the treatment combination will be considered for entry into the PanCAN Precision PromiseSM adaptive clinical trial platform for later-phase testing.