Targeting AXL May Improve Chemotherapy for Pancreatic Cancer

Pancreatic cancer is aggressive, and despite all available treatment options, longer-term patient survival has not kept pace with breakthroughs that have occurred for other aggressive malignancies, such as lung cancer.

New therapeutic agents that target tumor cell pathways associated with resistance to chemotherapy are needed, as pancreatic cancer is expected to become the second leading cause of cancer-related deaths in the United States within the next few years. Researchers at UT Southwestern Medical Center hope new research may make a much-needed difference in the lives of pancreatic cancer patients—almost all of whom who are eventually faced with their disease becoming resistant to chemotherapy.

In a new study, researchers will be targeting a specific receptor called tyrosine kinase AXL. This receptor was first isolated in 1988 and identified as an oncogene—a gene that can transform a cell into a tumor cell. Further research over the years showed that increased AXL expression is associated with numerous cancers, including lung cancer, breast cancer, colon cancer, melanoma, and pancreatic cancer, among others. It has also been shown to correlate significantly with poorer prognosis.

“Early work shows that AXL is a very important driver of resistance to things like targeted therapies, immunotherapies, and chemotherapies,” explains Dr. M. Shaalan Beg, a medical oncologist at UT Southwestern’s Harold C. Simmons Comprehensive Cancer Center, in Dallas, Texas. Aside from promoting therapy resistance, AXL also promotes proliferation and suppresses immune responses by decreasing antigen presentation and inhibiting natural killer cells.

About the Trial

Researchers will be testing a drug called bemcentinib, which is a first-in-class, orally bioavailable, highly selective AXL kinase inhibitor. It is already being evaluated as a therapy for other solid tumors. In the trial at UT Southwestern, Beg and colleagues will evaluate the efficacy of bemcentinib in combination with chemotherapies (nab-paclitaxel, gemcitabine, cisplatin) versus chemotherapies alone. The goal is to determine the complete response rate of bemcentinib plus chemotherapy (nab-paclitaxel/gemcitabine/cisplatin) in patients with metastatic pancreatic adenocarcinoma.

“Chemotherapy has worked so well in many other cancers, yet pancreas cancer is just so resistant to these efforts, so looking for novel ways to boost its effectiveness is absolutely of utmost importance in moving the field forward and, most importantly, improving the lives of our pancreatic cancer patients,” says Beg, UT Southwestern’s Dedman Family Scholar in Clinical Care, whose clinical work and research focus on early-phase drug development and clinical trials for gastrointestinal cancers. “In simplest terms,” he adds, “what we hope to do is give a boost to these chemotherapy agents so they can do their job of killing cancer cells.”

In pre-clinical work, targeting AXL improved the efficacy of chemotherapy in multiple robust animal models of pancreatic cancer, explains co-investigator Rolf Brekken, Ph.D. Blocking AXL reduced markers of chemotherapy resistance and decreased pancreas cancer cell proliferation and invasiveness, resulting in improved animal survival and reduced tumor spread. “This (pancreatic cancer) trial is early stage and we’ll be recruiting about 70 patients,” says Beg. “I’m very hopeful about this since early data has been so promising.”

Promise in Other Cancers

Bemcentinib given alone or in combination with other therapies has already shown promise in human trials targeting AXL. A total of 35 patients with relapsed/refractory acute myeloid leukemia or myelodysplastic syndrome received bemcentinib alone as part of another phase I/II trial. Of these 35 patients, two showed a complete response, and five achieved partial responses. Eight patients reported disease stabilization for more than four months. Preliminary results showed that six out of nine patients analyzed showed indications of increased immune activity as a result of AXL inhibition. The drug was well tolerated by these patients, who tend to be elderly and fragile.

Bemcentinib in combination with other therapies has shown particular potential in non-small cell lung cancer (NSCLC): Another investigator-led phase I/II trial running at UT Southwestern enrolled patients with advanced, later line, NSCLC. The participants received bemcentinib in combination with docetaxel. Out of 11 patients, two had a partial response and six had stable disease according to data presented at the World Conference on Lung Cancer in 2018.

Recently, at the Society of Immunotherapy for Cancer congress 2018, data was presented on the first stage of a Phase 2 trial combining bemcentinib with the immunotherapy Keytruda. Of 24 patients treated with the combination, five had objective responses and patients lived longer without their disease worsening compared to what would be typically expected with Keytruda given on its own. Importantly, this benefit was most pronounced in patients whose tumors were positive for the AXL biomarker, which was true for approximately half of the patients enrolled. Additional combination trials are ongoing and continue to report results.

For more information on the bemcentinib and pancreatic cancer trial, and to learn more about eligibility, please visit the ClinicalTrials.gov page for the trial.