CRI-Funded Trial Reveals Promising Potential of Immunotherapy Combination in Metastatic Pancreatic Cancer

A novel combination of immunotherapy and chemotherapy shows promise as a first-line option in patients with metastatic pancreatic cancer, according to interim results from a Cancer Research Institute-funded clinical trial that are being revealed today at the 2019 Annual Meeting of the American Association for Cancer Research (AACR19) in Atlanta.

This phase Ib trial is the first to emerge from the partnership between the Cancer Research Institute (CRI), the Parker Institute for Cancer Immunotherapy (PICI), and Bristol-Myers Squibb (BMS) that was formed in 2017 in order to accelerate promising immunotherapy to benefit the patients who need them most.

In this study, patients were treated with combinations of four different drugs, including two standard-of-care chemotherapies and two immunotherapies—one that inhibits the PD-1 immune checkpoint (nivolumab, BMS) and an experimental treatment that activates the CD40 pathway (APX005M, Apexigen).

The rationale behind this combination is three-fold. First, the chemotherapies are designed to kill some pancreatic cancer cells and cause them to release their antigens, or markers that can help the immune system identify what the tumors “look like.” These antigens are then taken up and displayed by antigen-presenting immune cells (APCs) for other immune cells to see. Next, the CD40 drug is used to activate these APCs and help stimulate them to coordinate immune responses against remaining tumor cells. Finally, the PD-1 checkpoint immunotherapy acts on the foot soldiers of the immune system—the T cells—to release their brakes and ensure that they are able to effectively eliminate cancer cells without being prematurely shut off.

Combining immunotherapy with chemotherapy shows early activity in patients with advanced pancreatic cancer, shrinking tumors in a majority of evaluable patients, 20 out of 24. All patients received the chemotherapy and CD40-targeting treatments, while half were also treated with PD-1 checkpoint immunotherapy.

“The idea is to attack the cancer from different angles. Although the results are early, we see encouraging signs that anti-CD40 immunotherapy, checkpoint inhibition, and chemotherapy in combination could be an effective new approach to treat patients with metastatic pancreatic cancer,” said study leader Robert H. Vonderheide, MD, DPhil, a member of the CRI Clinical Accelerator leadership, a PICI investigator, and the director of the Abramson Cancer Center of the University of Pennsylvania.

Vonderheide first demonstrated the potential benefits of CD40 activation in preclinical cancer work with mice and dogs, and acknowledged previously that this trial involving CD40 therapy “wouldn’t have been possible without the Cancer Research Institute, who really gave us what it took to get this over the goal line to start the study.”

“Compared with most other cancers, pancreatic cancer has a challenging prognosis, so to see patients continuing on the same treatment for a year and beyond is very promising,” said Eileen M. O’Reilly, MD, co-lead author of the study and associate director for clinical research at the David M. Rubenstein Center for Pancreatic Cancer at Memorial Sloan Kettering Cancer Center.

Pancreatic cancer is currently the third-leading cause of cancer-related death in the United States, where it claimed more than 44,000 lives in 2018. The most common form is called pancreatic ductal adenocarcinoma (PDAC), and once the disease has metastasized, or spread to other organs, it becomes especially hard to treat. Historically, fewer than one in ten patients survives at least five years. This urgent need for better options is why metastatic PDAC patients were chosen for this trial.

“There are more than 2,600 clinical trials looking at PD-1/L1 combinations to treat cancers, but only 89 of them are for pancreatic cancer versus 535 for lung cancer,” said Vanessa M. Lucey, PhD, a co-author of the study and the director of the Cancer Research Institute Anna-Maria Kellen Clinical Accelerator. “Considering that pancreatic cancer is expected to be the second leading killer in the U.S. by 2025, it highlights how much work is to be done to make progress for patients, which is exactly why we at CRI chose to help support this trial.”

Importantly, the main purposes of this trial were to understand the safety and tolerability of this four-drug combination, and to determine the appropriate dose of the CD40-targeting drug with which to move forward. “While these early data appear promising, the results of the phase II trial that is currently recruiting patients will be necessary to understand the full activity of these agents,” stressed Lucey.

This novel clinical trial approach also highlights the unique opportunities made possible by CRI’s Clinical Accelerator, with its global immuno-oncology network of 90 leading clinician-scientists who work collaboratively to identify potentially transformative treatments and design cutting-edge trials that can help de-risk the clinical study of next-generation combination cancer immunotherapies. The Clinical Accelerator’s nonprofit-academic-industry partnership model currently boasts 18 significant industry and nonprofit partners and utilizes a unique IP model that facilitates access to top drugs from different companies and enables multi-center studies to be conducted.

This model is powered by a nonprofit, philanthropic venture capital fund that provides financial support alongside other partners, and also benefits from the Immuno-Oncology (IO) landscape analysis that the CRI Clinical Accelerator team has spearheaded.

Given CRI’s history as one of the preeminent funding sources for IO research over the last six-and-one-half decades, it should come as no surprise that this trial also brings strong scientific disciplines into the clinical setting. Consequently, another exciting aspect of this study is the significant emphasis that has been placed on exploratory science being conducted in parallel—known as “deep immune profiling”—in order to better understand patients’ immune responses. These analyses include multidimensional imaging of tumor-infiltrating immune cells and characterization of the different T cell populations within tumors.

Additionally, circulating tumor DNA—in this case, the mutated Kras gene—is also being analyzed in order to understand the dynamics of using blood-based biomarkers to follow patient responses over time. This, along with the other therapeutic and analytical strategies being employed here, could unveil insights that can be applied well beyond this specific trial, regardless of the outcome. According to PICI’s Chief Medical Officer Ramy Ibrahim, MD, “What we learn in this trial will hopefully inform the work being done on other solid tumor types, so that we can make immunotherapy beneficial for more patients.”