Emerging Therapies for Pancreatic Cancer

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There are several promising therapies on the horizon for patients with advanced pancreatic cancer, including MM-398, immunotherapy, and targeted therapies. MM-398, a liposomal form of irinotecan, was evaluated in the phase III NAPOLI-1 trial and showed improved overall survival (OS) when added to infusional 5-FU and leucovorin. These data are under review by the FDA, with hope for approval in 2015. If this agent is approved, the next step will be to determine how this agent fits into the current treatment paradigm, notes Eileen O’Reilly, MD.

Another interesting novel agent is tarextumab (OMP-59R5), an anti-Notch2/3 antibody that received orphan drug status from the FDA for both pancreatic and small cell lung cancers in January 2015. This drug, currently in phase II testing, appears to work by two distinct mechanisms: 1) by downregulating notch pathway signaling, tarextumab has anti-cancer stem cell activity; and 2) by action on pericytes, it targets the stromal and tumor microenvironment.

JAK/STAT inhibitors, such as ruxolitinib and momelotinib, are also promising. Ruxolitinib, now being studied in the phase III JANUS I and JANUS II trials, appears effective when paired with capecitabine, particularly in patients who have elevated C-reactive protein levels.

Targeting the stroma is another very topical area in pancreatic cancer. In theory, stroma depletion may enhance drug delivery to tumor cells. Several drugs are designed to break down the stromal barrier: the pegylated recombinant human hyaluronidase, PEG-PH20, a drug that received FDA orphan designation in 2014, is now being studied in a randomized phase II trial with gemcitabine and nab-paclitaxel, and also in a phase Ib study with FOLFIRINOX.

Heparins have had a very interesting history in oncology, as well. There has always been the suggestion that patients who received low molecular—weight heparin have improved oncologic outcomes. Since there may be dual benefits in pancreatic cancer because of the very high rates of thromboembolic events, novel targeted heparin derivatives are also in development. Necuparanib (M402), a novel drug engineered from unfractionated heparin has just received FDA fast-track designation as a first-line therapy for use in combination with nab-paclitaxel and gemcitabine in metastatic disease.

For the 5% to 8% of BRCA-mutated pancreatic cancers and possibly other subgroups with DNA mismatch—repair deficiencies, PARP inhibitors are an area of active research. Several studies are looking at velaparib and olaparib.

Immunotherapeutic approaches have generated excitement across a variety of fields. In pancreatic cancer, GVAX, a therapeutic vaccine, is currently being evaluated in a rapidly accruing phase III trial. This vaccine has been shown to trigger recruitment of tumor infiltrating lymphocytes to pancreatic tumor cells. In mid-2014, the combination of GVAX and CRS-207, which is composed of live attenuated Listeria monocytogenes, received breakthrough therapy designation from the FDA for its potential as a treatment for patients with metastatic disease. Results of a recent study suggest that the combination works better than GVAX alone.

Other immune-based strategies in pancreatic cancer are chimeric antigen receptor modified T-cell approaches, which are in their relative infancy in pancreatic cancer, and immune modulating drugs such as ibrutinib. Although the immune checkpoint inhibitors have reached exciting milestones in other malignancies, the work has just begun in pancreatic cancer. It may prove to be a yet unsolved piece of the puzzle to add a checkpoint inhibitor to “take the brakes” off the T-cell response.