COMMENTARY

Chemo Combos Hit Pancreatic Cancer With Both Barrels

Michael J. Pishvaian, MD, PhD

Disclosures

February 12, 2016

Editorial Collaboration

Medscape &

Unprecedented 1-Year Median Survivals in Advanced Pancreatic Cancer

Although pancreatic cancer remains a deadly disease, new therapies are steadily improving patient outcomes. The effectiveness of the chemotherapy combinations of FOLFIRINOX[1] and nab-paclitaxel (Abraxane®) plus gemcitabine (Gemzar®) (nab/gem) as front-line therapy,[2] and more recently 5-FU plus nanoliposomal irinotecan (Onivyde™) as second-line therapy,[3] has led to improved overall survival times. In fact, the sequencing of these combinations has resulted in median survivals of well over 1 year,[4,5] an outcome not previously seen in pancreatic cancer. This has given researchers the opportunity to build on these effective regimens by investigating new therapies in a greater number of patients who are well enough to enroll in trials of novel agent combinations, creating a growing momentum in the clinical research of this disease.

This increased momentum in clinical research was evident in several studies of combination therapies presented at the 2016 Gastrointestinal Cancers Symposium (GICS). Among these studies was an update of a phase 2 randomized trial of nab/gem plus pegylated recombinant human hyaluronidase (PEGPH20) vs nab/gem alone, led by Sunil R. Hingorani from the Fred Hutchinson Cancer Research Center in Seattle, Washington. It has been established that tumors with a high expression of hyaluronic acid (HA) are associated with poor prognosis.[6,7] By combining nab/gem with PEGPH20, which breaks down HA, it was surmised that a greater efficacy might be achieved in pancreatic cancer patients with high-HA tumors. Early data from the phase 2 study, presented in June 2015,[8] showed that the combination was well tolerated and resulted in improved progression-free survival  in patients with high-HA tumors. The interim data presented by Dr Hingorani at GICS confirmed a 9.2-month median progression-free survival for patients with high-HA tumors.[9] These intriguing results have spurred the highly anticipated phase 3 trial of nab/gem plus or minus PEGPH20 in patients with high-HA tumors, which is launching this spring.

One important negative study showed us that the combination of evofosfamide and gemcitabine was not more effective than gemcitabine alone,[10] expanding the long list of failed trials of gemcitabine plus a new agent. Any new trials in this context should probably only explore a more effective backbone, such as nab/gem.

Cancer Stem Cells and Immunotherapy Yield New Approaches

Targeting the cancer stem cell pathway is proving to be an intriguing therapeutic option. The hypothesis is that tumors have a hierarchical organization in which stem cell–like cells sustain tumor growth, metastasis, and resistance to therapy. The specific elimination of these cancer stems cells or the inhibition of their driving pathways may enhance the benefits of chemotherapy for pancreatic cancer. Several studies are looking at the combination of experimental inhibitors in combination with a proven chemotherapy backbone. In one study, the combination of BBI-608 (an agent that appears to inhibit multiple cancer cell pathways) with nab/gem demonstrated a promising 86% tumor regression rate for evaluable patients.[11] The numbers were small, but a similarly high response rate of 50% was seen with another cancer stem cell–targeting agent, demcizumab, in combination with GA in 56 patients,[12] suggesting that agents that target cancer stem cells may have real value in pancreatic cancer.

Although immunotherapy has had limited success in pancreatic cancer, one trial presented at GICS showed indications of activity in a small subgroup of patients. Dung Le, MD, from the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University in Baltimore, Maryland, presented updated results of a phase 2 trial of single-agent pembrolizumab in patients with non-colorectal cancers that showed high levels of microsatellite instability (MSI-H). Although the numbers were quite low, 2 out of 4 pancreatic cancer patients achieved a partial response, suggesting a potential option for this small subgroup of pancreatic cancer patients.[13] These results were consistent with results previously observed in other MSI-H cancers, including colon cancer,[14] thus emphasizing the value of MSI testing in patients with pancreatic cancer.

New Directions: Local Therapies and Multi-omic Profiling

As chemotherapies prove to be more effective in disease control, there are growing opportunities to incorporate local therapies in the management of pancreatic cancer. Robert Martin, MD, from the University of Louisville in Louisville, Kentucky, presented observational data of 200 patients with locally advanced pancreatic cancer who underwent ablative therapy with irreversible electroporation.[15] This technique uses an energy delivery system to ablate tumors by inducing irreversible cell membrane destruction while sparing the surrounding connective tissue. Although this was not a prospective trial, the median overall survival of 25 months represents a major improvement for patients with locally advanced pancreatic cancer. Similarly, Alexander Kim, MD, and colleagues from the Lombardi Comprehensive Cancer Center in Washington, DC, presented a study in which patients with metastatic pancreatic cancer were treated concurrently with chemotherapy, stereotactic body radiation therapy to the primary pancreatic mass, and transarterial radioembolizaton to the liver metastases. This combination of therapies achieved a 22-month median overall survival, indicating that combined modalities have an important role in the treatment of this challenging disease.[16]

Finally, there were a number of presentations on the incorporation of molecular profiling for treatment decision-making. Preliminary data were presented from the Pancreatic Cancer Action Network's Know Your Tumor Project, in which pancreatic cancer patient tumors were assessed through multi-omic profiling. The multi-omic profiling of 175 pancreatic cancer patients included next-generation cancer-related DNA exome sequencing (from tumor and blood-borne cell-free DNA), immunohistochemistry, and phosphoprotein analysis.[17,18,19] The authors showed that molecular profiling identified actionable abnormalities in up to 40% of patients, including in up to 10% of patients with defects in the BRCA genes, or similar abnormalities in the homologous recombination (HR) pathway. The investigators also emphasized the value of tumor-based testing rather than a blood-based, cell-free DNA test. Such testing could be used to steer appropriate patients to clinical trials more ideally suited to their particular tumor characteristics.

Progress in the treatment of advanced pancreatic cancer, as seen in the identification of targetable mutations and a growing number of active combination therapies, is providing hope for patients with this deadly disease. Promising clinical trials in immunotherapy, and the highly anticipated phase 3 trial with PEGPH20, may lead to further improvements in patient outcome. Key to this progress is the change in practice which calls for oncologists to test patient tumor samples for actionable drivers, including MSI and HR defects, which, if identified, can substantially improve outcomes in these small subgroups of patients. In addition, to sustain the momentum in clinical research, continued accrual of patients to clinical trials is vital. Only 3% of cancer patients are enrolled in clinical trials; if that number could increase to 10%, the rate of progress could be tripled, potentially providing real benefit to pancreatic cancer patients in the near future.

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