expert roundtables

Treatments With Novel Modes of Action Being Studied in Pancreatic Cancer

by Thomas A. Abrams, MD, Andrew Hendifar, MD, MPH, Gauri Varadhachary, MD

Overview

The incidence of metastatic pancreatic cancer has increased over the past several decades, and it now ranks as the fourth leading cause of cancer death in the United States. Despite the high mortality rate, there is optimism surrounding improved outcomes with newly developed treatment regimens. Our featured experts in the field discuss emerging treatment options for metastatic pancreatic cancer.

Q:

Are there emerging treatment options with novel modes of action that show promise for improved outcomes in patients with metastatic pancreatic cancer?

Andrew Hendifar, MD, MPH

Co-Director, Pancreas Oncology
David Geffen School of Medicine
Cedars Sinai Medical Center
Los Angeles, CA

There are several emerging treatments with novel modes of action showing promise for improved patient outcomes, especially those targeting the BRCA mutation subgroup, as well as poly-ADP ribose polymerase (PARP) inhibitors. There is a randomized POLO study looking at maintenance PARP inhibitors after patients have responded to platinum-based chemotherapy. Those are very novel approaches. The other novel approaches are defining the damage repair deficiency (DDR) subtype and giving those patients platinum-based and PARP-based treatments. We are participating in a phase 3 hyaluronic-based clinical trial that is looking at a novel enzyme in patients with a subtype of pancreas cancer that has been described as HA high (high expression of hyaluronan, defined as >50% expression, or tumor volume, of this hyaluronan protein). Right now, the phase 2 study looks interesting. The data in the HA subtype look better than in the overall population, although the primary endpoints were met in the overall population. The progression-free survival was not robust in the overall population, but in the HA high subtype, it seemed pretty robust. I think it is interesting that drugs are now being developed to target the tumor stroma, which we know is a very characteristic attribute of pancreas cancer. We have also participated in studying the bruton tyrosine kinase (BTK) inhibitor, which is also a stromal targeting agent. I think that is the group of studies that most interest me. There are also several ongoing immunotherapy studies that, unfortunately, have not been showing much promise, but our colleagues who study immunotherapy do believe that if they have the right combination of medications or interventions, they will be able to elicit a response. I think those are the most promising and interesting from my perspective.

“There are several emerging treatments with novel modes of action showing promise for improved patient outcomes, especially those targeting the BRCA mutation subgroup, as well as PARP inhibitors.”

Andrew Hendifar, MD, MPH

Thomas A. Abrams, MD

Assistant Professor of Medicine
Harvard Medical School
Senior Physician
Dana-Farber Cancer Institute
Boston, MA

We are also enrolling patients in the pegylated recombinant human hyaluronidase (PEGPH20) trial, and I think that is an interesting trial. It has a putative biomarker in hyaluronan. As Dr Hendifar explained, there have been some interesting data with stemness kinase inhibitors and the BBI608 molecule (napabucasin). I think the issue is that a lot of these trials are very early, and in pancreas cancer we’ve had so much disappointment with novel combinations and new drugs. It does feel like the dominoes are starting to fall, but it’s definitely a long road. We are still treating a disease in which cytotoxic chemotherapy is the backbone as the major treatment of choice, and it does not appear that it will be shifting anytime soon – although these shifts tend to go quickly. With respect to immunotherapies, turning pancreas cancer – a really cold tumor, and an immunologically protected cancer – into something where we can really get some immune cell infiltration has posed numerous challenges. We are really trying different combinations to get pancreas cancer to start to respond to some of these immunological agents. This is something that we are really striving for as immunotherapy has taken over oncology in general, but it just has not made its way into pancreas cancer yet.

“We are really trying different combinations to get pancreas cancer to start to respond to some of these immunological agents. This is something that we are really striving for as immunotherapy has taken over oncology in general, but it just has not made its way into pancreas cancer yet.”

Thomas A. Abrams, MD

Gauri Varadhachary, MD

Professor and Medical Director, Gastrointestinal Center
University of Texas MD Anderson Cancer Center
Department of Gastrointestinal Medical Oncology
Houston, TX

I agree. We are looking at CXCR4 with immunotherapy and plan to start the CD40 study with the backbone of chemotherapy and anti-PD therapy. The question is, are we going to make a seismic shift? Some of the struggle that we have is that we have just not seen the preclinical data really influence development of novel regimens; we also have only a very small proportion of phase 2 and phase 3 randomized trials that are positive. These early nimble trials do now have more and more pre- and post-mandatory tissue acquisition, and at least that will help us understand why some therapies are not working. I too am concerned that none of the immunotherapy combinations have come through for all-comers. But the question is: could there be something there for the DDR subtype or the familiar pancreatic cancer patients? We have to get more tissue pre- and post-therapy to really understand what is working or not working.

“Some of the struggle that we have is that we have just not seen the preclinical data really influence development of novel regimens; we also have only a very small proportion of phase 2 and phase 3 randomized trials that are positive.”

Gauri Varadhachary, MD

References

Hubbard JM, Grothey A. Napabucasin: an update on the first-in-class cancer stemness inhibitor. Drugs. 2017;77(10):1091-1103.

Melstrom LG, Salazar MD, Diamond DJ. The pancreatic cancer microenvironment: a true double agent. J Surg Oncol. 2017;116(1):7-15.

Ueno M, Li CP, Ikeda M, et al. A randomized phase II study of gemcitabine plus Z-360, a CCK2 receptor-selective antagonist, in patients with metastatic pancreatic cancer as compared with gemcitabine plus placebo. Cancer Chemother Pharmacol. June 20, 2017. doi: 10.1007/s00280-017-3351-4. [Epub ahead of print].

Wong KM, Horton KJ, Coveler AL, Hingorani SR, Harris WP. Targeting the tumor stroma: the biology and clinical development of pegylated recombinant human hyaluronidase (PEGPH20). Curr Oncol Rep. 2017;19(7):47.

Yarchoan M, Myzak MC, Johnson BA 3rd, et al. Olaparib in combination with irinotecan, cisplatin, and mitomycin C in patients with advanced pancreatic cancer. Oncotarget. 2017;8(27):44073-44081.

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