Eileen O'Reilly, MD
There are several novel therapeutic approaches under investigation for the treatment of patients with pancreatic cancer. Immunotherapy, for example, has become an area of excitement, with early combination studies showing activity in these tumors.
A phase I study combining nivolumab (Opdivo) with nab-paclitaxel (Abraxane) and gemcitabine demonstrated that the combination is feasible and the antitumor activity of this regimen appears to be encouraging for patients with advanced pancreatic cancer. The combination led to objective responses or stable disease in 12 of 17 patients in 2 cohorts. One cohort consisted of patients who were previously treated, whereas the other included patients with no prior treatment.
In an interview during the 2017 OncLive®
State of the Science SummitTM
on Gastrointestinal Cancers, Eileen O’Reilly, MD, associate director for Clinical Research, David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, discussed novel therapeutic approaches for the treatment of patients with pancreatic cancer.
OncLive: Can you give an overview of your presentation on pancreatic cancer?
The initial part of my discussion was to review where we are with the current state-of-the-art frontline therapies for good performance status patients [treated] with FOLFIRINOX, gemcitabine, and nab-paclitaxel. There was a brief discussion of beyond frontline therapy with the relatively recent data of liposomal irinotecan [Onivyde] and fluorouracil.
We discussed the topic of sequencing in pancreatic cancer, which is new because there are now some choices to be made regarding defining treatment for a given patient.
The second part of my talk touched on genomic sequencing in pancreatic cancer from the tumor perspective, meaning somatic profiling. We also discussed it from the germline perspective, meaning the family lineage opportunity. Are there findings that can have an impact in terms of treatment decision making?
The learnings from somatic profiling have been modest in terms of the applications of that information. Nonetheless, we are on the cusp of learning how to do this in pancreatic cancer and applying that information. Targeted therapy options are available for a small percent of patients, but for that group it is arguably meaningful. For example, DNA-damage repair or hyper-mutated tumors occur in 1% of pancreas cancer, mostly in patients with germline Lynch syndrome and the rare NTRK
Germline testing is interesting. It is an emerging story in pancreas cancer. In solid tumors, we are finding that somewhere between 10% to 15% of patients with germline mutations are actionable and therapeutically important. For example, testing for BRCA, ATM,
is something that we are increasingly thinking about; should we be doing this on a routine basis with pancreas cancer?
The last part of my talk was about where the field is going and the promising areas. The whole field of immunotherapy is a huge focus in pancreas cancer. We are trying to understand the microenvironment, why the T cells are not effective, and if we can make a tumor immune-responsive by combining immunotherapies together or combining immunotherapy with chemotherapy. There are many studies addressing these questions so that, over the next couple of years, we will understand whether there are opportunities.
The 2 other major areas in terms of novel therapeutics are stromal disruption therapies. This is highlighted by PEGPH20 [pegvorhyaluronidase alfa], which is in late-stage development in pancreas cancer in a biomarker-selected population of patients with elevated levels of hyaluronidase. The phase III trial is underway so we will hopefully have data in the next 1 to 2 years.
Going back to the genomic story, the subset of patients with DNA-repair deficiencies that drugs, such as platinum agents and other DNA-damaging agents such as PARP inhibitors, may have a role. That concept is being developed now in pancreas cancer. There is a registrational study beyond the frontline setting looking at olaparib [Lynparza] in patients with germline-mutated pancreas cancer who have been treated with platinum-based therapy.
The next part of the equation is understanding where the limits of DNA-repair inhibition are in pancreas cancer. Do genes beyond BRCA matter? Should we be looking for those and see what the impact of these types of therapies in those subpopulations are? It is a very interesting time in pancreas cancer. A lot is happening but there is more work to do and we remain hopeful.
What is the standard approach for sequencing?
We do not know how to fully apply this information but hopefully we will soon. It is going to be beyond single mutations. We will have the benefit of looking at multiple patients with different patterns and having annotated clinical outcomes that might say if a therapy is best applied to this person.