Novel Approaches May Push Pancreatic Cancer Treatment Forward

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.

OncLive: Can you give an overview of your presentation on pancreatic cancer?

In an interview during the 2017 OncLive^® State of the Science Summit^TM 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.O’Reilly: 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 fusion.

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, and NBN 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.

What is the standard approach for sequencing?

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. 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.

If entrectinib is approved, could it help that small subset of patients with NTRK fusions?

Can you discuss the trials investigating immunotherapy in pancreatic cancer?

These multigene panels are relatively inexpensive compared with the applied therapy that one might use. In that sense, maybe it is justifiable, but we still have a lot to learn in this space in pancreas cancer. These therapies may be of high impact for that given individual. The number of individuals that are going to be impacted is relatively few, but it might make a big difference if you look at the larger population. Being able to refine treatments for a given person with pancreas cancer is an exciting concept because we have not had any good tools to do that yet. We are not there yet but there are hints that, for small groups of patients, there are realistic and useful ways of beginning to select treatments. The best and the most robust example that we have of that concept right now is deleterious germline or somatic BRCA mutations. A lot is happening in the immunotherapy field. We will see new data in 2018 looking at combinations of checkpoint inhibitors. We have had some data on single-agent checkpoint inhibitors, but the next wave will be combining immunotherapy with chemotherapy.

There are 2 big studies. One has started and the other will start soon. The one that is underway is looking at gemcitabine and nab-paclitaxel and adding a CD40 agonist with the potential to add nivolumab (Opdivo). This study has 2 different complimentary immune approaches on top of chemotherapy. In pancreas cancer, this makes sense because we need to get the disease under control. If we can get it under control with cytotoxic therapy, it may give these immunotherapies the opportunity to do their job.

A second study will be looking at gemcitabine and nab-paclitaxel and 1 or 2 checkpoint inhibitors in a randomized phase III study that will start in 2018. We have limited data but there is promise and potential. That is the strongest area right now where there may be signal with immunotherapies aside from the small subset of patients who have microsatellite instability-high tumors, which is about 1% of the population.

Wainberg ZA, Hochster HS, George B, et al. Phase I study of nivolumab (nivo) + nab-paclitaxel (nab-P) ± gemcitabine (gem) in solid tumors: interim results from the pancreatic cancer (PC) cohorts. J Clin Oncol. 2017;35(suppl 4S, abstr 412). doi: 10.1200/JCO.2017.35.4_suppl.412.