Sequencing Strategies: Metastatic Pancreatic Adenocarcinoma - Episode 10
Kenneth H. Yu, MD: We are always looking for new emerging agents to more effectively treat our patients with pancreatic cancer. One of the programs that we have been focused on, at Memorial Sloan Kettering Cancer Center, for a long time is the targeting of BRCA mutant—driven pancreatic cancer. As doctors know, BRCA mutations cause a lot of different cancers—particularly breast and ovarian cancer. But they also predispose patients to the development of pancreatic cancer.
Poly(ADP-ribose) polymerase (PARP) inhibitors have been studied as a way of targeting a weakness within these kinds of tumors. We have an ongoing clinical trial that uses 1 PARP inhibitor, veliparib, in combination with cytotoxic chemotherapy, gemcitabine and cisplatin. Our preliminary results are very encouraging. For patients with BRCA-driven tumors, the response rates in overall survival numbers are quite good.
We also have a second-line study looking at a separate PARP inhibitor, olaparib, used as a monotherapy in patients who have BRCA-driven tumors that remain sensitive to platinum agents. This would be a way of putting them on a lower-intensity, less-toxic regimen of just a PARP inhibitor without chemotherapy to try to maintain control over the cancer and help patients live longer.
Beyond that, because not very many patients, nationwide, have BRCA-driven pancreas cancer, we’re interested in studying whether PARP inhibitors can also be used for treating tumors with mutations and related genes—genes that also participate in the BRCA pathway or other related pathways. That remains exploratory. We don’t really have any sense as to whether that is going to be effective. So, stay tuned. We’ll see how that goes.
Fadi Braiteh, MD: Clinical researchers who have an expertise in pancreatic adenocarcinoma, and who conduct and design clinical trials in pancreatic adenocarcinoma, are referred to as the romantic or eternal optimists. Why? There is a reality. A majority of molecules that made it to a clinical trial in pancreatic adenocarcinoma in the first-line, second-line, or third-line setting have failed to prove superiority. In fact, many studies that even succeeded in the second-line setting have failed in the third-line setting. I can go on and list about 7 or 8 molecules that were exciting in the phase II setting, that didn’t make it to the phase III setting. That didn’t stop us. That didn’t stop scientists, industry, and government agencies. One of the most exciting is pegylated hyaluronidase, which is referred to as PEGPH20. Recently, we published phase II data with the subgroup analysis. And, as we speak, there is an ongoing phase III clinical trial that is enriched by a population of patients whose tumors’ hyaluron (HA) levels are about 50%. The idea is to provide this pegylated intravenous formulation of the natural enzyme, hyaluronidase. It’s going to really dismantle the microenvironment that shelters that cancer from the immune system and from the vasculature. It may allow for a better delivery of the cytotoxic and the immune cells to the cancer environment.
As we speak, this is being proven in preclinical data. It’s been very encouraging in phase II data. The phase III study is ongoing, as we speak. Only time will tell if this is going to be proven a superior addition to frontline albumin-bound paclitaxel plus gemcitabine or not. I encourage patients and providers to look for the nearest centers that are enrolling on the study and to refer patients for enrollment.
John L. Marshall, MD: I believe every patient with metastatic cancer, including metastatic pancreas cancer, should have tissue acquisition for broad molecular profiling. We uncover things that we weren’t expecting. We know about BRCA and PARP and MSI and checkpoint inhibitors. But if you look at pancreas cancer, across the board, as high as 25% of patients will have some sort of actionable mutation. Some are better than others, but at least there’s stuff there.
An incredible project that I’m very proud to discuss, as one of my colleagues is running this across the country, is this “Know Your Tumor” Precision Promise project in pancreas cancer. If you’ve done molecular profiling, there are opportunities to have tailored therapies offered to you, based on what the patient’s gene expression was.
I think the world of precision medicine is just really beginning. We’ve got a few things that we’ve been able to pull off. But this study is taking this data, integrating it with the best knowledge that we have, today, and turning that into a therapeutic recommendation for an individual patient. This is what precision medicine is about: giving that patient the best therapy that our brains can come up with, today, in the hopes that it improves outcome. So, it’s really the way to go.
Transcript Edited for Clarity