With that being said, 1 of the elements that is important to keep in mind is that many physicians confuse performance status with symptoms that are not well controlled. Once you optimize the symptom control for patients, then you can better assess performance status. If a patient has a poor performance status, they often have pain and are not eating well. However, if they are put on enzymes, pain medications, and occasionally steroids, it can improve their appetite and activity.
Some patients went from a performance status of 2 or 3 to a performance status of 0 or 1. Many of them benefitted from treatment so it is important to keep in mind that performance status is a big detriment of who should get aggressive therapy versus no therapy. However, we don't make conclusions about performance status until we optimize the symptoms of the patient.
What targeted therapies and immunotherapy agents are coming down the pipeline?
Pancreatic cancer is now seeing more of an understanding of the molecular and genetic drivers. We are understanding what subsets of patients may benefit from certain treatments. For patients with microsatellite instability-high (MSI-H) tumors, immunotherapy works best. That subgroup was included in the study that led to the approval of pembrolizumab (Keytruda) in MSI-H cancers. There were a few patients with pancreatic cancer who had incredible responses. One patient continues to be in a complete remission from that treatment.
mutations and homologous recombination deficiency (HRD) as they may benefit from platinum-based treatment and PARP inhibitors. There are studies evaluating different PARP inhibitors in pancreatic cancer.
Can you hone in on the PARP inhibitor approaches in these patients?
The 3 PARP inhibitors that have been studied the most are veliparib, olaparib, and rucaparib. Veliparib appears to be the least potent. There are rare reports of any single-agent activity of this drug in pancreatic cancer. I don't think that this agent should be developed for pancreatic cancer. I am not even sure that it has enough potency as a PARP inhibitor.
The other 2 PARP inhibitors, olaparib and rucaparib, have shown single-agent activity in refractory patients. I don't believe that single-agent PARP inhibitors are going to be the answer for an aggressive disease like pancreatic cancer, but they would be optimally combined for maintenance phases. There are maintenance studies being done where patients receive FOLFIRINOX and then go on to receive olaparib after 4 months. Patients are randomized to olaparib versus observation.
The other strategy that is more interesting, in my opinion, is combining these agents when feasible with regimens containing either irinotecan-based compounds and then a liposomal irinotecan or a platinum-based agent, such as cisplatin. Preclinical data suggest that those agents synergize better with those inhibitors than they do with a platinum-based agent.
These strategies are being looked at in various studies. There are studies with oxaliplatin, cisplatin, veliparib, and rucaparib. One study that we will be launching soon is looking at 5-FU in combination with rucaparib. This will be a phase I trial that will lead into a phase Ib and II study for unselected patients and then eventually in BRCA1/2
-mutant and HRD patients.
I am hopeful that this area with show benefit for at least 20% of patients so we can have around 20% to 25% of patients, including those with MSI-H tumors, with stronger remissions and more durable responses.
What are other novel agents are showing encouraging activity?
There are 2 other agents and pathways that are showing promise. The first is PEGPH20, which is an agent that targets the stroma and hyaluronan (HA). It breaks down that stroma to allow chemotherapy into the tumor to maximize the kill. It is a great concept and looks very promising. There were 2 studies running parallel with each other; one is with gemcitabine and nab-paclitaxel and the other with FOLFIRINOX. Both were randomized trials.
The development of these drugs saw [adverse events] with blood clots—some being lethal—which changed the whole paradigm. Patients receiving the drug had to receive an anticoagulant low-molecular-weight heparin to help prevent the clotting events. This was smoother in the second stage. The study with gemcitabine and nab-paclitaxel in the exploratory analysis suggested that there may be a benefit for those patients who have HA-high tumors.
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