A Glimpse into the Pancreatic Cancer Pipeline
The passing of renowned singer Aretha Franklin has focused attention on pancreatic cancer. Franklin, 76, succumbed to a neuroendocrine tumor of the pancreas. According to the National Cancer Institute (NCI), about 55,440 cases of pancreatic cancer are diagnosed annually, representing about 3.2 percent of new cancer cases. But each year, 44,330 Americans die from the disease, or about 7.3 percent of cancer deaths. It is now the third-leading cause of cancer death in the United States. And it’s a tough cancer to beat, with only 8.5 percent surviving for five years.
One problem is, like cancer itself, pancreatic cancer is not a single disease. Anirban Maitra, scientific director of the Sheikh Ahmed Pancreatic Cancer Research Center at the University of Texas MD Anderson Cancer Center, told Forbes, “The first thing to do if somebody gets a diagnosis of pancreatic cancer is to know what they are dealing with. Because everything they deal with will change dramatically based on that.”
Forbes points out that neuroendocrine tumors, the type that Aretha Franklin had, as did Apple founder Steve Jobs, are the rarer type of pancreatic cancer. Forbes writes, “Afinitor, a drug made by Novartis, has been shown to help patients whose neuroendocrine tumors have spread outside the pancreas, increasing the time before their tumors grow by six months, to 11.5 months. In a clinical trial, patients who got Afinitor did not live longer than those who received placebo; this may be because the study allowed patients in the placebo group to get the drug once their tumors start to grow.”
For patients with the more common form of pancreatic cancer, adenocarcinoma, the prognosis is worse. Famous people who died from adenocarcinoma include Dirty Dancing actor Patrick Swayze and opera singer Luciano Pavarotti. For these types, there are typically two chemotherapy regimens, one a combination of Gemzar and Abraxane, and the other a mixture of drugs called FOLFIRINOX. They extend survival from about four months to nine months in the average patient.
Maitra points out that surgical removal when the tumor is small gives the best odds of survival.
If one problem is the type of cancer, early detection is another. Pancreatic cancer is one of those types of cancer that is typically diagnosed from symptoms—abdominal pain, jaundice, weight loss, for example, in many cases. And by that time, the cancer has often spread, and surgery is not an option. Diagnosis is performed using a CT scan or an invasive procedure, such as a needle biopsy and invasive ultrasound.
In March 2018, OncLive discussed pancreatic cancer drugs currently in the pipeline with Tanios Bekaii-Saab, professor of medicine at Mayo Clinic. He noted, “Over the last few years, we have developed new strategies to extend survival for our patients. Half of the patients are crossing the one-year survival line, with 25 percent crossing the two-year survival line. We have patients who survive, three, four, and five years, but it is less than 5 percent of patients. However, this would be unheard of five or six years ago, so we are doing better. We are on the right path to ultimately bring pancreatic cancer into the mainstream.”
He notes there are two primary pathways for treating pancreatic cancer. The first is gemcitabine and Abraxane (nab-paclitaxel). When that fails, they receive 5-fluorouracil (5-FU) and MM-398 (irinotecan liposomem injection; Onivyde) based on the NAPOLI-1 trial. For the third-line setting, they try a platinum-based approach, such as FOLFOX or cisplatin.
Bekaii-Saab notes that genetic understanding of the disease is improving, and along with that understanding, some successes with new therapies have been seen. “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.”
That’s a rare subset of pancreatic cancers. Another group has BRCA1/2 and PALB2 mutations and homologous recombination deficiency (HRD). Bekaii-Saab says that platinum-based treatment and PARP inhibitors are showing promise for treating these subgroups. “The three 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…. The other two 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.”
He believes that combining these drugs with irinotecan-based compounds and then a liposomal irinotecan or platinum-based drug might be a good approach.
There are also at least two other approaches and drugs that show promise, Bekaii-Saab says. “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.” PEGPH20 is being developed by Halozyme Therapeutics.
And finally, Bekaii-Saab brings up napabucasin (BBI-608), a stem cell inhibitor under development by Boston Biomedical. “Napabucasin seems to inhibit and facilitate killing lowering the chemosensitizing capacity against these pancreatic cancer cells. If you give it with chemotherapy and gemcitabine, nab-paclitaxel, or paclitaxel, you seem to kill those cancer cells more efficiently and prevent them from reverting to the stemless phenotype.”
As frustratingly slow as treatments for this rare cancer may be, there are signs of progress.