BARCELONA, Spain—New disease-stabilizing therapies for metastatic pancreatic cancer are giving researchers an opportunity to test immune-based regimens, which may be the future of treatment for this rapidly progressing disease.
“There's actually been very little effort in immune-based regimens [until now] because these patients didn't live long enough to benefit from immune therapy,” said Margaret A. Tempero, MD, Director of the University of California, San Francisco Pancreas Center and Professor of Medicine in the Division of Hematology and Oncology, speaking here at the European Society for Medical Oncology World Congress on Gastrointestinal Cancer.
“We now have multiple options for disease-stabilizing chemotherapy, and it is only because of those options that we have the right sort of infrastructure to be able to explore new strategies.”
Considering the genetic heterogeneity in cancer, adaptive immunity may be the best asset in controlling disease progression, said Tempero, also a member of a Stand Up To Cancer dream team examining the case for a number of innovative clinical trials with immunologic targets including PD-1, BTK, CXCR4, and CD47.
“We have a lot of activity trying to find drugs that will disable RAS—one of the drivers of this disease—and the National Cancer Institute is investing a huge amount of resources into drugs that will disable RAS. But substantial research efforts are also addressing stromal-associated targets, especially immune targets.”
To date, however, immune therapy for pancreatic cancer has had an effect only in metastatic disease. “That's kind of odd, but at least [researchers] are going to focus on that subset going forward,” she said.
Meanwhile, disease-stabilizing therapies that are now standard will aid in that research by making “window-of-opportunity trials” feasible after patients respond to chemotherapy.
Tempero's presentation focused on choosing regimens for initial therapy for patients with metastatic disease. In reviewing the recent history, she called FOLFIRINOX (folinic acid [leucovorin], fluorouracil [5FU], irinotecan, oxaliplatin) a breakthrough in treatment as shown in the randomized PRODIGE 4/ACCORD 11 trial (Conroy et al: NEJM 2011;364:1817-1825). That trial compared FOLFIRINOX with gemcitabine monotherapy for patients with high performance status, and the results led to the adoption of FOLFIRINOX as a front-line standard.
“The results were nothing less than dramatic—an improvement in overall survival, with a hazard ratio of 0.57. That's a hazard ratio we would like to see in every trial that we do.”
Still, that improvement comes at a cost: “It's a tough regimen, with dominating toxicities of myelosuppression, diarrhea, and neuropathy. We are getting better at making FOLFIRINOX more tolerable by omitting the bolus 5FU, reducing doses, and using chemotherapy holidays. We're still figuring it out, and as more trials are done with FOLFIRINOX-like regimens we will finally settle into a regimen that is more tolerable.”
The next contender for standard treatment was nab-paclitaxel, as demonstrated in a trial of that plus gemcitabine versus gemcitabine alone (Von Hoff et al: NEJM 2013:309:1691-1703).
“The overall survival benefit was not as dramatic as with FOLFIRINOX, but it had a respectable hazard ratio of 0.72,” Tempero said. “A clinically meaningful hazard ratio of anything less than 0.75 has to be taken very seriously.”
But nab-paclitaxel plus gemcitabine is also not an easy regimen to take—“perhaps easier to manage than FOLFIRINOX but not a walk in the park.”
Global vs. Regional
There is still myelosuppression and neuropathy with nab-paclitaxel—a different form of neuropathy than with FOLFIRINOX, but a neuropathy nonetheless, she said. “I'm often asked which is better and why don't we compare these two, but I don't believe they can be compared, because one was regional, in one country, and the other was global. A global trial will never see the same results as a regional trial or an institutional trial.”
Eligibility was slightly different in the global trial, and patients in some countries may have had less than optimal supportive care and fewer opportunities for second-line treatments, she explained.
“But I don't like to think of this as a contest, I like to think that for the first time in my career I have two options to talk about with patients.”
She said she can also give patients a toxicity scale: Gemcitabine and capecitabine are suitable for patients who are not fit enough for combination regimens, or are not willing to risk the potential toxicities. Patient tolerance for differing toxicities is one consideration for choosing a treatment for this disease, she said, along with the goals of treatment, comorbidities, compatibility with investigational agents, and biomarkers, which may be developed going forward.
“You would be surprised at the number of patients who prefer FOLFIRINOX just because they don't want to lose their hair, or who don't want the risk of irreversible peripheral neuropathy,” she said, recalling a patient who is a violinist.
‘More Subtle Factors’
Other factors in choosing a regimen for metastatic pancreatic cancer are more subtle, she said:
- Age: “I don't give any of these regimens to patients over the age of 80. Patients over 80 might look fit but they are frail. For patients between 70 and 80, I might use either regimen.”
- Performance status: Tempero said she is likely to give an asymptomatic patient gemcitabine and nab-paclitaxel.
- Incomplete biliary decompression: “That is definitely a choice of gem-nab-paclitaxel,” she said.
- Travel: “If the patient lives very far from the clinic—and that's common in the U.S.—we tend to use an alternate-week regimen and arrange to have the pump disconnected at home for FOLFIRINOX, and we are less likely to recommend gemcitabine-nab-paclitaxel because that requires more frequent visits to the clinic.”
Other Options from NCCN Guidelines
Tempero listed other options in the National Comprehensive Cancer Network (NCCN) guidelines:
- Gemcitabine and capecitabine for elderly patients who are still fit enough to have more than gemcitabine monotherapy;
- Gemcitabine and cisplatin is a preferred option for patients who have mutations in DNA repair pathways;
- Gemcitabine, docetaxel, and capecitabine (GTX) is a very commonly used, highly active regimen, although it has never been compared with gemcitabine monotherapy; and
- Gemcitabine and erlotinib are still on the list of recommendations, but on a less preferred level.
Build on The Standards
“None of us are happy with the state of management of this disease as it is, and moving forward we need to build on both FOLFIRINOX and gemcitabine-nab-paclitaxel,” Tempero said.
There are currently 54 open clinical trials in the U.S. for patients with metastatic pancreatic cancer, she said, but only two of those incorporate FOLFIRINOX. And there is only one randomized Phase II or III first-line trial with FOLFIRINOX, a trial that adds the enzyme PEGPH20.
There are, though, several that are building with gemcitabine-nab-paclitaxel as a backbone—adding, for example, ibrutinib, demcizumab, MM-141, and PEGPH20. “I think we are seeing a trend that [gemcitabine-nab-paclitaxel] may be an easier regimen to work with when adding additional new drugs,” she said.
Window of Opportunity for Trials
Researchers might consider taking advantage of the situation in which patients have good disease control with very deep responses but are unable to continue due to cumulative toxicity, Tempero said. “This maintenance period may be a window of opportunity for clinical trials.”
At UCSF, she noted, some of these patients are taken off therapy at six months and observed until disease progression, and then are retreated. To have something to offer these patients during maintenance, UCSF researchers are collaborating on an immunotherapy trial at Johns Hopkins comparing the GM-CSF cell-based vaccine GVAX with the anti-CTLA-4 agent ipilimumab versus capecitabine as front-line therapy in patients with metastatic disease who are stable following treatment with FOLFIRINOX.
Two other new drugs Tempero said are poised to move into first line for metastatic pancreatic cancer:
- MM398 (liposomal irinotecan) is likely to be approved for second-line treatment combined with 5FU/leucovorin, she said; and
- There are very encouraging second-line results in a Phase III trial of ruxolitinib for patients with high C reactive protein levels. Tempero said she sees ruxolitinib as potentially combined with FOLFIRINOX or gemcitabine-nab-paclitaxel.
TNM Staging: Tumor-Node Combinations Showing Progression of Pancreatic Cancers
- Stage IIB (purple), and N1 borderline resectable;
- Stage III (red) are unresectable;
- Stage IV (black) are metastatic.
- Stage 0 = yellow;
- Stage IIA = green;
- Stage IIA = blue;
- Stage IIB = purple;
- Stage III = red; and
- Stage IV (metastatic) = black.