Moving Beyond Chemotherapy in Metastatic Pancreatic Cancer

Chemotherapy regimens continue to dominate the metastatic pancreatic cancer treatment paradigm, but novel combinations with monoclonal antibodies and PARP inhibitors are under investigation in the locally advanced and metastatic settings, respectively, according to Zev A. Wainberg, MD.

“In pancreatic cancer, we are struggling with finding targets of interest and novel drugs beyond chemotherapy that get people excited,” Wainberg said. “We have a lot of work to do to identify the right patients. It is still a chemotherapy-heavy disease so it is going to be tricky [to move beyond this,] but we are trying. Novel immunotherapy targets and approaches are hopefully on the way.”

In an interview with OncLive^® during an Institutional Perspectives in Cancer webinar on gastrointestinal malignancies, Wainberg, co-director of the UCLA GI Oncology Program, and a professor of medicine at UCLA, discussed the role of neoadjuvant chemotherapy in resectable pancreatic cancer, emerging approaches in locally advanced disease, the promise of PARP inhibitors in the metastatic setting, and other future research directions of interest.

OncLive^®: In resectable pancreatic cancer specifically, is the jury still out on whether neoadjuvant chemotherapy is more beneficial than immediate surgery? If so, is there an optimal chemotherapy regimen?

Wainberg: The jury is still out; I do not believe that we have too much data to support one [approach] or the other. Historically, we have always taken patients who are resectable straight to the operating room without [considering] neoadjuvant chemotherapy. A recently published Japanese study demonstrated value in treating patients neoadjuvantly, although they used different chemotherapy in an exclusively Japanese patient population. They did show a survival advantage [with] neoadjuvant [treatment]; that was proof of principle that there is some value in that.

In some respects, I do not consider it wrong to treat patients who are resectable with neoadjuvant chemotherapy, and I think it is an appropriate option for many patients. I cannot call it a standard of care yet. However, ongoing studies are [examining this further], so we will see whether the paradigm changes.

What has been done to increase resectability in borderline resectable patients?

A few things have been done. With better cross-sectional imaging and specialization, more patients [have been able] to [get to] resection. It requires a group of people who really know what they are looking at and have a good sense of whether a patient is resectable or not, or borderline resectable. The other thing it involves is multiagent chemotherapy because if you are really trying to increase the ability to make a R0 resection, in that circumstance, it does make sense not to treat with palliative regimens but to treat with a more aggressive combination chemotherapy regimen up front. [Those regimens are often] used in metastatic disease, but here, dose intensity may be more important.

In terms of adjuvant therapy, do you have a preferred option?

The National Comprehensive Cancer Network guidelines say that adjuvant FOLFIRINOX is the appropriate [option with] level 1 evidence. Many patients, after they get through the surgery, are perhaps not suitable candidates for adjuvant FOLFIRINOX. Some regard gemcitabine/capecitabine as a suitable option, as well. At the end of the day, the challenge is getting these drugs into patients, which is part of the impetus perhaps when neoadjuvant approaches are going to be more promising moving forward.

Are there any emerging approaches that you’re excited about?

A number of new trials are looking at investigative neoadjuvant approaches for locally advanced disease. Pamrevlumab is a monoclonal antibody factor that has been studied in combination with gemcitabine and nab-paclitaxel [Abraxane] in a randomized phase 3 study done in [patients with] locally advanced [disease]. The premise there is that we will be able to get more of those patients to surgery where they not may have otherwise been eligible.

An Alliance study is looking at patients with borderline resectable disease and the question of sequencing: neoadjuvant versus adjuvant [therapy]. This is a very important study if it can be successfully completed. Finally, a European study is looking at patients with borderline resectable disease and the role of radiation. An earlier-line study suggested [that this approach might] not benefit as many patients as we might have thought. This will be a larger randomized study that will be done in France.

Turning to the metastatic setting, it cannot be denied that PARP inhibitors have made a splash. Could you speak to the data reported with these agents?

PARP inhibitors in pancreatic cancer have shown us proof of principle that we can target patients with BRCA mutations and germline mutations. The phase 3 POLO trial [NCT02184195] did show a progression-free survival advantage [with this approach]. Many people find this is just the start; it is not sufficiently compelling to automatically require every patient with BRCA-mutated pancreatic cancer to receive a PARP inhibitor. The first thing [we need to do is] to test for BRCA. We must do a better job of testing more patients. We still have a long way to go.

Secondly, if you recognize that a patient with pancreatic cancer is a BRCA carrier, use regimens that are less toxic than FOLFIRINOX, perhaps gemcitabine and cisplatin; this is what I use in those patients. [This regimen] is gentle and platinum is the key. Perhaps [patients] do not need all those intense chemotherapy regimens—at least not initially.

We [need to] do a better job [of] getting durable, stable disease, or even responses in germline pancreatic cancer. So far, it has been a real struggle; this is not ovarian or breast cancer where we see long disease-free intervals or long maintenance phases with a PARP inhibitor. It is going to take a little nuance, and perhaps combination strategies. Many ongoing studies are looking at smaller doses of PARP inhibitors, or smaller doses of chemotherapy with full-dose PARP inhibitors.

Just about every PARP inhibitor is being studied with chemotherapy in pancreatic cancer. Rucaparib [Rubraca] is being examined with nanoliposomal irinotecan–type of regimen in an international study. Another interesting trial will examine whether olaparib [Lynparza] can be extended to not just [patients with] germline BRCA [mutations] but also to [those who have mutations in] DNA damage repair [DDR] pathway genes.

What trials should your colleagues keep an eye on?

The 2 or 3 trials that people are watching right now in metastatic pancreatic cancer include the phase 3 AVENGER trial [NCT03504423], which combined FOLFIRINOX with or without devimistat [CPI-613]. The study has completed enrollment, so we expect to see results sometime in the next 6 months. Obviously, that is a very ambitious strategy to go from a phase 1 response rate to a randomized phase 3 trial but it accrued very quickly.

I am also excited about the phase 3 NAPOLI 3 trial [NCT04083235] because the NALIRIFOX regimen is perhaps more tolerable than classic FOLFIRINOX. It will be interesting to see how that translates in a randomized setting. That trial is randomizing patients to either the NALIRIFOX regimen or to gemcitabine/nab-paclitaxel. It is one of the largest global phase 3 studies going on right now for metastatic pancreatic cancer. This study is still enrolling.

Other smaller trials are examining combinations with immunotherapy, second-generation immunotherapy agents are being tested now, like CXC-R5 inhibitors. All these approaches look interesting, but it’s still early days.