Expert Discusses Frontline Standards, Dosing, and Novel Agents in Pancreatic Cancer

Benjamin Weinberg, MD

For patients with metastatic pancreatic cancer, frontline therapy includes FOLFIRINOX or the combination of gemcitabine and nab-paclitaxel (Abraxane). Although the combination of gemcitabine and nab-paclitaxel is associated with greater tolerability, both regimens may require dose reductions as a result of low blood counts, explained Benjamin Weinberg, MD.

“We think there are [certain] patients who can tolerate the FOLFIRINOX regimen, whereas the gemcitabine/nab-paclitaxel regimen is usually much more tolerable,” said Weinberg. “That said, both can be hard on a patient's blood count.”

For those who progress, the only FDA-approved therapy is nanoliposomal irinotecan (Onivyde) in combination with 5-fluorouracil (5-FU) and leucovorin, which is indicated primarily for patients who received gemcitabine-based therapy in the frontline setting. However, ongoing research is dedicated to providing more options for patients with the development of novel therapies, which include pegylated recombinant human hyaluronidase (PEGPH20) and napabucasin (BBI-608).

For example, in the CanStem111P trial (NCT02993731), patients with metastatic disease were randomized to receive either napabucasin plus nab-paclitaxel and gemcitabine or nab-paclitaxel and gemcitabine alone. The study has an expected primary completion date of December 2020.

Prior to its readout, physicians can anticipate the results of the phase III HALO-109-301 trial (NCT02715804) comparing PEGPH20 and placebo with the combination of gemcitabine and nab-paclitaxel in treatment-naïve patients with hyaluronan-high metastatic disease.

OncLive: What treatment options are available for patients with metastatic pancreatic cancer?

How do clinicians decide between frontline FOLFIRINOX and gemcitabine/nab-paclitaxel?

How is FOLFIRINOX tolerated?

In an interview during the 2019 OncLive^® State of the Science Summit™ on Gastrointestinal Cancers, Weinberg, a gastrointestinal medical oncologist, assistant professor of medicine, Division of Hematology/Oncology, Lombardi Comprehensive Cancer Center, Ruesch Center for the Cure of Gastrointestinal Cancers, Georgetown University, discussed frontline standards of care in metastatic pancreatic cancer and highlighted emerging agents targeting the stroma.Weinberg: There are several viable treatment options for patients with metastatic pancreatic cancer. There are a couple of standard frontline regimens: one is FOLFIRINOX with 5-FU, irinotecan, oxaliplatin, and leucovorin, and the other is gemcitabine and nab-paclitaxel; those are our basic standard frontline regimens. We also have an [FDA-]approved second-line regimen with nanoliposomal irinotecan, leucovorin, and 5-FU for patients who have disease progression on gemcitabine. Those are essentially the 5 active drugs that we have [in this space].That's a very difficult question. It's very patient dependent. It is possible to have low blood counts with both regimens, so that's often what we're working between. We do think that older patients who don't have as good of a performance status or who are not walking around as much tend to not do as well with FOLFIRINOX, especially if they have other medical problems. That said, it's often a discussion we have with the patient. We try to expose the patient to all 5 drugs at some point, whether that's the 3 upfront and then the other 2 later on [or vice versa].In my practice, I often trim some of the doses a little bit because I think it makes it much more tolerable. We often use things like white blood cell growth factor support for patients who have low blood counts on that regimen. That's definitely something we're always thinking about. We know that there are some patients from a cancer standpoint who respond better to one versus the other. We tend to falsely think that FOLFIRINOX has a better response rate compared with gemcitabine/nab-paclitaxel.

Will these regimens ever be directly compared to one another?

Although gemcitabine/nab-paclitaxel is considered a “lighter” regimen, will some patients require a dose reduction?

What data came from the PRODIGE 35/PANOPTIMOX trial?

In both of the trials that led to their approvals [the regimens] were compared with single-agent gemcitabine; they weren't compared head-to-head. FOLFIRINOX had a response rate in the low 30s, and gemcitabine and nab-paclitaxel had a response rate in the low 20s. These were slightly different patient populations that were never compared head to head. Going forward, we need better tests to figure out which patient should receive a 5-FU—based regimen and who should receive a gemcitabine-based regimen.Probably not, but a lot of molecular profiling groups are interested in finding that signature that could potentially predict response to one versus the other. This idea becomes especially important in the earlier setting of neoadjuvant therapy where we're trying to get [a patient] to a surgical resection. We don't want to waste time trying one regimen over the other if we could find a test that could predict which regimen we should choose. There, it becomes even more important because you have a limited time frame to get [the patient] to a surgery.Definitely. There are a lot of data to support giving gemcitabine/nab-paclitaxel every 2 weeks as opposed to the FDA label of a 3-weeks-on/1-week off schedule; that’s mostly because of blood counts. If we're giving it 3 weeks in a row, we're often omitting or severely dose reducing the third and sometimes even the second dose. In older patients, especially patients who have low blood counts, I often quickly default to an every-other-week regimen at about an 80% dose of the total. Patients do pretty well with that.In the PRODIGE 35/PANOPTIMOX study, investigators looked at a couple of different maintenance approaches. They tried to see how long we should give FOLFIRINOX and whether we should give it for all 12 cycles. Additionally, [they tried to determine] whether we could stop earlier, give maintenance, pause completely, or switch to a completely different regimen. Interestingly, patients seemed to live a little longer if they paused therapy and were later restarted on the full regimen. However, the side effects of restarting oxaliplatin showed high rates of neuropathy.

In my practice, it's very patient dependent. I don't think there's anything magical about 12 [cycles], but if patients are tolerating it, I will often continue for all 12 cycles. I usually don't go beyond 12 cycles of oxaliplatin due to the concern for neuropathy. If a patient is not tolerating it, I'm quick to de-escalate, ideally down to maintenance 5-FU or capecitabine-based therapy. I’ll escalate [the dose back up] if the disease starts to grow back.

Following progression of frontline therapy, what are some available therapies?

At our institution, we have a maintenance trial of capecitabine with a vaccine and a checkpoint inhibitor. That trial only allows up to 16 weeks of frontline therapy, so it forces us to stop FOLFIRINOX or gemcitabine/nab-paclitaxel after 8 cycles. That's probably a nice stopping point as well, but nobody really knows the [optimal cycle length]. It's all very patient dependent.In the second-line setting, we only have 1 FDA-approved option and that’s nanoliposomal irinotecan, 5-FU, and leucovorin, which is designed for patients who had frontline gemcitabine. The question is, “What to do after that?” That's where many clinical trials come in.

What investigational agents have shown promise in this disease?

Usually for patients who received FOLFIRINOX in the frontline setting, we give them gemcitabine/nab-paclitaxel in the second-line setting. There are some data to suggest that patients who can receive FOLFIRINOX should probably receive it upfront rather than later on; it's probably better tolerated upfront as well.There are a variety of novel agents that are being tested in combination with gemcitabine/nab-paclitaxel because that is the easier regimen to combine agents with. A lot of those agents target elements of the stroma or the tumor microenvironment. The theory is that this dense stroma is walling off the cancer on a microscopic level.

What is your take-home message for clinicians?

Many trials are combining gemcitabine/nab-paclitaxel with, for instance, a hyaluronidase inhibitor, such as in the PEGPH20 trial. There, we’re trying to bust up this sort of dense hyaluronan that forms the stroma. There are others, such as napabucasin, which is trying to target tumor stem cells. That's another very active agent.Clinicians are going to have to be more upfront about doing broad molecular profiling for these tumors. We do find rare tumor types, and the NTRK story is a good example of that. These mutations or fusions are very rare, and you have to go out and look for them, although they may only pop up in 1% or less of all patients. When you do find it, it can be a “silver bullet” because we have drugs to target it. There are low rates of HER2 positivity, microsatellite instability—high, and NTRK fusions, but if you start building that bucket like in lung cancer, you find more and more.

The best story is with the homologous recombination repair [alterations], the BRCA or BRCA-like family of genetic defects, which can be inherited or required de novo. Those patients respond to platinum-based chemotherapy and they also probably respond to PARP inhibitors. A lot of our work is trying to combine those agents together or find a way to get PARP inhibitors to those patients because they definitely seem to benefit from them.