Modest Gains in Metastatic Pancreatic Cancer Leave Room for Improvement

Jordan D. Berlin, MD

Although a number of treatment options are available to patients with metastatic pancreatic cancer, regardless of whether they received FOLFIRINOX or the combination of gemcitabine and nab-paclitaxel (Abraxane) in the frontline setting, more data and more effective treatment regimens are needed to truly move the needle forward, explained Jordan D. Berlin, MD.

“Treatments for patients with pancreatic cancer have gotten better,” said Berlin. “We really have 2 to 3 lines [of treatment] depending on how you spread out the drugs. However, we need more [active] regimens.”

In an interview with OncLive® during an Institutional Perspectives in Cancer webinar on Gastrointestinal Malignancies, Berlin, Ingram Professor of Cancer Research, professor of medicine, VICC associate director for clinical research strategy, director, Phase I Program, gastrointestinal malignancies, clinical trials, Department of Medicine, Vanderbilt University Medical Center, discussed the current treatment algorithm in metastatic pancreatic cancer and ongoing research efforts in the space.

OncLive®: What is the current treatment landscape of metastatic pancreatic cancer?

Berlin: We have 2 regimens: FOLFIRINOX and gemcitabine plus nab-paclitaxel. Both regimens are equally reasonable to give. Though, we are unsure if they’re equally effective. Some data suggest that they might be [equally effective in terms of outcomes] in the neoadjuvant setting. However, that’s more of a response rate issue. Whether or not starting with 1 regimen versus the other [is better in the metastatic setting] is unproven since they’ve never been compared head to head.

The trials that evaluated those 2 regimens had very different eligibility criteria and therefore may not be comparable. I tend to use FOLFIRINOX in the first-line setting, which means I almost never use nanoliposomal irinotecan in the second-line setting because there are no data to suggest that we should use that treatment after FOLFIRINOX. Nanoliposomal irinotecan is something you would consider after gemcitabine and nab-paclitaxel based on the data that are available. In that case, several options are available, one of which would be FOLFIRI. Other options include nanoliposomal irinotecan plus 5-fluorouracil (5-FU) and leucovorin or FOLFOX. If the patient has a really good performance status, you could also use FOLFIRINOX. We have a lot of options. We don’t know what the best option is because we have limitations on the number of trials [that have been done]. The only true randomized phase 3 trial to show a benefit after gemcitabine-based therapy was the trial that evaluated nanoliposomal irinotecan /5-FU.

What is the role of nanoliposomal irinotecan in the metastatic setting?

The first trial was a second-line trial that was conducted several years ago in patients who had been previously treated with gemcitabine-based therapy. The trial had 3 arms: nanoliposomal irinotecan alone,nanoliposomal irinotecan plus 5-FU/leucovorin, and 5-FU/leucovorin. Nanoliposomal irinotecan plus 5-FU was more effective than the other 2 arms. The investigators didn’t directly compare the triplet to nanoliposomal irinotecan alone, but the single-agent arms were both about the same.

The other trial is looking at incorporating nanoliposomal irinotecan into a first-line regimen in combination with oxaliplatin and 5-FU. That trial is ongoing; we don’t have any data yet. 

How does performance status impact treatment decisions?

If we start with FOLFIRINOX, we’ll switch to gemcitabine and nab-paclitaxel. If we start with gemcitabine and nab-paclitaxel, we go to FOLFIRINOX. Off of a clinical trial, I generally use FOLFIRINOX if the patient is eligible for it. Most of the time, my choice is based on the clinical trial we have. We prefer to enroll patients on clinical trials. I still think that is the best option for patients.

The combination of gemcitabine and nab-paclitaxel was tested in patients with a performance status of 2 and a Karnofsky performance of 60% to 70%, so we know it’s safe in those patients. However, FOLFIRINOX has not been utilized in patients with a poor performance status of 2. In that case, one would consider nanoliposomal irinotecan plus 5-FU, FOLFIRI, or FOLFOX. All of those options would be equally reasonable. Though, they haven’t been compared head to head, so we don’t know what the most effective regimen is.

The truth is that if you progress on 1 regimen, one would consider the other. Because nab-paclitaxel and oxaliplatin has a risk for neuropathy, I would go for one of the 2 irinotecan-based second-line regimens before I go for the oxaliplatin-based regimens to spread out the neuropathy-causing drugs.

Could you elaborate on the results of the NAPOLI-1 trial?

NAPOLI-1 was a randomized trial of 5-FU/leucovorin versus nanoliposomal irinotecan versus nanoliposomal irinotecan plus 5-FU/leucovorin. The study was originally just the 2 single-agent arms. After a conversation with a brilliant physician, they added the third arm, and therefore there were some modifications to the trial. The third arm was the [best-performing arm]. In that arm, the median survival was 6.2 months versus 4.2 months for the control arm. The hazard ratio was under 0.7, which is what we consider more clinically significant.

We really want to start talking more about hazard ratios than medians because median is a simple time point. Because curves wave up and down, time points may not be as important as the hazard ratio, which really compares a line to a line. The hazard ratio was very good for overall survival as well as progression-free survival. [Nal-IRI plus 5-FU/leucovorin] is a very reasonable regimen to utilize since its FDA approval.

Could you shed light on the NAPOLI-3 trial?

This was presented as a trial in progress poster at the 2020 ASCO Virtual Scientific Program. However, the investigators didn’t present their calculation for how they chose 750 participants. The trial is essentially replacing the irinotecan in FOLFIRINOX with nanoliposomal irinotecan and comparing it with gemcitabine and nab-paclitaxel.

From this trial, we’ll determine how nanoliposomal irinotecan plus oxaliplatin plus 5-FU/leucovorin compares with gemcitabine and nab-paclitaxel. We will not know how it compares with FOLFIRINOX. It will be an interesting study. The company believes [the nanoliposomal irinotecan] regimen will [be superior] to gemcitabine and nab-paclitaxel. The choice of the control arm is simply because they needed an FDA standard to compare it with, and FOLFIRINOX is not an FDA standard as it has not been FDA approved. The problem is that [if the trial is positive], many of us will just consider it as justification to use FOLFIRINOX as modified FOLFIRINOX is tolerable. However, that’s not for me to worry about.

What is the significance of these data?

The first study, [NAPOLI-1], was quite significant in that it was really the first good-sized phase 3 trial in second-line pancreas cancer that accrued, which is a big issue, and showed statistical significance and a clinically meaningful benefit for patients. It gave us a new agent. Many of us are curious if it’s a better irinotecan in the laboratory. It looks that way, but we have not proven that in humans. If it is a better irinotecan, is it much better? That dilemma still hasn’t been answered. The generic irinotecan is a lot cheaper than a company sponsored agent. It’s a difficult issue. Though, it’s helping to learn about.

The NAPOLI-3 study will be significant in that it is going to be the first comparison of a FOLFIRINOX-like regimen to gemcitabine and nab-paclitaxel. A lot of us are very interested to see what the outcomes are. What we won’t know is whether or not FOLFIRINOX would have performed as well or as poorly [as nanoliposomal irinotecan plus 5-FU/leucovorin] depending on what the outcome is.

What are some unanswered questions that you hope are going to be addressed with future research?

We need to improve upon what we have. Can we get new drugs? Can we figure out a way to make immune-oncology work in pancreas cancer because it doesn’t, except in the rare microsatellite instability–high patient.

Additionally, PARP inhibitors have been brought into pancreas cancer, but only in germline BRCA-mutated patients. Can PARP inhibitors work in other settings in pancreas cancer, most importantly, in other patients with DNA damage repair defects, or in patients with germline PALB2 mutations? Those questions have yet to be answered but will be in the near future. We’re excited about the era of [targeted therapy] and other DNA damage repair modifying agents.

What is your take-home message for your colleagues?

We need [therapies that are] more active. Although [our current agents] have a median survival of 6 months in the second-line setting, that isn’t impressive compared to what we see in other diseases like breast cancer and prostate cancer. We really need a lot more data. My personal belief is we really need to better understand the disease with the science so we can approach this disease very logically.