Saif Shares Key Treatment Considerations for Advanced Pancreatic Cancer

For patients with advanced pancreatic cancer, approved treatment regimens come with a host of factors to consider, as far as how they will be tolerated and how they should be sequenced, according to Wasif Saif, MD. To continue to improve outcomes, biomarkers must be identified, a multidisciplinary team must be utilized, and enrollment to clinical trials must be encouraged.

“We have made tremendous improvements in the outcomes for patients [with pancreatic cancer], but really, that is limited to 2 major regimens that consist of FOLFIRINOX, and gemcitabine plus nab-paclitaxel [Abraxane],” Saif said. “So which regimen should be picked, and based on what characteristics? Right now, everything is based on subjective and objective evaluation on patient performance status, comorbidities, toxicities, and acceptance from the patient on adverse effects [AEs] and goals of care.”

In an interview with OncLive^® during an Institutional Perspectives in Cancer webinar on Lung Cancer, Saif, the Deputy Physician in Chief at Northwell Health Cancer Institute, and a professor at the Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, discusses factors to consider when choosing a frontline treatment strategy in pancreatic cancer, highlights the hunt for helpful biomarkers of response to available options, and offers sequencing suggestions.

OncLive^®: For the frontline treatment of patients with advanced pancreatic cancer, how do you choose between nab-paclitaxel/gemcitabine and FOLFIRINOX?

It’s very good that we have a richness of knowledge about these regimens. One regimen, FOLFIRINOX, is given once every 2 weeks, and it also includes the 5-fluorouracil [5-FU] infusion pump that the patient gets for 46 hours; that is an important part to discuss with the patient. We also know that oxaliplatin is known to cause peripheral neuropathy triggered by the cold exposure and that irinotecan has more gastrointestinal AEs in terms of diarrhea and nausea.

On the other hand, nab-paclitaxel plus gemcitabine is given on a weekly basis, 3 weeks out of 4 weeks if we go by the phase 3 MPACT trial. However, there is a modification of that regimen, where patients receive [the combination on] day 1 and day 15, every 28 days. The benefit of that regimen is that it seems to be a little more tolerable and does not have to be discontinued. [We don’t see] cold-triggered neuropathy with this regimen, so that is [another] benefit. The regimen also does not cause diarrhea or nausea to the extent that FOLFIRINOX might.

These are very important factors. We also know that some patients do not want to receive a 5-FU pump because they live far or they have a hard time coming back. That is the reason it has to be a very open discussion. We also have to keep in mind that a majority of patients end up getting both regimens because we sequence them. None of these regimens, in general, cause cure. We know that they work for a time and then they stop working, or the patient cannot tolerate them, and then we sequence these regimens.

In a way, patients are comparatively healthier when they are first diagnosed, unless they have symptoms from their cancer. If we are trying to really help the patient to treat those symptoms, we want to achieve a response rate. With FOLFIRINOX compared against gemcitabine, and similarly, gemcitabine plus nab-paclitaxel compared with gemcitabine alone, we do know that response rates were superior, up to 32%, in those who received FOLFIRINOX. This is what we know, but overall, relatively young patients [with a] performance status of 0 or 1 are who we offer FOLFIRINOX to.

When examining standard combinations in the first line, what are you looking at in terms of biomarkers of response?

Unfortunately, we do not have any biomarker available at this time. Some pharmacogenetic biomarkers [exist with] 5-FU, such as dihydropyrimidine dehydrogenase and UGT1A1. [However] those markers really [have to do] more [with] toxicity to the drug; they do not really validate or define the benefit from the chemotherapy. That is where organoids come in. Organoids are basically a miniaturized and simplified form of an organ, which is produced in vitro from the cells. That is a 3D organ development, and we can test the sensitivity of chemotherapy in that organoid.

We are collaborating with Cold Spring Harbor laboratories and opening a study called PASS-01 [NCT04469556]. In this clinical trial, patients will be randomized to these 2 regimens and then [investigators will] collect the organoid. When they progress, based on the organoid sensitivity, the patient will be matched to that particular therapy based on what genetic mutation, abnormality, or sensitivity we see on the organoid. We are not as successful as we have been in other tumors such as lung cancer [when it comes to biomarkers], but I'm hoping that with the constant struggle, hard work, and collaboration with our scientists, we will [get] there soon.

With more options available, how do you approach sequencing?

If you look by the FDA approval, gemcitabine alone, gemcitabine along with the EGFR TKI erlotinib [Tarceva], and gemcitabine plus nab-paclitaxel are the approved regimens for the first-line treatment of patients with metastatic pancreatic cancer. On the other hand, the only regimen approved by FDA for the second line is liposomal irinotecan [Onivyde], along with 5-FU/leucovorin.

Historically, some studies looked at FOLFOX. However, patients who received liposomal irinotecan plus 5-FU/leucovorin were those who had only received gemcitabine-based therapy. Right now, a majority of the patients, 60% or more, do receive FOLFIRINOX as a first-line therapy. When those patients cannot tolerate the regimen, we can sometimes modify it; however, if it ultimately fails, then we go to gemcitabine plus nab-paclitaxel. We also have to keep in mind that some patients who start gemcitabine plus nab-paclitaxel may go to the next regimen, and we need to now think about a commonality.

The commonality about the 2 regimens is that gemcitabine plus nab-paclitaxel causes peripheral neuropathy. In the MPACT study, about 17% of patients developed grade 3 or higher neuropathy. On the other hand, with FOLFIRINOX, 9% or more of patients developed grade 3 or 4 neuropathy. That tells us that it is quite possible that that patient when receive gemcitabine plus nab-paclitaxel, and when they fail, they may end receiving liposomal irinotecan plus 5-FU/leucovorin. If their neuropathy has resolved or improved, they may receive oxaliplatin-based therapy in the third line if they do not get on a clinical trial.

The same stands for patients getting FOLFIRINOX. If they progress and they have neuropathy, they may not be candidates to receive nab-paclitaxel; they may receive gemcitabine alone, or maybe even some other agent. That's what we are trying to learn about, and that is where the field is moving. How can we incorporate these agents and be more proactive in developing regimens? Also, how can we bring liposomal irinotecan into the first line?

What is needed to improve outcomes in those with this disease?

Many, many years ago, when I was a professor, someone asked me a question and I told them that I don't treat cancer; I treat [patients with] cancer. That is the mentality I like to bring up because we need to consider treating patients [by also thinking about] the symptomatology caused by the cancer. Keep in mind that pancreatic cancer is accompanied by diabetes mellitus. If someone has diabetes and they have become very fragile, they can develop thromboembolism, fever, and depression. We need to consider starting palliative supportive care simultaneously when we are trying to treat a patient with pancreatic cancer, irrespective of the disease stage.

We also need to use a multidisciplinary approach. A surgeon, medical oncologists, radiation oncologists, pathologists, radiologists, gastroenterologist, need to work together as a team to give input [and decide what is best for] the patient. This is life-and-death situation. We need to do the best that we can for that patient because we know this is a deadly disease, and we know this is a systemic disease.

Lastly, it is extremely important that we encourage the development of clinical trials and ensure there is patient-friendly access. At the end of the day, we are all talking about developing these novel agents and trying to figure out how best to use them. However, we all know that the best option for any patient, for any stage of pancreatic cancer, is still a clinical trial. Not only should we encourage enrollment, but we need to make it very easy to access clinical trials. I do not want a patient to be put on hold on the telephone for hours when they are already anxious to start therapy.