Clinical Trials Will Change the Metastatic Pancreatic Cancer Landscape

Clinical trials should not be viewed as a last resort for patients with metastatic pancreatic cancer, explained Allyson Ocean, MD, who added that even frontline standards of care should be considered after exhausting all available study options.

“There are plenty of clinical trials available for your patients. Clinical trials should always be the first consideration for patients with metastatic pancreatic cancer because that’s the only way we’re going to really move the bar in this disease,” said Ocean.

To that end, Ocean cited the phase 3 NAPOLI-3 trial (NCT04083235), in which patients with previously untreated metastatic pancreatic cancer will be randomized to liposomal irinotecan (Onivyde; nal-IRI) plus 5-fluorouracil (5-FU)/leucovorin and oxaliplatin (NALIRIFOX) versus the combination of gemcitabine and nab-paclitaxel (Abraxane).

Additionally, Ocean called attention to a phase 3 trial (NCT03512756), which is evaluating the amino acid analogue, SM-88, in patients with metastatic pancreatic cancer whose disease has progressed on 2 prior lines of chemotherapy. Eligible patients will be randomized 1:1 to SM-88 or physician’s choice of capecitabine (Xeloda), 5-FU, or gemcitabine.

In an interview with OncLive® during the 2020 Institutional Perspectives in Cancer webinar onGastrointestinal Malignancies, Ocean, ​ an associate attending physician, NewYork-Presbyterian Hospital, and associate professor of clinical medicine at Weill Cornell Medicine, discussed ongoing research that has the potential to expand the armamentarium in metastatic pancreatic cancer.

OncLive®: How do you approach frontline treatment decisions in metastatic pancreatic cancer?

Ocean: My first go-to is a clinical trial. It’s very important for us to look into clinical trials for anyone diagnosed with this very aggressive, very hard-to-treat disease. If we don’t have a clinical trial available for the patient, or perhaps the patient does not want to participate in a trial, then I consider more standard treatment regimens, such as FOLFIRINOX or gemcitabine and nab-paclitaxel.

There are a few factors that determine which regimen a patient with metastatic pancreatic receives in the frontline setting, including how strong they are, their performance status, their preference, their quality of life, and their goals of their care. Also, sometimes their symptoms and whether or not they’re having a lot of pain or a lot of problems related to their disease burden. If we need to achieve a quicker response, that may dictate choosing one regimen over the other.

Shifting to clinical trials, how did the results of the NAPOLI-1 trial pave the way for the NAPOLI-3 study?

We knew that we were getting a survival advantage in the first-line setting with regimens like FOLFIRINOX and gemcitabine/nab-paclitaxel. However, these patients do progress and need to go on second-line therapy. More and more patients are eligible for second-line therapy.

What led to the research and development of nal-IRI was the fact that we did need better therapies overall in the toolbox for patients with pancreatic cancer. What is unique about this compound is that its liposomal formulation ensures that there’s more tumor penetration. Additionally, the molecules of irinotecan and its active moiety, SN-38, lasts longer in the tumor, creating more of a response and more of a cancer-killing effect.

The NAPOLI-1 study was published in 2016 by Andrea Wang-Gillam, MD, PhD, of Washington University School of Medicine in St. Louis, in Missouri. This was a phase 3 study that compared the combination of nal-IRI and 5-FU/leucovorin with 5-FU/leucovorin alone and nal-IRI alone. Each of the arms were compared with 5-FU/leucovorin alone. The results showed a significant improvement in overall survival (OS) in the second-line setting with the nal-IRI combination compared with 5-FU/leucovorin. The combination of nal-IRI plus 5-FU/leucovorin had a median OS of 6.1 months versus 4.2 months with 5-FU/leucovorin, with a hazard ratio of 0.57 and a significant P value of .0009.

To have a median OS of 6 months in the second-line setting was an improvement upon what we had before. Now patients have a second-line option that improves OS and progression-free survival. The combination was definitely better than each agent alone. Those data led to the approval of nal-IRI and 5-FU/leucovorin given every 2 weeks in the second-line setting.

This regimen is mainly for patients who have not received irinotecan in the past. However, the NAPOLI-1 trial did allow patients who received prior irinotecan on the study. Some of those patients still benefited from receiving a different form of irinotecan. If a patient starts first-line chemotherapy with gemcitabine/nab-paclitaxel, it’s a natural change to consider nal-IRI/5-FU/leucovorin in the second-line setting.

However, if the patient received FOLFIRINOX in the first-line setting and then progressed, they could still receive nal-IRI plus 5-FU/leucovorin in the second-line setting even though they had received irinotecan previously. We could also switch patients to gemcitabine/nab-paclitaxel.

How might the results of the randomized phase 3 NAPOLI-3 trial affect the paradigm?

FOLFIRINOX has a median OS of 11.1 months in the first-line metastatic setting. That’s the bar that the combination of [NALIRIFOX] is hoping to surpass. We have a median OS approaching 1 year with FOLFIRINOX in the first-line metastatic setting. The NAPOLI-3 trial, which is currently ongoing, is comparing nal-IRI plus 5-FU/leucovorin and oxaliplatin versus gemcitabine and nab-paclitaxel.

Keep in mind that FOLFIRINOX was compared with gemcitabine alone in the [phase 2/3 study led by Thierry Conroy, MD, of the Institut de Cancérologie de Lorraine, not gemcitabine and nab-paclitaxel. It’s not really fair to do cross-trial comparisons with regard to which regimen is better in the first-line setting. That being said, now we have a triplet that is being tested in the frontline setting versus a doublet. We will have an answer when the study is completed as to which of these 2 regimens is superior in the first-line setting.

Both FOLFIRINOX and gemcitabine/nab-paclitaxel have efficacy for patients in the first-line setting. Some patients respond amazingly well to FOLFIRNOX and vice versa. Both regimens are used very frequently. It really depends on the performance status of the patient as to which one you start with. It’ll be good to get the results of NAPOLI-3, so that we can see more of a head-to-head clinical trial of 2, hopefully, very active regimens.

With regard to novel agents, could you highlight the preliminary data with SM-88 that supported its development in the metastatic setting?

SM-88 is an amino acid analogue. It’s a tyrosine, which is an essential amino acid analogue. Cancer cells need amino acids for energy and to increase their metabolism. This agent falls into a class of cancer metabolism therapies. It is an oral compound called racemetyrosine, and it’s given daily. It is given in combination with methoxsalen, phenytoin, and sirolimus in very small amounts. Those [medications] are given to help SM-88 enter the cancer cell better, but they are used at such a low concentration that they don’t appreciably collect in the bloodstream. It’s not something we could measure in the bloodstream; they’re more so acting on the cellular level.

The preclinical data in pancreatic cancer cell lines showed that there was a increase in killing in the cancer cell lines. Sometimes it happened right away, but the majority of the time, it took a little while for the killing to happen. That is consistent with metabolic killing because it’s consuming the energy of the cell, and that takes time. It’s not just killing the cell by intercalating into the DNA and causing the cell not to divide rapidly. It’s basically starving the cancer cell of its energy supply and that takes some time.

Then, the investigators did a phase 1 trial in patients with pancreatic cancer and other solid tumors. We did see an efficacy signal in patients; that’s what led to the phase 2 study. A total of 38 patients with metastatic pancreatic cancer received SM-88 in the phase 2 study. It didn’t matter how many prior lines of therapy they had received. In 2019, at the first data collection, 19 of the 28 evaluable subjects were alive at a median follow-up of 4.3 months, with a range of 1.3 to 8.3 months. Keep in mind that a lot of these patients were heavily pretreated.

The important thing to remember about SM-88 is that its [adverse effect] profile is very favorable. It has a very low incidence of grade 3 toxicities. People usually feel better on it; they have said that they get an energy boost. There is a chance of developing skin hyperpigmentation with the medication, but on the whole, it is tolerated very well.

That is really refreshing for patients who have received a lot of prior chemotherapy. If their disease can be maintained with an agent that doesn’t cause a lot of toxicity, that’s really important. A lot of patients who enter trials in the third-line setting and beyond, who are heavily pretreated, can’t really handle further chemotherapy and need something to control their cancer without producing a lot of toxicities.

Two national studies are now ongoing. One is TYME’s randomized phase 3 study in the third-line setting. Patients will be randomized to physician’s choice of capecitabine, 5-FU as an infusion, or gemcitabine, or SM-88 daily. Patients will be evaluated after 8 weeks. The 2 prior lines of chemotherapy have to have included a gemcitabine backbone and a 5-FU backbone. Imagine someone getting frontline FOLFIRINOX, and then progressing, then getting gemcitabine and nab-paclitaxel in the second-line setting, and then progressing. That patient would be eligible to go on this trial.

The other ongoing clinical trial is part of the PanCAN Precision Promise clinical trials framework. SM-88 is part of this clinical trials framework in a second-line study. [In the trial,] patients who progressed on frontline chemotherapy are randomized to SM-88 or FOLFIRINOX or gemcitabine/nab-paclitaxel—–whichever they didn’t receive up front.

What would you like to emphasize for your colleagues who are treating patients with metastatic pancreatic cancer?

We really need to think about what patients are going to receive in terms of chemotherapy because now we have first- and second-line chemotherapy options. Hopefully, we will have a third-line chemotherapy option as well. To be able to have a toolbox of regimens that I can look forward to giving a patient [can provide some] hope for them.

It’s also important to know that there is an FDA-approved second-line chemotherapy regimen with nal-IRI plus 5-FU/leucovorin. The NAPOLI-1 study showed an improved survival of 6.1 months in the second-line metastatic setting versus 4.2 months with 5-FU/leucovorin alone. That is an FDA-approved second-line chemotherapy regimen.

There are a lot of clinical trials ongoing right now in the first-, second-, and third-line settings. I highlighted SM-88, [which is being evaluated as a] second-line drug in the PanCAN Precision Promise clinical trial framework. Also, there is a third-line clinical trial with SM-88 after patients have progressed on a gemcitabine-based or 5-FU-based chemotherapy regimen.

The National Comprehensive Cancer Network guidelines have changed now and include the incorporation of germline genetic testing for pancreatic cancer. That’s really important because the more we test patients, the more we are uncovering genetic mutations that can change therapy. It’s really important to sequence the tumor and do somatic tumor testing, but also germline genetic testing for patients with pancreatic cancer.

I always direct patients to the digital platform that I co-founded called Letswinpc.org. It’s a fabulous resource for patients with metastatic pancreatic cancer. We are affiliated with the Lustgarten Foundation, which is the nation’s biggest funder of pancreatic cancer research. You can find information about clinical trials, about new science, and promising science. What’s most powerful on that site are survivor stories from patients with metastatic pancreatic cancer that have been living many years.

I always like to send all patients to watch those videos because it really gives them hope. It makes them realize that their treatment journey is unique and there’s no reason why that the patient sitting in front of you can’t have the same success as all these other patients that did have success with stage IV pancreatic cancer. It’s a very important resource that that patients should know about. I’m very proud of Let’s Win! Pancreatic Cancer.

This article was originally published on OncLive as, "Ongoing Studies Could Modify the Script in Metastatic Pancreatic Cancer."