Patient Factors, Toxicities Key to Selecting NALIRIFOX or Other Chemo Options in Advanced Pancreatic Cancer

With the addition of NALIRIFOX (irinotecan liposome [Onivyde] with oxaliplatin, 5-fluorouracil, and leucovorin) to the treatment paradigm for patients with metastatic pancreatic cancer, considering patient factors and the known toxicity profiles of approved chemotherapy regimens is key for selecting first-line therapies for patients with locally advanced or metastatic disease, according to Kian-Huat Lim, MD, PhD.

In February 2024, the FDA approved NALIRIFOX for the frontline treatment of patients with metastatic pancreatic adenocarcinoma.¹ Notably, NALIRIFOX is also listed as a preferred first-line regimen for patients with locally advanced or metastatic disease in the most recent National Comprehensive Cancer Network (NCCN) Guidelines.²

Although another chemotherapy option is now approved for patients with metastatic disease, Lim noted that there is still significant progress to be made in the pancreatic cancer space.

“Overall, the field is moving forward a little bit slower than the other diseases, but we're hoping that there will be more newer therapies coming out,” Lim said.

In an interview with OncLive^®, Lim detailed the current treatment landscape for patients with metastatic pancreatic cancer; highlighted the differences in the toxicity profiles of NALIRIFOX and FOLFIRINOX; and explained how to approach treatment for patients with potentially resectable or locally advanced disease.

Lim is a medical oncologist and an associate professor of medicine in the Division of Medical Oncology at Siteman Cancer Center and the Washington University School of Medicine in Missouri.

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

Lim: In 2024, we are still using systemic, combination chemotherapy to treat patients with metastatic pancreatic cancer in the first- and second-line settings. There has not been a lot of progress in the realms of targeted therapies or immunotherapies. Although there are some interesting data coming out with KRAS inhibitors and some immunotherapy combinations, those [studies] are still early. For now, chemotherapy is what we use heavily. The two chemotherapy regimens that we use heavily are FOLFIRINOX [leucovorin, fluorouracil, irinotecan, and oxaliplatin] and gemcitabine plus nab-paclitaxel.

NALIRIFOX is a newer regimen that is now FDA approved and is in the NCCN Guidelines as another option [as one of the preferred first-line regimens for locally advanced or metastatic disease]. NALIRIFOX is similar to FOLFIRINOX; it has similar efficacy and survival benefit compared with FOLFIRINOX but different toxicity profiles.

What factors influence the choice between FOLFIRINOX and NALIRIFOX regimens for patients with metastatic pancreatic cancer?

For [NALIRIFOX], there seems to be more gastrointestinal adverse effects [AEs], including diarrhea, and a little bit less toxicity in terms of neuropathy and bone marrow suppression. [The AE profiles] will be something that treating oncologists will take into consideration when choosing [NALIRIFOX vs FOLFIRINOX].

The only difference between [NALIRIFOX and FOLFIRINOX] is that we’re replacing the free form of irinotecan [in FOLFIRINOX] with liposomal irinotecan [in NALIRIFOX], which tends to be retained within the tissue longer; therefore, it may have a prolonged effect on the tumor cells.

In terms of patient selection, we have to look at the toxicity profile. It's quite clear already that NALIRIFOX is associated with a little bit more nausea, vomiting, and diarrhea. In patients who tend to have these AEs, you try to avoid [exasperating those toxicities].

One strength of NALIRIFOX is that you are reducing oxaliplatin, which can cause neuropathy, or numbness and tingling in the fingertips and toes for almost all patients. For example, patients who have preexisting neuropathy or long-term diabetes, or older patients, may benefit from NALIRIFOX over FOLFIRINOX, [the latter of] which uses a higher dose of oxaliplatin. The other thing is: if you think about the effect on bone marrow suppression, because of the low dose [of oxaliplatin], NALIRIFOX tends to have a bit less of that compared with FOLFIRINOX.

These are some things to consider [when choosing between NALIRIFOX and FOLFIRINOX]. In terms of outcomes, they are quite similar. Overall survival is quite similar. There may be a higher response rate [with NALIRIFOX], so that’s something we consider if we’re trying to achieve tumor response for patients with locally advanced or borderline resectable disease. These are the patients where we're trying to down stage their tumors. [Notably, the phase 3 NAPOLI 3 study (NCT04083235)] was [conducted] in the metastatic setting. We’re not sure if that signal of a higher response rate will apply to patients with borderline resectable or locally advanced disease when we are trying to shrink the tumor and allow surgery to happen.

What is the current standard of care for patients with resectable or borderline resectable pancreatic cancer?

For patients with localized, seemingly resectable disease, we look at tumor markers as well as CA19-9 to see if that's markedly elevated. We are concerned about micrometastases in those patients [with elevated CA19-9], and we typically give neoadjuvant chemotherapy [to those patients].

For patients [with] borderline resectable or locally advanced disease, we definitely give neoadjuvant chemotherapy to try to down stage [the tumor]. In this case, you can give anywhere from 4 to 6 months of chemotherapy.

[A case series] published in JAMA Surgery [in 2020] compared FOLFIRINOX vs gemcitabine plus nab-paclitaxel [as first-line treatment for patients with localized pancreatic ductal adenocarcinoma],³ and responses were higher for FOLFIRINOX, so this is actually the preferred regimen when we're trying to down stage disease in patients who are relatively robust. Again, FOLFIRINOX and NALIRIFOX are associated with unique AEs, so you want to be careful regarding which patients you choose [for these regimens].

We will probably choose to give [FOLFIRINOX or NALIRIFOX] to patients [with locally advanced disease] who are aiming for surgery. Could [FOLFIRINOX] be something that's preferred over NALIRIFOX? We don't know. We need to have a [prospective] study to address that.

References

1. FDA approves irinotecan liposome for first-line treatment of metastatic pancreatic adenocarcinoma. FDA. February 13, 2024. Accessed April 30, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-irinotecan-liposome-first-line-treatment-metastatic-pancreatic-adenocarcinoma
2. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines): pancreatic adenocarcinoma. NCCN. April 30, 2024. Accessed April 30, 2024. https://www.nccn.org/professionals/physician_gls/pdf/pancreatic.pdf
3. Perri G, Prakash L, Qiao W, et al. Response and Survival Associated With First-line FOLFIRINOX vs Gemcitabine and nab-Paclitaxel Chemotherapy for Localized Pancreatic Ductal Adenocarcinoma. JAMA Surg. 2020;155(9):832-839. doi:10.1001/jamasurg.2020.2286