Toxicity, Sequencing Considerations Are Key for Frontline Chemotherapy Selection in Metastatic Pancreatic Cancer

Although targeted therapies and other novel agents could ultimately affect the frontline treatment paradigm in metastatic pancreatic cancer, chemotherapy regimens remain the current standard of care (SOC) for this patient population. However, selecting between options such as FOLFIRINOX (leucovorin, fluorouracil, irinotecan, and oxaliplatin), NALIRIFOX (irinotecan liposome [Onivyde], oxaliplatin, 5-fluorouracil [5-FU], and leucovorin), and gemcitabine plus nab-paclitaxel (Abraxane) requires consideration of patient factors and potential toxicities, according to Brandon G. Smaglo, MD, FACP, who added that the varying adverse effect (AE) profiles of FOLFIRINOX and NALIRIFOX can be key in making this decision.

“[We have to] look at [FOLFIRINOX and NALIRIFOX] as probably being pretty similar [in terms of] outcomes, but we know that the only way we're going to get to a good outcome is if the patient can tolerate [treatment] consistently. We have to anticipate what's going to be—if anything—a barrier to them continuing with [a given treatment] in the long term,” Smaglo said in an interview with OncLive® following a session at the 2025 Gastrointestinal (GI) Cancers Symposium on upfront treatment considerations in advanced or metastatic pancreatic cancer.

In the interview, Smaglo highlighted factors influencing the use of regimens like FOLFIRINOX and NALIRIFOX vs gemcitabine plus nab-paclitaxel in the frontline setting; the importance of molecular testing for optimizing treatment planning and identifying potential clinical trials early on in treatment; and emerging targeted therapies that may push the frontline treatment for metastatic pancreatic cancer beyond traditional chemotherapy alone/

Smaglo is an associate professor in the Department of Gastrointestinal Medical Oncology of the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center in Houston.

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

Smaglo: For more than 10 years, we've been able to consider a very reasonable frontline option for the treatment of these patients, FOLFIRINOX, with emphasis on irinotecan in that [combination]. Approximately 2 years ago, we saw newer data from the [phase] NAPOLI 3 study [(NCT04083235) showing] that another very good option would be NALIRIFOX, which replaced conventional irinotecan with the liposomal-bound version of that drug. Both [FOLFIRINOX and NALIRIFOX] are reasonable and have some [advantages and limitations]. However, they have not yet been directly compared [in a prospective trial].

The discussion [we had in the GI panel at the 2025 GI Cancers Symposium] was [centered on the advantages or disadvantages] of either regimen [and how these factors] might make one or the other preferable to offer to patients in the frontline setting, either as an all-comers approach or for certain patients with certain features.

Where do FOLFIRINOX and NALIRIFOX fit into the current frontline treatment paradigm alongside gemcitabine plus nab-paclitaxel?

The other conventional frontline therapy considered for patients with [pancreatic] cancer is the 2-drug regimen of gemcitabine and nab-paclitaxel. For almost as long as we've had FOLFIRINOX, we've also had [this doublet] as an option without understanding whether one was superior. In the NAPOLI 3 study, conventional irinotecan [as a part of FOLFIRINOX] was not part of the treatment arms; gemcitabine plus nab-paclitaxel was [the comparator arm], and NALIRIFOX was clearly superior to gemcitabine plus nab-paclitaxel.

One of the major takeaways is that we now have is that the 3-drug regimen of 5-FU, oxaliplatin, and then one of the versions of irinotecan is probably superior [in efficacy], if more toxic, than gemcitabine plus nab-paclitaxel as frontline therapy. This is a big treatment paradigm shift. We were probably a little bit more comfortable offering gemcitabine and nab-paclitaxel—a less toxic treatment—to a lot of our patients as a frontline therapy. However, we're starting to appreciate that there is benefit with [NALIRIFOX or FOLFIRINOX despite] the added toxicity.

The bigger question then becomes, ‘Does it matter if we use FOLFIRINOX or NALIRIFOX?’ There's no direct comparison; indirectly, the survival data [with these regimens] do seem comparable, but the AEs that pose more of a problem are different between the 2 regimens. That might guide what [treatment we ultimately select]. What everybody's struggling with right now is trying to decide [whether] we are going to [broadly] use liposomal irinotecan or be more selective about its use over [conventional] irinotecan.

Given that the National Comprehensive Cancer Center Guidelines list FOLFIRINOX, NALIRIFOX, and gemcitabine plus nab-paclitaxel as preferred frontline options with category 1 recommendations for metastatic pancreatic cancer, what factors influence your choice between these options?

There's probably no reason for any individual patient at different stages or different lines of therapy to get both [conventional] irinotecan and liposomal irinotecan. There is a reason for patients to get both 5-FU–based therapy and gemcitabine-based therapy. A different way to think about this might [be to ask oneself], ‘What am I going to do next?’ rather than, ‘What am I going to do first?’ If a patient receives either NALIRIFOX or FOLFIRIFOX as frontline therapy, gemcitabine plus nab-paclitaxel is a good second-line option. If they're going to receive gemcitabine and nab-paclitaxel as their frontline option, they'll get a 5-FU–based therapy later on.

For a patient who doesn't have a particularly robust performance status, who may bring a host of other comorbidities to their treatment, and for whom we have a sense that treatment with a more intensive, toxic therapy is something they're not going to tolerate, I would still offer them gemcitabine plus nab-paclitaxel in the frontline. [For these patients], the second line might be 5-FU plus [liposomal irinotecan] without oxaliplatin.

For a frontline patient who is more robust, it is inappropriate nowadays to offer them gemcitabine plus nab-paclitaxel [in the frontline]. FOLFIRINOX or NALIRIFOX are clearly superior [to gemcitabine and nab-paclitaxel], and patients should get the benefit from that in the frontline.

[It is necessary to consider] what we are worried about, if anything, in terms of their specific AEs. Diarrhea, which is a common irinotecan AE, does seem to be more of a problem with NALIRIFOX, whereas neuropathy and cytopenias seem to be a bigger problem with conventional FOLFIRINOX. [If, for example, we see a] diabetic patient who already has a lot of neuropathy, [FOLFIRINOX] may not be a good choice for them. Are they somebody who presented with a lot of pancreatic insufficiency and diarrhea was already a big problem? Maybe NALIRIFOX is not a good option for them.

What are the challenges and opportunities for incorporating targeted therapy into the frontline setting for pancreatic cancer, whether as a single agent or in combination with chemotherapy?

As a blanket statement, I think that the chemotherapy story for pancreatic cancer is probably now written. I don't see another chemotherapy drug adding much benefit at this point. Frankly, I don't think much is being done to study that now. We are looking at some of these other agents and options.

We have gotten to a point where any patient with a diagnosis of pancreatic cancer in the frontline setting should have both additional tumor sequencing and germline genetic testing performed because that will certainly provide us with a sense of what their options are. Very few of those results are going to [direct us toward] otherSOC] options; however, 2 very notable exceptions that we would never want to overlook would be a germline BRCA mutation and a microsatellite instability–high [MSI-H] tumor phenotype.

A germline BRCA mutation is fairly common; relatively speaking; we'd say that 1 in 10 patients [with pancreatic cancer] will display a BRCA mutation. That's important for 2 reasons. The first is that in, those patients, chemotherapy that includes a platinum drug, like oxaliplatin plus 5-FU or cisplatin alongside gemcitabine, tends to have much better [efficacy] than usual. It's not that chemotherapy without platinum is inferior; it's that platinum-based chemotherapy is superior, so we want to make sure that we're [getting the most benefit] from the choices we have. The other thing is that those patients are candidates for maintenance olaparib [Lynparza] once chemotherapy has gotten their disease under good control. Olaparib, which is a PARP inhibitor, is a good non-chemotherapy option to keep patients’ disease under control, and oftentimes [it keeps responses] quite durable. Everybody's going to have a different experience, but some patients have done very well with olaparib for a long period.

The MSI-H phenotype is not a common finding from tumor testing; 1% to 2% of pancreatic cancers will fall into that category. However, when it does occur, these tumors do respond to immune checkpoint inhibitors. Pembrolizumab [Keytruda] plus chemotherapy, for example, might be a very reasonable [option to choose], and this can [generate] deep, prolonged responses. Although [the MSI-H phenotype] is not common, when we do find it, it is a great finding for patients with an otherwise terrible disease.

How could emerging targeted therapies improve frontline treatment for biomarker-selected populations? How might this subsequently impact the role of chemotherapy in pancreatic cancer?

There is a ton of promising work being done to target other tumor alterations we might find in pancreatic tumors with genomic sequencing. KRAS mutations are a common, almost ubiquitous finding in pancreatic cancer. The studies being done now with KRAS inhibitors and other KRAS-targeting agents are showing a lot of promise. I'd go so far as to say that there's an almost certain chance that we're going to see KRAS-targeting agents become a part of the SOC in the next few years.

[KRAS] is not the only target that is emerging. Claudin 18.2 [CLDN 18.2] is another target that shows a lot of promise and already has a SOC agent for other types of cancer, like gastric cancer. MTAP testing is another good example. There are a lot of options available to patients on clinical trials [directed towards those] targets that are rapidly finding their way into earlier lines of therapy. It’s within the scope of [possibility] that in the next 5 to 10 years, we won't be using chemotherapy in the front line. [Instead] we'll be using chemotherapy plus a KRAS inhibitor or CLDN 18.2–targeted agent, which will hopefully be more specific in terms of targeting these cancers. This could also mean [in the future], maybe they don't need as much chemotherapy. Maybe we don't need to use FOLFIRINOX and NALIRIFOX, but [could instead use] 5-FU plus 1 of those agents and a targeted agent. In theory, this would be a better-tolerated treatment or at least would not compound chemotherapy-related toxicity.

What guidance would you offer to colleagues regarding the current and future frontline treatment paradigm in pancreatic cancer and the importance of early molecular testing and clinical trial consideration?

[Pancreatic cancer] is still a cancer where the best outcomes for patients do seem to be [achieved with] what we can do earlier on in the course of therapy. We need to get away from the mentality that this is something where we're just going to roll through chemotherapy, know the patient’s prognosis is poor, and then hope we can give them something as salvage therapy [from a] phase 1 trial later [in the treatment journey]. This has been a pretty appropriate approach to treatment for a long time, but we're making some good progress now [that allows us to] consider what our patients could benefit from in an earlier line of therapy, probably in a clinical trial setting. Not every patient needs to obtain 2 or 3 opinions before they start therapy, particularly [considering] how aggressive this cancer is.

At the very least while they're starting that frontline therapy, getting that germline testing, and tumor sequencing done is key [and allows us to] start exploring clinical trial options early. Not everybody's not in a position to do that logistically or location wise, but to have at least an opinion or a review from a center that does offer trials before that second-line therapy is needed [would be ideal], rather than waiting and hoping that there's a slot available for [a given therapy] later on and that the patient is robust enough to get it as salvage therapy. If we think back to around 2011 or 2012, when [the field of] melanoma was [introducing] pembrolizumab and other checkpoint inhibitors, I almost feel like we're on the verge of that in pancreatic cancer. I'd encourage everybody who does take care of these patients to be thinking about novel therapies and having patients consider and ask questions about trials earlier on in their therapy. We do have studies that are showing tremendous promise for a space that hasn’t had anything like this in a long time.