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Zev A. Wainberg, MD, discusses different palliative chemotherapy regimens, their use cases, and other recent developments in pancreatic cancer.
As ongoing research pushes to bring RAS inhibitors and other novel approaches to the pancreatic cancer treatment paradigm, chemotherapy remains the standard treatment approach. When navigating frontline chemotherapy options for patients with newly diagnosed pancreatic cancer, factors such as toxicity profiles and patient goals can help inform selection between NALIRIFOX (irinotecan liposome [Onivyde], oxaliplatin, 5-fluorouracil [5-FU], and leucovorin) and FOLFIRINOX (leucovorin, 5-FU, irinotecan, and oxaliplatin) in the absence of head-to-head data, according to Zev A. Wainberg, MD.
In February 2024,
In an interview with OncLive®, Wainberg dove into the strengths, weaknesses, and similarities of palliative chemotherapy regimens in pancreatic cancer, along with the factors that can help inform selection of NALIRIFOX or FOLFIRINOX. He also highlighted developments and ongoing research to keep an eye on with novel agents beyond chemotherapy.
Wainberg is a professor of medicine and co-director of the UCLA GI Oncology Program.
Wainberg: When a patient is newly diagnosed with advanced pancreatic cancer, it is usually an emotional discussion, having to deal with the fact that the disease has unfortunately spread and now needs to be treated with palliative chemotherapy. By and large, there have [historically] been 2 standard palliative chemotherapy regimens [for advanced pancreatic cancer]: gemcitabine plus nab-paclitaxel and modified FOLFIRINOX. There have not been large, randomized phase 3 trials directly comparing those 2 [regimens], so historically, there was a discussion about the pros and cons of each [regimen, evaluating factors such as] toxicity profiles, supporting data, and treatment tradeoffs.
The NAPOLI 3 trial compared NALIRIFOX with gemcitabine plus nab-paclitaxel in a randomized, phase 3 [setting]. NALIRIFOX is a version of modified FOLFIRINOX that incorporates liposomal irinotecan in place of regular irinotecan and slightly different doses of oxaliplatin. In [NAPOLI 3], NALIRIFOX was associated with a statistically significant median OS improvement of a couple months, [in addition to] PFS and overall response rate improvements. Because of [these data], the NALIRIFOX regimen was approved [by the FDA in 2024]. Clinicians have used [NALIRIFOX since its approval], and people have also interpreted [the NAPOLI 3 data] to use FOLFIRINOX a little more, as well.
We have a distribution of frontline regimens being used with FOLFIRINOX, NALIRIFOX, and gemcitabine plus nab-paclitaxel, which is also appropriate in certain patients [in the frontline setting]. There have also been studies that did not show much difference in survival between [gemcitabine plus nab-paclitaxel and FOLFIRINOX]. There was a Japanese study that was paused early because it was not likely that one arm would show benefits over the other arm. The [phase 2] PASS-01 study [NCT04469556], which was mainly biomarker focused, did not show [significant] differences [between regimens]; if anything, gemcitabine plus nab-paclitaxel outperformed FOLFIRINOX in that study.
There is a lot of confusing information, and [we do not have] a lot of phase 3 trials [comparing any of these 3 regimens head-to-head], except for the NAPOLI-3 trial.
The comparisons between NALIRIFOX and FOLFIRINOX are all cross-trial comparisons, [and clinicians] to end up looking at toxicity profiles [between the regimens], which do not look too different. NALIRIFOX has lower doses of oxaliplatin than FOLFIRINOX, and thus [is associated with] a lower rate of peripheral neuropathy. NALIRIFOX also theoretically has some advantages in patients with UGT1A1 polymorphisms, demonstrating that these patients are less likely to be adversely affected. By and large, [treatment decision-making requires] similar calculations and discussions on both [of these regimens]. We try not to get into [these discussions] too much because they end up being cross-trial comparisons that can go on forever. We try to put the data out there and talk through it [with patients].
The most common scenario where gemcitabine plus nab-paclitaxel will be used in the frontline setting is in a patient who has already received adjuvant FOLFIRINOX. This scenario is probably the most common and easiest decision [to make in the frontline setting]. It doesn’t make sense to circle back [to FOLFIRINOX or NALIRIFOX after adjuvant exposure to FOLFIRINOX]. When [these] patients progress on [frontline gemcitabine plus nab-paclitaxel], we use NALIRI—liposomal irinotecan and 5-FU—which is an approved second-line regimen.
In patients who are newly diagnosed and previously untreated, choosing NALIRIFOX is completely appropriate. [This decision] sometimes has to do with payers, institutions, and country-specific factors. There are many variables [that go into frontline treatment selection]. If you look at the totality of that [NALIRIFOX] data, they hold up, and as we follow patients for longer, the separation of the [OS] curves is sustained. [NALIRIFOX] is a reasonable treatment regimen to consider in any patient with newly diagnosed disease.
The future is changing fast. Pancreatic cancer is one of these spaces where I predict everything is going to be different 2 years from now than it is today. Everything is now centering on RAS inhibition as a premium strategy to treat patients, either as single agents or in combinations, and there are ongoing studies generating a huge amount of enthusiasm in the pancreatic cancer space. We are excited to see what happens in the next few years, and we need phase 3 data [for these targeted therapies]. I personally think the pancreatic cancer space has to move past chemotherapy, and for the first time, these new drugs give us the comfort that [moving away from chemotherapy] is possible.
There are other targeted therapies [under investigation]. RAS Inhibitors are at the top of the list. There is also a vaccine group trying to take advantage of the fact that KRAS is an immunogenic protein, and [thus are] trying to generate immune responses by any means necessary. There are several vaccine approaches out there, primarily used in adjuvant disease or minimal residual disease contexts. We have been involved with a lot of these [vaccines], and they are very exciting as well, because they show you can use [this approach] to delay the onset of recurrence. Those proteins are also going to hit [the metastatic] space soon.
Finally, beyond KRAS inhibitors, there are also many second-generation immunotherapy drugs, which look really promising and target aspects of the adenosine access. The [phase 3] PRISM-1 study [NCT06608927] recently completed enrollment and should read out soon. There are a lot of other pathways that are indirectly related to the immune system rather than checkpoint inhibitors. Hopefully, we will see positive results from those drugs in the years to come.
