First-Line NALIRIFOX Demonstrates Survival Advantage Over Standard Gemcitabine/Paclitaxel in Metastatic PDAC

Eileen M. O’Reilly, MD

Survival outcomes with liposomal irinotecan (Onivyde) plus 5-fluorouracil (5-FU), leucovorin, and oxaliplatin (NALIRIFOX) continued to be statistically superior to standard gemcitabine and nab-paclitaxel (Abraxane) at 12 and 18 months in patients with metastatic pancreatic ductal adenocarcinoma (PDAC). This signifies the potential for this regimen to become a standard frontline option in this population if it gains FDA approval, according to Eileen M. O’Reilly, MD.

At the 2023 ASCO Annual Meeting, a presentation of updated overall survival (OS) data from the phase 3 NAPOLI 3 trial (NCT04083235) showed that treatment with NALIRIFOX resulted in a 12-month OS rate of 45.6% (95% CI, 40.5%-50.5%) and an 18-month OS rate of 26.2% (95% CI, 20.9%-31.7%). These rates were 39.5% (95% CI, 34.6%-44.4%) and 19.3% (95% CI, 14.8%-24.2%), respectively, with nab-paclitaxel/gemcitabine. The duration of response with NALIRIFOX was also prolonged vs gemcitabine/nab-paclitaxel, at 7.3 months (range, 5.8-7.6) and 5.0 months (range, 3.8-5.6), respectively.¹

Data from the trial were previously presented at the 2023 Gastrointestinal Cancers Symposium. At a median follow-up of 16.1 months, patients in the intent-to-treat population experienced a median OS of 11.1 months (95% CI, 10.0-12.1) with NALIRIFOX vs 9.2 months (95% CI, 8.3-10.6) with nab-paclitaxel plus gemcitabine (HR, 0.83; 95% CI, 0.70-0.99; P = .04).²

“We have many examples in the past 5 years of negative randomized phase 3 studies [in pancreatic cancer]. The fact that this study met its end point [of OS] is clinically meaningful, and has application for practice,” said O’Reilly, who is the Winthrop Rockefeller Endowed Chair of Medical Oncology and co-director of Medical Initiatives at the David M. Rubenstein Center for Pancreatic Cancer Research. O’Reilly also serves as section head of Hepatopancreaticobiliary & Neuroendocrine Cancers at Memorial Sloan Kettering Cancer Center, New York, New York.

In an interview with OncLive^®, O’Reilly expanded on the updated survival data from NAPOLI-3, explained how NALIRIFOX could fit into the current PDAC treatment paradigm, and shared potential opportunities to build upon this research moving forward.

OncLive: Could you discuss the rationale for investigating NALIRIFOX vs nab-paclitaxel plus gemcitabine in the NAPOLI 3 trial?

O’Reilly: For almost a decade now, we’ve had 2 frontline treatment options for metastatic PDAC: quadruplet therapy with oxaliplatin, irinotecan, 5-FU, plus leucovorin, and gemcitabine plus paclitaxel. A big question in the advanced disease space is [whether] the preferential treatment for good performance status is individual. There are some retrospective data and [other] data in localized pancreatic cancer suggesting that one of these regimens might be superior, [although] none of it was definitive.

The specific question of the NAPOLI 3 trial was to evaluate whether NALIRIFOX was superior to nab-paclitaxel and gemcitabine. NALIRIFOX [consists of] oxaliplatin, and a liposomal formulation of irinotecan. [This] can theoretically lead to higher levels of SM-38, the active moiety of irinotecan, both in the circulation and at the tumor site. [The agents are] combined with infusional 5-FU and leucovorin. The question [is essentially whether] 4 or 3 drugs, depending on how you value leucovorin, are better than gemcitabine and nab-paclitaxel. That critical question was framed, asked, and answered in the NAPOLI 3 trial.

At the 2023 Gastrointestinal Cancers Symposium earlier this year, this approach was found to have produced a clinically meaningful and statistically significant improvement in OS and progression-free survival (PFS). Could you expand on the key findings that were previously presented at that meeting?

Top-line results from the NAPOLI 3 trial were presented by Zev Wainberg, MD, of University of California, Los Angeles Health, at [that meeting. Data] demonstrated that NALIRIFOX [produced] a median OS of 11.1 months. With gemcitabine and nab-paclitaxel, [the median OS] was 9.2 months. That was statistically significant, [with a] hazard ratio of 0.3 and a P value of 0.040. By statistical design, the study had to have a P value of less than or equal to 0.048, so it was a positive [result].

It’s important to note that this [study was conducted] in the era of crossover. For patients on either arm of the study, there was opportunity to receive a related regimen at the time of disease progression. There was still a survival [benefit with NALFIRIFOX despite] a high frequency of patients who received additional therapy, as well as significant crossover. The important take-home message for a fit individual with an ECOG performance status of 0 to 1, is that a combination regimen with oxaliplatin and irinotecan is superior for the average individual with metastatic disease compared with gemcitabine and nab-paclitaxel.

What updated survival data were presented at the 2023 ASCO Meeting? How did these findings compare with what was expected?

The updates that were presented at the 2023 ASCO Meeting followed up on the presentation of the OS and PFS outcomes that were reported at the 2023 Gastrointestinal Cancer Symposium. The PFS [with NALIRIFOX] was statistically [significant,] with a hazard ratio of 0.69, so that’s a big delta between the arms in terms of PFS. Looking at those updates at 12 and 18 months, the outcomes were held up in favor of NALIRIFOX compared with gemcitabine and nab-paclitaxel. At each time point that [we] looked at, the outcome on the NALIRIFOX arm was better relative to gemcitabine and nab-paclitaxel. That supported the initial results of the study.

[There were] also numerically more responses in the NALIRIFOX arm compared with [the] gemcitabine and nab-paclitaxel [arm], although they were mostly partial responses. There was a longer duration of treatment [with NALIRIFOX], as you might expect. This was a mature study, [with] an average of 16 months of follow-up for patients enrolled. At the time of study analysis, which was July 2022, more patients remained on the study in the NALIRIFOX arm compared with [those on the] gemcitabine/nab-paclitaxel [arm].

What should be known about the regimen’s toxicity profile as seen in this study?

It’s always important to [look at] outcomes in the context of toxicity profiles as we think about how we should integrate data into practice. For both treatment regimens, we saw expected toxicity, myelosuppression, and gastrointestinal [GI] toxicity. There was more anemia, thrombocytopenia, and neutropenia on the gemcitabine/nab-paclitaxel arm, and more GI toxicity, which [included] nausea, vomiting, diarrhea, hypokalemia, on the NALIRIFOX arm. You might predict this [based on] the composition of each regimen. Early and preemptive intervention in terms of toxicity management, [such as] dose adjustments, hydration, anti-diarrheal medications, and growth factor supports are the best way to mitigate the downstream consequences of these regimens.

What is the clinical significance of this research?

This is an important study. It’s the first study [in PDAC] in a decade that has met its end point of OS, acknowledging that OS is a high bar in any disease, and certainly in pancreatic cancer. This is the only [recent phase 3] study [in PDAC] that met its end point, barring the [phase 3 POLO trial (NCT02184195,)] which was conducted in the BRCA-mutated pancreatic cancer setting using a PARP inhibitor [as maintenance therapy. However], that end point was PFS.

How might these data influence treatment selection in clinical practice?

Where some of the controversy surrounding the results of this study comes in is [when we ask]: What’s the difference between this regimen and FOLFIRINOX [5-FU, leucovorin, irinotecan, and oxaliplatin]? How can we utilize this today for the care of the patient in front of us? In some regard, there’s a straightforward answer to this question, and in other regard, there isn’t. The straightforward answer is because NALIRIFOX is not yet FDA approved or in the guidelines, we don’t directly have the option to use it today. [We are] waiting for the mature data in the publication, and presumably, these considerations will follow. [This] does support the use of FOLFIRINOX as the initial treatment choice for a fit individual with untreated metastatic disease.

In my mind, there are exceptions to everything. Patient preferences are always an important consideration. In general, [these data] would [slightly] demote gemcitabine and nab-paclitaxel to a second-line option. Having said that, nothing is simple in life. We know that we’re in the era of biomarkers and can select treatment based on individual patient or disease characteristics. Some additional data are emerging [to] suggest that, aside from the overall unselected population results of this study, there may be discrete settings where we’ll end up picking one treatment approach vs the other. As we see maturation of other data, [this could be used] to inform treatment selection.

Are there any future avenues for investigation based on this research?

Assuming NALIRIFOX becomes FDA approved and guideline endorsed, the question is going to be what should be our comparator regimen moving forward? Outside of clinical practice, is NALIRIFOX the regimen that we want to compare new therapies against? The answer is potentially. How can we build on it? Opportunities will be [to explore] what other agents might be added to this to improve outcomes and bring it into earlier-stage setting. For example, localized pancreatic cancer, [as well as] the whole spectrum of resectable, borderline resectable and locally advanced disease, is also a ripe area for research. [There are] a lot of [potential] combinations that might be considered, including molecularly targeted therapies, immunotherapies, etc. We’re in the RAS[-targeted] treatment era now, starting in pancreatic [cancer] and other malignancies. They will be examples of things that might be, in due course, evaluated and combined with a multidrug [regimen], such as NALIRIFOX.

What other presentations at the 2023 ASCO Annual Meeting did you find particularly interesting or practice-changing within pancreatic cancer?

One abstract that I thought was interesting and provocative was the NorPACT-1 trial [NCT02919787]. This was a randomized phase 2 [study] from our European colleagues looking at perioperative FOLFIRINOX in the setting of resectable pancreatic cancer vs going directly to surgery followed by adjuvant FOLFIRINOX. This generated a fair bit of discussion. The study suggested that the outcome was superior for up-front surgery, followed by adjuvant therapy. Having said that, there’s a lot of points to think about. It’s a randomized phase 2 study, so it’s not a definitive study. It was [also] a small study, and not everybody received FOLFIRINOX; in fact, many patients received gemcitabine-based treatments. [Therefore], it wasn’t fully answering the question that it was posing. What it does tell the field is that the ongoing studies [in this space are important.]

There are 2 major ones: the [phase 3] PREOPANC-2 trial in Europe, which is looking at perioperative FOLFIRINOX vs up-front surgery, followed by FOLFIRINOX. That’s completed accrual and we’re awaiting the maturation of those results. It remains a very important trial. In North America, the Alliance study AO21806 [NCT04340141] is a similarly designed and powered phase 3 trial looking at the same question. It is approaching the halfway mark in terms of accrual. Both studies, the European and our North American one, remain key to our understanding [of whether] we should be going directly to surgery, or be recommending neoadjuvant FOLFIRINOX for an average patient [with] localized operable pancreatic cancer.

[Another important study presented at the meeting] is much earlier in development. [AMPLIFY-201 (NCT04853017)] is a phase 1 first-in-human dose- and safety-finding, immunogenicity-determining and clinical signal-seeking study of a RAS vaccine. KRAS is an important “public” neoantigen. It’s a shared neoantigen almost ubiquitous for individuals who have pancreatic cancer. Using a sort of platform backbone of a delivery system, a KRAS peptide vaccine has been developed targeting G12D, and G12R, 2 of the common KRAS variants that we see in pancreatic cancer. This was delivered as a subcutaneous vaccine in patients who were at a very high risk of relapse based on either rising tumor markers or circulating tumor DNA [ctDNA] positivity after they completed definitive local treatment. In that setting, this vaccine was deemed to be very safe and generated a potent immune signal. There are prerequisites to potentially have a clinical signal. There was also a clinical signal of declining tumor markers and/or clearance of ctDNA in a subset. This is undergoing further development, and ultimately randomized evaluation, but the whole area of RAS[-targeted] therapeutics is one to [continue investigating] in this field.

Disclosures: Dr O’Reilly serves as a consultant or in an advisory role for AstraZeneca; Autem Medical, Boehringer Ingelheim; Eisai, Exelixis, Genentech/Roche, Helio Health, Incyte, Ipsen; Merck; Novartis; QED Therapeutics, Yiviva, and Yiviva; she received institutional research funding from Arcus Ventures, AstraZeneca/MedImmune, BioNTech, Bristol Myers Squibb, Bristol Myers Squibb, Celgene, Genentech, Helsinn Healthcare, Puma Biotechnology, QED Therapeutics, Roche, and Yiviva.

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References

1. O'Reilly E, Melisi D, Macarulla T, et al. Liposomal irinotecan + 5-fluorouracil/leucovorin + oxaliplatin (NALIRIFOX) versus nab-paclitaxel + gemcitabine in treatment-naive patients with metastatic pancreatic ductal adenocarcinoma (mPDAC): 12- and 18-month survival rates from the phase 3 NAPOLI 3 trial. J Clin Oncol. 2023;41(suppl 16):4006. doi:10.1200/JCO.2023.41.16_suppl.4006
2. Wainberg ZA, Melisi D, Macarulla T, et al. NAPOLI 3: a randomized, open-label phase 3 study of liposomal irinotecan + 5-fluorouracil/leucovorin + oxaliplatin (NALIRIFOX) versus nab-paclitaxel + gemcitabine in treatment-naïve patients with metastatic pancreatic ductal adenocarcinoma. J Clin Oncol. 2023;41(suppl 4):LBA661. doi:10.1200/JCO.2023.41.3_suppl.LBA661