Wainberg Weighs in on Favorable Frontline Activity With NALIRIFOX Regimen in Pancreatic Cancer

Zev. A. Wainberg, MD, discusses findings from a phase 1/2 study of NALIRIFOX in patients with pancreatic ductal adenocarcinoma.

Non-liposomal irinotecan plus 5-fluorouracil (5-FU), leucovorin, and oxaliplatin (FOLFIRINOX) has been a standard frontline treatment for patients with pancreatic ductal adenocarcinoma (PDAC), said Zev. A. Wainberg, MD. However, more effective and less toxic treatment regimens represent an unmet need in this space.

To that end, investigators launched a phase 1/2 study to evaluate liposomal irinotecan plus 5-FU/leucovorin plus oxaliplatin (NALIRIFOX) as frontline treatment for patients with locally advanced or metastatic PDAC. The results, which were presented during the 2020 ESMO World Congress on Gastrointestinal Cancer, showed that the regimen had antitumor activity and a manageable safety profile in this setting.

The regimen induced a 9.2-month median progression-free survival (PFS; 95% CI, 7.69-11.96) and a 12.6-month median overall survival (OS; 95% CI, 8.74-18.69). Additionally, the overall response rate with NALIRIFOX was 34.4% (95% CI, 18.6%-53.3%).

Regarding safety, 68.8% of patients experienced grade 3 or higher treatment-emergent adverse events (TEAEs), with the most common toxicities being neutropenia (31.3%), febrile neutropenia (12.5%), and hypokalemia (12.5%).

“We are excited about [these data], and we are poised to answer the question of whether [we should choose] this regimen or gemcitabine/nab-paclitaxel (Abraxane),” said Wainberg. “[Our goal is to accrue patients to] the phase 3 trial, so that we can [improve treatment] for this [patient population]. Now more than ever, we need some enthusiasm to develop new therapies.”

In an interview with OncLive, Wainberg, an assistant professor of medicine and co-director of the GI Oncology Program at the University of California, Los Angeles, discussed findings from the phase 1/2 study, as well as the next steps with NALIRIFOX in PDAC.

OncLive: Could you discuss the current treatment landscape for patients with PDAC and the unmet needs that exist in the space?

Wainberg: There are 2 standard frontline treatment options that are generally used interchangeably. One is FOLFIRINOX which is often used as modified FOLFIRINOX, and the other is gemcitabine plus nab-paclitaxel (Abraxane). Those are the standard, FDA-approved choices that we discuss with our [newly diagnosed] patients.

What was the rationale for evaluating NALIRIFOX as a frontline treatment regimen for patients with PDAC?

Liposomal irinotecan in combination with 5-FU was approved in the United States a number of years ago as second-line treatment for metastatic pancreatic cancer. It is often used as second-line therapy for patients who progress on gemcitabine-based therapy in the frontline setting.

The principle [of our study] was to move this regimen in combination with oxaliplatin up front and ultimately, to test it in a defined group of patients.

How was this trial designed, and what patients were included?

All patients [required] frontline [treatment]. The majority of patients, 29 out of 32, had metastatic disease. However, 3 patients had locally advanced disease because we did not specify metastatic versus locally advanced disease in the original [inclusion criteria]. Additionally, all patients were untreated but were eligible for FOLFIRINOX-based regimens.

Originally, this started as a dose-escalation strategy in which both oxaliplatin and liposomal irinotecan were escalated while 5-FU and leucovorin remained at fixed doses throughout the protocol. Ultimately, there were 4 dose-escalation cohorts. We landed on what is referred to as a 50/60 [dosing strategy], which is 50 mg/m2of liposomal irinotecan and 60 mg/m2 of oxaliplatin. That is a lower dose of oxaliplatin than is typically used in the classical FOLFIRINOX regimen. 

What were the findings?

We confirmed our top dose of 50/60 plus 5-FU in the dose-escalation phase of the study. Then we expanded to a total of 32 patients.

From an efficacy perspective, we showed similar results to what we expected based on what we have seen with FOLFIRINOX. We had a nice PFS of just over 9 months and a nice survival of about 1 year.

This was a small non-randomized cohort of 32 patients, but we think that is sufficient enough to move this forward in development.

How did the safety profile of NALIRIFOX compare with FOLFIRINOX?

Overall, the safety profile was fairly consistent with what was expected. Interestingly, although this is a small cohort of patients, we did report a lower rate of GI toxicities like diarrhea than has typically been associated with classical FOLFIRINOX. There was also less fatigue and less peripheral neuropathy.

One of the interesting things about oxaliplatin dosing is that it is fixed at 60 mg/m2, which is less than [the standard dosing of] 85 mg/m2. This means that over a 6-month period, patients are getting about 25% less oxaliplatin. In some respects, we consider that an advantage to this regimen because it may be more sustainable with less peripheral neuropathy.

We are seeing typical AEs like neutropenia, and some patients developed neutropenic fever.

I will note however that there was no mandated granulocyte colony-stimulating factor (G-CSF). Nowadays, with modified FOLFIRINOX, a majority of providers in the United States use prophylactic G-CSF or some form of growth factor with this regimen. Because this was not mandated in our study, we expect [the rate of neutropenia] to be diminished in the current study population.

What are the next steps for this research?

We found a tolerable, sustainable dose that elicited promising efficacy in a 32-patient cohort. We are excited by what we saw. Certainly now, the next step is to develop this regimen further, and that is going to be done in a number of ways.

The first and most immediate method is to randomize patients to the regimen as frontline therapy in a clinical trial. The trial is set to enroll about 750 patients globally who will be randomized to NALIRIFOX or gemcitabine/nab-paclitaxel. Really, [this is comparing] the 2 standard combination chemotherapy options.

That randomized trial has launched, and I encourage others to consider that trial for their patients. There will be other expansions. In my opinion, NALIRIFOX could be considered as a [backbone] with which we can add other therapies to. This regimen doesn’t have the same degree of cumulative peripheral neuropathy or GI toxicities [that we normally see]. It might lend itself to adding additional agents to NALIRIFOX if we can reproduce some of the efficacy demonstrated here.


Wainberg Z, Bekaii-Saab T, Boland PM, et al. First-line liposomal irinotecan + 5-fluorouracil/leucovorin + oxaliplatin in patients with pancreatic ductal adenocarcinoma: long-term follow-up results from a phase 1/2 study. Presented at: 2020 ESMO World Congress on Gastrointestinal Cancer; July 1-4, 2020; Virtual. Abstract LBA-001.