Liposomal Irinotecan for Pancreatic Cancer: Is It Worth It?

In February, the US Food and Drug Administration approved irinotecan liposomes (Onivyde) as part of a new first-line regimen for metastatic pancreatic adenocarcinoma called NALIRIFOX.

The main difference between NALIRIFOX and a standard use regimen for the indication, modified FOLFIRINOX, is that liposomal irinotecan irinotecan encapsulated in a lipid nanoparticle is used instead of free irinotecan.

Trial data suggested a better overall response rate, a slight progression-free survival advantage, and potentially fewer adverse events with the liposomal formulation.

Replacement, however, significantly increases the cost of treatment. According to one estimate, a single cycle of FOLFIRINOX costs about $500 on a body surface area of ​​2 m.²while the equivalent single cycle of NALIRIFOX costs $7,800 over 15 times more expensive.

While some oncologists have called the NALIRIFOX regimen a potential new standard first-line treatment for metastatic pancreatic adenocarcinoma, others have expressed serious doubts about whether the potential benefits are worth the additional cost.

“I can’t really see a single scenario where I would recommend NALIRIFOX over FOLFIRINOX,” said Ignacio Garrido-Laguna, MD, PhD, a gastrointestinal oncologist and pancreatic cancer researcher at the University of Utah, Salt Lake City, Utah. Medscape Medical News. “Most of us in academia have the same attitude about it.”

There is no head-to-head comparison

Uncertainty about the benefits of NALIRIFOX is driven primarily by the fact that NALIRIFOX was not compared to FOLFIRINOX in the phase 3 trial that won approval of liposomal irinotecan.

Instead, the 770-patient NAPOLI 3 trial compared NALIRIFOX which also includes oxaliplatin, fluorouracil and leucovorin with a two-drug regimen, nab-paclitaxel and gemcitabine. In the trial, overall survival and other outcomes were on average better with NALIRIFOX.

Oncologists have said the real value of the trial is that it definitively demonstrates that a four-drug regimen is superior to a two-drug regimen for patients who can tolerate more intensive therapy.

Eileen O’Reilly, MD, senior investigator on NAPOLI 3, made this point when she presented the phase 3 results at the ASCO 2023 annual meeting.

The trial “answers the question of four drugs versus two” for first-line metastatic pancreatic cancer, but “doesn’t address the question of NALIRIFOX versus FOLFIRINOX,” said O’Reilly, a pancreatic and hepatobiliary oncologist and researcher at the Memorial Cancer Center. Sloan Kettering. , New York City.

Comparing them directly in the study “probably wouldn’t have been in the sponsor’s best interest,” O’Reilly said.

Without a head-to-head comparison, oncologists have compared the results of NAPOLI 3 with those from PRODIGE 4, the 2011 trial that won FOLFIRINOX’s place as the first-line regimen.

When comparing trials, median overall survival was exactly the same for both regimens at 11.1 months. FOLFIRINOX was associated with a slightly higher 1-year survival rate of 48.4% with FOLFIRINOX versus 45.6% with NALIRIFOX.

However, O’Reilly and her colleagues also pointed out the comparisons between the two trials that favored NAPOLI 3.

NAPOLI 3 had no age limit, whereas PRODIGE subjects were no older than 75 years. Median progression-free survival was 1 month longer among patients receiving NALIRIFOX 7.4 months versus 6.4 months in PRODIGE and overall response rates were higher as well as 41.8% in NAPOLI 3 versus 31.6%. Patients receiving NALIRIFOX also had lower rates of grade 3/4 neutropenia (23.8% vs. 45.7%, respectively) and peripheral sensory neuropathy (3.5% vs. 9.0%, respectively).

The authors explained that the lower rate of neuropathy may be because NALIRIFOX uses a lower dose of oxaliplatin (FOLFIRINOX), at 60 mg/m.² instead of 85 mg/m².

Is it worth it?

During a presentation of the phase 3 findings last year, study author Zev A. Wainberg, MD, of the University of California, Los Angeles, said the NALIRIFOX regimen could be considered the new reference regimen for the first-line treatment of metastatic adenocarcinoma. of the pancreas.

Study discussant Laura Goff, MD, MSCI, of Vanderbilt-Ingram Cancer Center, Nashville, Tennessee, agreed that the results support the NALIRIFOX regimen as “the new standard for fit patients.”

However, other oncologists remain skeptical about the benefits of the new FOLFIRINOX regimen for patients with metastatic pancreatic adenocarcinoma.

In a recent editorial, Garrido-Laguna and University of Utah gastrointestinal oncologist Christopher Nevala-Plagemann, MD, compared the evidence for the two regimens.

Experts noted that overall response rates were assessed by investigators in NAPOLI 3 rather than by an independent review committee, as in PRODIGE 4, and may have been overestimated.

Although the lack of an age limit was touted as a benefit of NAPOLI 3, Garrido-Laguna and Nevala-Plagemann doubt whether enough patients over 75 participated to draw any meaningful conclusions about the use of NALIRIFOX in older, older patients. weak. However, patients in PRODIGE 4 may have been underpowered because, among other things, the study allowed patients with serum albumin <3 g/dL.

Regarding adverse events, the authors noted the higher incidence of grade 3 or more severe diarrhea with NALIRIFOX (20% vs. 12.7%) and questioned whether there is truly less neutropenia with NALIRIFOX because high-risk patients in NAPOLI 3 were treated with granulocyte colony-stimulating factor to prevent it. The pair also asked whether the differences in neuropathy rates between the two trials were large enough to be clinically meaningful.

Insights from a recent meta-analysis may further clarify some of the lingering questions about the efficacy of NALIRIFOX versus FOLFIRINOX.

In the analysis, the team found no significant difference in overall and progression-free survival between the two regimens. Differences in rates of peripheral neuropathy and diarrhea were not statistically significant, but NALIRIFOX had a statistically significant advantage in lower rates of febrile neutropenia, thrombocytopenia, and vomiting.

The team concluded that “NALIRIFOX and FOLFIRINOX may provide equal efficacy as first-line treatment of metastatic pancreatic cancer but with different toxicity profiles,” and called for careful patient selection when choosing between the two regimens. as well as considering financial toxicity.

Garrido-Laguna had a different take. With the current data, NALIRIFOX does not appear to “add anything fundamentally different from what we already have” with FOLFIRINOX, he said Medscape Medical News. Given this, “we cannot really justify NALIRIFOX over FOLFIRINOX without more head-to-head comparison.”

The higher cost of NALIRIFOX, in particular, remains a major obstacle.

“We believe it would be an economic detriment to our health care systems if we were to use NALIRIFOX instead of FOLFIRINOX for these patients based on [NAPOLI 3] data,” said Bishal Gyawali, MD, PhD, and Christopher Booth, MD, gastrointestinal oncologists at Queen’s University in Kingston, Ontario, Canada, in a recent essay.

Garrido-Laguna and Nevala-Plagemann echoed this concern.

Overall, “NALIRIFOX does not appear to raise the level, but instead exposes patients and health care systems to financial toxicities,” Garrido-Laguna and Nevala-Plagemann wrote in their review.

NAPLES 3 was funded by Ipsen, and PRODIGE 4 was funded by the government of France. No funding source was reported for the meta-analysis. NAPOLI 3 investigators included Ipsen employees. O’Reilly disclosed grants or contracts from Ipsen and many other companies. Garrido-Laguna reported institutional research funding from Bristol Myers Squibb, Novartis, Pfizer, and other companies, but not from Ipsen. Nevala-Plagemann is a consultant for Seagen and reported institutional research funding from Theriva. Gyawali is a consultant for Vivio Health; Booth had no revelations. Two authors of the meta-analysis reported grants or personal fees from Ipsen as well as affiliations with other companies.