Invited discussant Laura Goff, MD, MSCI, Associate Professor of Medicine and Executive Medical Director for the Cancer Patient Care Center at Vanderbilt-Ingram Cancer Center, Nashville, said that with the results of NAPOLI-3, clinicians have a third effective first-line regimen for metastatic pancreatic cancer.
“For the past decade, we’ve had two primary treatments—FOLFIRINOX [leucovorin, fluorouracil, irinotecan, oxaliplatin] and gemcitabine/nab-paclitaxel—both of which were shown to be superior to gemcitabine alone. There are pros and cons to both regimens and lots of biases or beliefs about them. Essentially, it’s been ‘dealer’s choice,’” she said.
Liposomal irinotecan, which was used in the NALIRIFOX [liposomal irinotecan, fluorouracil, leucovorin, and oxaliplatin] regimen, was designed to improve upon conventional irinotecan, based largely on longer exposure to its active metabolite, SN-38. “The NALIRIFOX regimen, therefore, was designed to be a more effective FOLFIRINOX,” she explained.
Laura Goff, MD, MSCI
The NALIRIFOX regimen did indeed improve progression-free and overall survival over nab-paclitaxel/gemcitabine. The improvement in overall survival could not be accounted for by subsequent anticancer therapy, as this was generally balanced between the arms, she noted.
Putting NAPOLI-3 in Context
“The authors’ conclusion was that NALIRIFOX demonstrated clinically meaningful and statistically significant improvements in overall survival and progression-free survival compared with gemcitabine/nab-paclitaxel in the first-line setting of patients with metastatic pancreatic adenocarcinoma, and I agree. We are seeing these findings across all subgroups,” Dr. Goff commented.
“So, did gemcitabine/nab-paclitaxel just underperform in the NAPOLI-3 setting?” she questioned. “Based on what we know historically, median overall survival (9.2 months) looks pretty similar to that seen in the seminal Von Hoff study1 (8.5 months). Progression-free survival was also similar, and response rates even looked a little better,” she said.
“Would we have seen the same results if FOLFIRINOX had been used [as the control]? We do not have a head-to-head comparison of FOLFIRINOX to gemcitabine/nab-paclitaxel, nor are we likely to get it, but it’s provocative that the median overall survival for both FOLFIRINOX2 and NALIRIFOX in this front-line setting is 11.1 months,” she said.
SWOG S1505 aimed to determine the relative efficacy of FOLFIRINOX vs gemcitabine/nab-paclitaxel but found no difference in outcomes.3 Following this study, “there was a lot of chatter around whether the results should put an end to the distinction between FOLFIRINOX and gemcitabine/nab-paclitaxel,” she said. “Because it was a randomized study and the outcomes looked similar,” many people concluded that the regimens were comparable, but SWOG S1505 was a neoadjuvant study in patients with resectable disease and was not a head-to-head comparison. “I would argue that this randomized trial of NAPOLI-3 should supersede our opinion about the efficacy of these regimens in the metastatic setting,” she said.
In Summary
Altogether, she added, numerous outcomes favor NALIRIFOX over gemcitabine/nab-paclitaxel, including progression-free survival and response. And, apart from the higher rate of diarrhea (which may be related to the higher exposure to SN-38), grade 3 or 4 sensory neuropathy appears to be less frequent (possibly a result of less oxaliplatin or the mechanism of data capture), and hematologic toxicity is clearly less (possibly accounted for by the use of growth factors with NALIRIFOX).
“Both regimens have high toxicity rates and different profiles of toxicity, which may factor into the decision for patients who are unfit and unable to tolerate an aggressive regimen. But I do feel that for fit patients, the results of NAPOLI-3 support NALIRIFOX as a new reference regimen for the first-line treatment of metastatic pancreatic adenocarcinoma,” Dr. Goff concluded.
DISCLOSURE: Dr. Goff has served as a consultant or advisor to AstraZeneca, Athenum Consulting, Boehringer Ingelheim, Cardinal Health, Exelixis, Genentech, Merck, and QED Therapeutics; and has received research funding from Agios, ASLAN Pharmaceuticals, Basilea, BeiGene, Bristol Myers Squibb, and Merck.
REFERENCES
1. Von Hoff DD, Ervin T, Arena FP, et al: Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med 369:1691-1703, 2013.
2. Conroy T, Desseigne F, Ychou M, et al: FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med 364:1817-1825, 2011.
3. Sohal D, Duong MT, Ahmad SA, et al: SWOG S1505: Results of perioperative chemotherapy with mFOLFIRINOX versus gemcitabine/nab-paclitaxel for resectable pancreatic ductal adenocarcinoma. ASCO20 Virtual Scientific Program. Abstract 4504. Presented May 25, 2020.
