Pancreatic Cancer: Data With Liposomal Irinotecan/5-FU
Insights From: Fadi Braiteh, MD, University of Nevada School of Medicine; John L. Marshall, MD, Georgetown University Hospital ; Kenneth H. Yu, MD, Memorial Sloan Kettering Cancer Center
John L. Marshall, MD: New drug development in pancreas cancer has been very interesting for almost 10 years. After gemcitabine’s original approval, we kept trying to put everything with gemcitabine. “This,” with gemcitabine. “That,” with gemcitabine. Even taxanes with gemcitabine. It really didn’t help until we used a liposomal taxane, which is nab-paclitaxel (Abraxane). We don’t really know why it worked. We think that it may be its pharmacology. It may be a delivery thing—that the drug actually gets there better and the half-life is longer. But it worked. And so, some smart people said, “Well, if it works with that, let me try it with irinotecan.” And so, Onivyde (irinotecan) is essentially a medicine that is irinotecan wrapped into a lipid, just like a nab-paclitaxel is.
The study that was done with this is for second-line and beyond settings. It randomized patients to 5-FU by itself or as a combination. The combination showed an improvement in response rate, progression-free survival, and overall survival, which justified its approval. We do give irinotecan, by itself, without the lipid layer in frontline therapy with FOLFIRINOX. But what we’re seeing is that maybe the pharmacology or delivery is superior and should be used. Thus, we have the approval for the new medicine.
Fadi Braiteh, MD: Innovation in the field of oncology and how we treat systemic disease has really taken a boom in the last 10 years. Biologics, new cytotoxics, and, now, even totally new mechanism of action molecules—such as immunomodulators—have been brought on board. In the field of the cytotoxic therapies, we have had some totally new molecules brought into the market; some have been studied in clinical trials and some have even been approved. These molecules are referred to as cytotoxic because they fundamentally interfere with DNA synthesis and mitosis. But another innovation that has been happening relates to the way that we administer or we formulate the products. There is a hypothesis and preclinical data about how it affects the microenvironment and considerations that the intoxicate might be the bad macrophage. The same thing happened with the liposomal formulation. The liposomal formulation, in the drug development field, is not totally new. We have seen it with some antifungal, and we have seen it with other cytotoxic therapies like doxorubicin.
And here, we recently had the nanoparticle liposomal formulation of irinotecan. This has allowed us to really put a dense dose in a nanoparticle. You theoretically reduce the shedding and the systemic exposure of the irinotecan, which is the prodrug of the active compound. So, you target the delivery more toward your tumor. Again, this systemically may reduce the toxicity. Or you can have a smaller dose provided. The liposomal formulation allowed for more favorable pharmacokinetics and has a longer half-life—of the drug in circulation with minimum systemic toxicity. The goal is to have that delivery target the pancreatic adenocarcinoma cell and, more importantly, the microenvironment—which is the hard shell to crack—and to have a better, favorable vasculature delivery of the drug.
This exciting preclinical discovery of the formulation of liposomal irinotecan is behind taking it to the clinic and, of course, follows the development of phase I and recommended phase II studies of combining 5-FU/leucovorin plus liposomal irinotecan. Hence, the dose is 70 mg/m2 in the patient with advanced relapsed or refractory pancreatic adenocarcinoma.
NAPOLI was a 3-arm clinical trial of single-agent nanoliposomal irinotecan and single-agent 5-FU/leucovorin. There was an amendment, later on, to do the third arm, which is the 5-FU/leucovorin plus nanoliposomal irinotecan. It was 2:2 factorial comparison. The patients who were enrolled were your typical ECOG 0, ECOG 1, and even ECOG 2 patients who had good kidney and liver function. A requirement was that the bilirubin should be within the normal range. If the patients are known to have Gilbert syndrome, where the bilirubin can be slightly elevated, the recommended starting dose was lower, 50 mg/m2. It doesn’t mean we have to test every patient for Gilbert syndrome, but it’s important to recognize this entity when we choose the dose.
Otherwise, these are all patients with advanced disease. All of them have received gemcitabine and have progressed. This gemcitabine could have been in the neoadjuvant or adjuvant setting or in the frontline setting. This is not necessarily a second-line scenario. A certain percentage of patients were third-line and beyond. But every patient has been exposed to gemcitabine. There was a proportion of patients, up to between 10% and 20%, who had no treatment in the metastatic setting. The only gemcitabine exposure was in the neoadjuvant or adjuvant setting. But again, they should have progressed within 6 months. The primary endpoint in the frontline study of pancreatic cancer is obviously the overall survival. There were also secondary endpoints of progression-free survival, objective response rates, quality of life, etc.
The outcome of the study was in favor of the combination. That’s why we say it’s not nanoliposomal irinotecan. Rather, it’s nanoliposomal irinotecan plus 5-FU/leucovorin. I refer to this as the NAPOLI regimen. It showed superiority and improvement of median overall survival and median progression-free survival. Hence, the drug was granted approval on the US market for the treatment of patients with advanced pancreatic cancer, post gemcitabine. The inclusion, in the National Comprehensive Cancer Network guidelines, is category level 1.