Reema A. Patel, MD, discusses the potential for nanoliposomal irinotecan in pancreatic cancer and other emerging approaches under exploration.
As more is learned about nanoliposomal irinotecan (Onivyde), the safety and efficacy benefits of this approach over conventional chemotherapy have become more pronounced, according to Reema A. Patel, MD. She added that if the data continue to be positive, the agent has the potential to transform treatment in the frontline setting.
“Historically, pancreatic cancer has always been considered a dismal and depressing disease. Treatment options are limited; thus, we cannot offer patients as many therapies as we would like,” said Patel. “However, as we continue to enhance our knowledge and evaluate treatment strategies that have been utilized in other tumor types, we hope to discover new opportunities for our patients in the near future.”
In October 2015, the FDA approved nanoliposomal irinotecan for use in combination with 5-fluorouracil (5-FU) and leucovorin in patients with metastatic pancreatic cancer following prior treatment with a gemcitabine-based regimen, based on findings from the pivotal phase 3 NAPOLI-1 trial (NCT01494506).
Now, the ongoing phase 3 NAPOLI 3 trial (NCT04083235) is examining the regimen in combination with oxaliplatin (NALIRIFOX) in the frontline treatment of patients with metastatic pancreatic ductal adenocarcinoma.1 In June 2020, the FDA granted a fast track designation to NALIRIFOX as a treatment for patients with previously untreated, unresectable, locally advanced or metastatic pancreatic ductal adenocarcinoma.2
In an interview with OncLive® during a 2020 Institutional Perspectives in Cancer webinar on gastrointestinal malignancies, Patel, an associate program director of Hematology & Medical Oncology Fellowship and an assistant professor of medicine in the Division of Medical Oncology at the University of Kentucky, discussed the potential for nanoliposomal irinotecan in pancreatic cancer and other emerging approaches under exploration.
Patel: Pancreatic cancer is a difficult disease for a multitude of reasons. For one, patients could have a hostile stroma. It's difficult to get chemotherapy into the tumor itself, which is one advantage that liposomal irinotecan may offer over conventional chemotherapy. In addition, genetic predispositions and the tolerance of aggressive chemotherapy regimens also play a role in whether patients can [receive] chemotherapy [for their disease].
First, we learned that heavily pretreated patients can still respond to the combination [of liposomal irinotecan, 5-FU, and leucovorin], even if they received previous chemotherapy. In this study, patients mostly received prior gemcitabine-based therapy; however, some patients had received irinotecan in their chemotherapy regimens. Although the responses were less robust in the patients who received the latter, responses were still observed.
Impressively, the progression-free survival [PFS] was doubled in this trial. Although 3.1 months may not seem like a lot, in pancreatic cancer, [any improvement in] PFS is very meaningful. Patients actually had a 45% reduction in risk of progression, which is also important and indicates that patients may have longer-term disease control than what we’ve seen in other older trials.
In terms of the subgroup analysis, we didn’t see many exciting discoveries. Overall, the groups responded well to the combination arm. However, interestingly, the patients who received prior irinotecan did not respond as well as the other subgroups did. Of course, it’s hard to use a subgroup analysis and apply it to an entire population; however, even so, it gave us some food for thought.
When sequencing therapies for my patients, if they’ve previously been exposed to irinotecan, I don’t give them liposomal irinotecan back-to-back; I like to give another regimen, if tolerable, in between to give them a break and, hopefully, allow them to respond [to treatment] later on.
We found that there was less diarrhea [with the combination], which was very exciting. When it comes to conventional irinotecan, diarrhea is among the most common dose-limiting factors, and it is linked with how long patients can receive therapy. Notably, regarding conventional irinotecan, diarrhea can occur in up to 30% of patients. With this novel agent, however, we are able to keep patients on therapy longer with fewer adverse effects.
Early data appear to be very promising. We are eager to learn more about the overall survival [OS] in this trial, especially with this larger patient population. In addition, it will be really interesting to see what the disease control rate [DCR] is, because the best overall response rate [ORR]—which included stable disease, partial responses, and complete responses—was 81%. If we are seeing DCRs and ORRs this high, we feel this could potentially change what we’re doing in the frontline setting for these patients.
Looking forward, we want to focus on how we can utilize immunotherapy in pancreatic cancer. Unfortunately, monotherapy and vaccine trials have not panned out in this disease. As such, we are starting to learn from the lung cancer space, where investigators have explored conventional chemotherapy in combination with immunotherapy and have seen really nice results.
Moreover, there’s a study in Canada that is evaluating a mesothelin inhibitor, as well as immunotherapy in combination with chemotherapy, and I believe this could be very promising for these patients. At the University of Kentucky, we are looking at MEK inhibition along with PD-L1 inhibition based on some preclinical data. We are looking at more targeted therapies, especially since many past studies targeted a microenvironment that has not been fruitful. Actually, targeting something intrinsic to the cell cycle may be more beneficial to these patients.