Liposomal Irinotecan Regimen Pushes Toward Frontline Treatment in Metastatic Pancreatic Cancer

Dae Won Kim, MD

Among limited options, moving effective therapies into earlier lines of treatment is an area of significant interest in metastatic pancreatic cancer, said Dae Won Kim, MD.

In October 2015, the FDA approved liposomal irinotecan (Onivyde) in combination with 5-fluorouracil (5-FU)/leucovorin for the treatment of patients with metastatic pancreatic cancer following prior gemcitabine-based chemotherapy, according to findings from the pivotal phase 3 NAPOLI-1 trial.

Now, the ongoing phase 3 NAPOLI-3 trial (NCT04083235) is evaluating the regimen plus oxaliplatin (NALIRIFOX) in the frontline setting for patients with metastatic pancreatic ductal adenocarcinoma (PDAC).

During the 2020 ESMO World Congress on Gastrointestinal Cancer, updated data from the phase 1/2 trial (NCT02551991) demonstrated promising antitumor activity and a tolerable safety profile with the frontline regimen in patients with locally advanced or metastatic PDAC.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 PDAC.²

In an interview with OncLive^® during an Institutional Perspectives on Cancer webinar on Gastrointestinal Malignancies, Kim, a medical oncologist in the Department of Gastrointestinal Oncology at Moffitt Cancer Center, discussed the NAPOLI-1 and NAPOLI-3 trials in metastatic pancreatic cancer, as well as the role of PARP inhibitors and remaining challenges in the space.

OncLive^®: What does the current treatment landscape of metastatic pancreatic cancer look like?

Kim: In the first-line setting, there are 2 chemotherapy regimens. One is FOLFIRINOX and the other is gemcitabine plus nab-paclitaxel (Abraxane). This is compounded by the phase 3 randomized study. At this time, the only FDA-approved regimen in the second-line setting is liposomal irinotecan plus 5-FU.

Liposomal irinotecan is an effective, second-line treatment for patients with metastatic pancreatic cancer after gemcitabine-based chemotherapy. The ongoing NAPOLI-3 clinical trial [is evaluating] the efficacy of liposomal irinotecan in the first-line setting of metastatic pancreatic cancer.

How did the results of the NAPOLI-1 trial impact the landscape?

Previously, we didn’t have an effective FDA-approved chemotherapy [regimen] for the second-line treatment [of patients with metastatic pancreatic cancer]. The NAPOLI-1 study showed the efficacy of liposomal irinotecan in the second-line setting after progression on gemcitabine plus nab-paclitaxel.

Could you discuss the NAPOLI-3 trial?

At this time, we have gemcitabine/nab-paclitaxel and FOLFIRINOX as first-line treatments for patients with metastatic pancreatic cancer. In the NAPOLI-3 study, the investigators are evaluating liposomal irinotecan combined with 5-FU and oxaliplatin as a first-line treatment for patients with metastatic pancreatic cancer to see if this regimen is better [than our current standards of care].

The primary end point of the NAPOLI-3 trial is overall survival (OS). OS with gemcitabine/nab-paclitaxel is 5.8 months, and OS with FOLFIRINOX is 11.1 months. In NAPOLI-3, we’ll see whether liposomal irinotecan plus 5-FU and oxaliplatin is associated with better responses or anti-cancer activity [versus those 2 regimens].

What differentiates liposomal irinotecan from standard irinotecan?

There is a major difference between irinotecan and [liposomal irinotecan]. Irinotecan is metabolized in the peripheral blood. Liposomal irinotecan gets encapsulated by a nanoliposomal particle to prevent rapid metabolism in the peripheral blood and to increase the concentration of this active drug in the tumor microenvironment.

What next steps are planned to further evaluate liposomal irinotecan in metastatic pancreatic cancer?

Several ongoing clinical trials are [evaluating] the efficacy of [liposomal irinotecan] in the second-line setting for patients with metastatic pancreatic cancer. At this point, the phase 3 NAPOLI-3 study is the most promising.

What role do PARP inhibitors play in pancreatic cancer?

Recently the phase 3 POLO study showed the efficacy of the PARP inhibitor [olaparib (Lynparza)] in germline BRCA-mutated pancreatic cancer. It showed an improvement in progression-free survival [versus placebo].

Do responses with chemotherapy differ in patients with BRCA-mutated metastatic pancreatic cancer compared with the overall patient population?

Patients who have germline BRCA mutations have better responses to platinum-based chemotherapy and PARP inhibitors. For a patient who has a germline BRCA mutation, we usually use FOLFIRINOX or gemcitabine plus cisplatin, depending on their performance status.

Also, following platinum-based chemotherapy, we use a PARP inhibitor as maintenance treatment.

Where are ongoing research efforts with PARP inhibitors focused?

Currently, a lot of ongoing clinical trials are evaluating other PARP inhibitors for patients with germline BRCA mutations. Also, [we’re studying whether] PARP inhibitors are effective for patients with homologous recombination repair gene–mutated pancreatic cancer.

At this time, we are using olaparib for the germline BRCA-mutated patients. Trials are ongoing to see if this PARP inhibitor is effective for the somatic BRCA-mutated patients.

What are some remaining challenges in the treatment of patients with metastatic pancreatic cancer?

In contrast to other cancers, pancreatic cancer is not sensitive to immunotherapy or other treatment modalities. At this point, we only have chemotherapy as first-line treatment. We have to develop more of an understanding of the tumor microenvironment in pancreatic cancer to see if we can use other modalities, such as immunotherapy or other targeted therapies.

A lot of clinical trials are ongoing to try to [identify] a different modality of treatment that can be applied in metastatic pancreatic cancer.

References:

1. Wainberg Z, Bekaii-Saab T, Boland P, 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-1.
2. Ipsen receives FDA fast track designation for liposomal irinotecan (ONIVYDE®) as a first-line combination treatment for metastatic pancreatic cancer [news release]: Paris, France. Ipsen. Published June 17, 2020. Accessed August 17, 2020. https://bit.ly/2BkyKbG.