Liposomal Irinotecan Is Active After Prior Treatment in Pancreatic Cancer

Several combination chemotherapy regimens are in use for patients with metastatic pancreatic ductal adenocarcinoma. Liposomal irinotecan (Onivyde) has been introduced in place of unencapsulated irinotecan, leading to trials investigating its efficacy and safety in different patient populations, as was discussed in a Case-Based Roundtable event moderated by Kashif Ali, MD, a medical oncologist of Maryland Oncology Hematology in Silver Spring, Maryland. Ali reviewed multiple trials tracking the development and optimization of the regimens in use today that modified the framework of FOLFIRINOX (5-FU, leucovorin [folinic acid], irinotecan, and oxaliplatin).

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Targeted Oncology: What is the significance of the NAPOLI-1 trial (NCT01494506)?

Kashif Ali, MD: This is the first trial that that looked at liposomal irinotecan. This trial was for patients with metastatic pancreatic cancer, but it was not for newly diagnosed patients, so these are patients with previously treated metastatic pancreatic cancer. In order to be on this trial, you had to have gemcitabine as prior treatment. Also, you were allowed to have irinotecan or 5-FU (5-fluorouracil) as your regimen previously. This is interesting, because you're allowed irinotecan, but the trial is looking at liposomal irinotecan. So you're giving liposomal irinotecan to someone who's already had irinotecan, which we do in clinical practice, meaning that we have patients who get FOLFIRINOX and then go on to later have liposomal irinotecan as part of a FOLFIRI-type of regimen, and it tends to work.

The tricky thing here is this trial is not meant to compare FOLFIRI to liposomal irinotecan. This is FOLFIRI with liposomal irinotecan vs liposomal irinotecan alone vs 5-FU plus leucovorin, a [poor] control arm. The first arm is supposed to be compared with the control arm. The liposomal irinotecan is supposed to be compared with the control arm. You're not supposed to compare the 2 [experimental] arms, because that's not the way the trial is designed.

The primary end point is overall survival [OS]. Secondary end points include progression-free survival [PFS], overall response rate [ORR], and CA [carbohydrate antigen] 19-9 response. The single-agent liposomal irinotecan did not work. That was a negative trial. When they compared liposomal irinotecan monotherapy vs 5-FU plus leucovorin, there was no benefit. The HR was 1 and the P value was not significant.

What were the outcomes in the main experimental arm?

Focusing on FOLFIRI with liposomal irinotecan vs 5-FU plus leucovorin, there was an advantage. The P value was not the best, at .039, but the HR was 0.75, and the median OS was 6.2 months, so there was some benefit. We do use this regimen, and at 12 months, 26% of people are still alive. As far as the PFS goes, there was also a significant P value of .001; the HR was 0.57, and the median PFS was 3.1 months for the treatment arm.

As far as response rates—remember, these are pretreated patients. They all had gemcitabine. Many of them had irinotecan already. Most of them had 5-FU. But despite that, there was a 17% ORR.

Comparing [single-agent liposomal irinotecan] with control arm, that was a negative trial. We're just looking at FOLFIRI with liposomal irinotecan vs a control arm. The ORR was 17% vs 1%; 5-FU plus leucovorin clearly doesn't help there. Thirty-two percent of people have stable disease on this regimen. [Concerning] CA 19-9 reduction, 28% of people had 50% reduction in CA 19-9 and 40% had 20% reduction of CA 19-9.

What dose modifications were there in this trial?

There were dose delays in 63.2% of patients. Dose reductions were in 34.2% of patients. A good number of people are dose reducing. The No. 1 reason for dose reduction and dose delays was neutropenia in both of those cases, and the treatment discontinuation rate was 12.8%; you're always going to have those patients.

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DISCLOSURES: Ali had no known relevant disclosures.

REFERENCE:

1. Wang-Gillam A, Hubner RA, Siveke JT, et al. NAPOLI-1 phase 3 study of liposomal irinotecan in metastatic pancreatic cancer: Final overall survival analysis and characteristics of long-term survivors. Eur J Cancer. 2019;108:78-87. doi:10.1016/j.ejca.2018.12.007