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Combination therapy may extend OS in metastatic pancreatic cancer
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A treatment regimen of nanoliposomal irinotecan, fluorouracil and folinic acid appeared to prolong survival in patients with metastatic pancreatic cancer previously treated with gemcitabine-based chemotherapy, according to the results of a randomized, open-label phase 3 trial.
The safety profile of the combination appeared manageable, according to the researchers.
Nanoliposomal irinotecan (Onivyde, Merrimack Pharmaceuticals) exhibited clinical activity in a prior phase 2 study of previously treated patients with metastatic pancreatic cancer.
Thus, Li-Tzong Chen, MD, PhD, investigator and attending physician at National Institute for Cancer Research in Taiwan, and colleagues conducted their study to assess the effect of nanoliposomal irinotecan in this patient population.
The researchers randomly assigned patients to nanoliposomal irinotecan monotherapy (120 mg/m2 every 3 weeks, equivalent to 100 mg/m2 of irinotecan base) or fluorouracil and folinic acid.
In a protocol amendment, they added a third arm that consisted of nanoliposomal irinotecan (80 mg/m2, equivalent to 70 mg/m2 of irinotecan base) in combination with fluorouracil and folinic acid every 2 weeks.
Treatment continued until disease progression or unacceptable toxicity.
OS served as the primary endpoint. Key secondary endpoints included PFS, objective response rate and time to treatment failure. The researchers planned to conduct a primary analysis after 305 events.
The analysis included data on 417 patients (nanoliposomal irinotecan plus fluorouracil and folinic acid, n = 117; nanoliposomal irinotecan monotherapy, n = 151; fluorouracil and folinic acid, n = 149).
After 313 events, researchers reported longer median OS among patients assigned combined nanoliposomal irinotecan, fluorouracil and folinic acid than those assigned fluorouracil and folinic acid (6.1 months vs. 4.2 months; HR = 0.67; 95% CI, 0.49-0.92).
The researchers did not observe a significant difference in median OS among patients assigned nanoliposomal irinotecan monotherapy and those assigned fluorouracil and folinic acid (4.9 months vs. 4.2 months; HR = 0.99; 95% CI, 0.77-1.28).
Patients assigned nanoliposomal irinotecan plus fluorouracil and folinic acid achieved a median PFS of 3.1 months, compared with 1.5 months for patients assigned fluorouracil and folinic acid (HR = 0.56; 95% CI, 0.41-0.75). Patients assigned nanoliposomal irinotecan monotherapy achieved a median PFS of 2.7 months (vs. fluorouracil and folinic acid, HR = 0.81; 95% CI, 0.63-1.04).
The median time to treatment failure was 2.3 months among patients assigned nanoliposomal irinotecan plus fluorouracil and folinic acid and 1.4 months among those assigned fluorouracil and folinic acid (HR = 0.6; 95% CI, 0.45-0.78). Median time to treatment failure did not significantly differ among those assigned nanoliposomal irinotecan monotherapy and those assigned fluorouracil and folinic acid (HR = 0.82; 95% CI, 0.65-1.03).
Patients assigned nanoliposomal irinotecan plus fluorouracil and folinic acid achieved a higher objective response rate than those assigned fluorouracil and folinic acid (16% vs. 1%; P < .0001).
The most frequently reported adverse events among patients assigned nanoliposomal irinotecan plus fluorouracil and folinic acid included neutropenia (27%), diarrhea (13%) and fatigue (14%).
Forty-seven patients died during the study or within 30 days of the last study dose. The majority (n = 30) were due to prostate cancer. Sixteen patients died of adverse events (treatment related, n = 5), and one patient died of an unknown cause.
“It is not possible to generalize the results of this study to patients with low performance status, as shown by a Karnofsky performance status less than 70 and albumin less than 30 g/L, and those with increased bilirubin, all of which occur with this disease,” Chen and colleagues wrote. “Future studies will assess the use of nanoliposomal irinotecan in other settings, including first-line therapy and the role of sequencing various regimens for pancreatic cancer.”
The addition of nanoliposomal irinotecan to the pancreatic cancer treatment platform may open more surgical treatment options in this vulnerable patient population, Helmut Oettle, MD, PhD, of the Center for Tumor Medicine and Thorsten Lehmann, MD, of Klinikum Friedrichshafen, both in Friedrichshafen, Germany, wrote in an accompanying editorial.
“Administration of nanoliposomal irinotecan within new chemotherapy combinations and sequences and alongside new drugs (eg, programmed death–ligand 1 inhibitors) could provide better disease control in the future,” Oettle and Lehmann wrote. “Better disease control might create a situation similar to that seen with metastatic colorectal cancer, whereby resection of single liver metastases is worth doing, with the possibility of some patients being cured. Moreover, as well as reducing cumulative toxic effects, the sequence of first-line albumin-bound paclitaxel plus gemcitabine, second-line nanoliposomal irinotecan plus fluorouracil and folinic acid, then third-line oxaliplatin, fluorouracil, and folinic acid could also represent an overall therapeutic strategy, thereby providing patients with ongoing effective options.” – by Cameron Kelsall
Disclosure: Merrimack Pharmaceuticals funded this study. Chen reports funding from Merrimack Pharmaceuticals during this study, as well as personal fees from PharmaEngine outside the conduct of this study. Please see the full study for a list of all other researchers’ relevant financial disclosures. Oettle and Lehmann report no relevant financial disclosures.
Perspective
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Philip A. Philip, MD, PhD, FRCP
Unlike other cancers that have benefited from the introduction of novel targeted agents, drug developments in pancreatic cancer have been limited to convectional cytotoxic agents with the expected very modest improvements in survival.
Nevertheless, the combination of nanoliposomal irinotecan (Onivyde, Merrimack Pharmaceuticals) with fluorouracil and folinic acid fills an unmet need in the treatment of metastatic pancreatic cancer because an increasing number of patients are candidates for second-line therapy after failing frontline treatment. An oxaliplatin/fluoropyrimidine-based strategy has been a treatment standard in patients failing gemcitabine-based frontline therapy for several years.
However, the very modest clinical benefit of oxaliplatin/fluoropyrimidine-based therapy associated with risk for worsening neuropathy from previous treatment was inconsistent across randomized studies. Gemcitabine with or without nab-paclitaxel followed by nanoliposomal irinotecan with fluorouracil and folinic acid establishes a much-needed treatment strategy of sequential tolerable cytotoxic doublets in patients with metastatic pancreatic cancer that can be used in most patients. Lack of neurotoxicity with nanoliposomal irinotecan is an advantage when using it after the increasingly used frontline regimen of gemcitabine and nab-paclitaxel.
At this time, no data are available for nanoliposomal irinotecan with fluorouracil and folinic acid following FOLFIRINOX regimen and, in my opinion, it is unlikely to provide a clinically worthwhile benefit unless failure on FOLFIRIONX was due to toxicity and not disease progression.
Nanoliposomal irinotecan with fluorouracil and folinic acid may also be considered in patients who experience early disease relapse following adjuvant gemcitabine-based therapy.
We await the results of testing the incorporation of nanoliposomal irinotecan into frontline therapy of metastatic disease, although it is unlikely that it would lead to major improvements in survival over the currently used frontline regimens.
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