Conventional Versus Liposomal Irinotecan for Advanced Pancreatic Cancer

Justin C. Tossey, PharmD BCOP
Hematology/Oncology Clinical Specialist Pharmacist
The Ohio State University Comprehensive Cancer Center – James Cancer Hospital and Solove Research Institute
Columbus, OH

Pancreatic cancer remains one of the leading causes of cancer-related death in the U.S., despite being only the eleventh-most common new cancer diagnosis. The vast majority of pancreatic cancers are diagnosed at an advanced stage—either locally advanced and not surgically resectable or metastatic—so treatment relies primarily on systemic chemotherapy.

Over the last decade, research has led to increased survival using chemotherapy combinations such as FOLFIRINOX (leucovorin, 5-fluorouracil, irinotecan, and oxaliplatin) or gemcitabine and nab-paclitaxel as first-line treatment options. More recently, nanoliposomal irinotecan (nal-iri), a novel formulation, gained FDA approval in 2015 for the treatment of advanced pancreatic cancer in combination with leucovorin and 5-fluorouracil (5FU) after progression on gemcitabine-based therapy based on the results of the multinational phase III NAPOLI-1 trial.¹

Prior to nal-iri/5FU, there was no systemic therapy specifically approved beyond first-line treatment for advanced pancreatic cancer. Treatment recommendations were extrapolated from the activity of first-line regimens and included a fluoropyrimidine combined with either oxaliplatin or conventional irinotecan (i.e. FOLFOX or FOLFIRI, respectively) after first-line gemcitabine-based treatment. Studies of FOLFIRI in this setting have often been retrospective in nature, though a phase II study comparing FOLFIRI and FOLFOX for second-line treatment found similar overall survival of about 4 months.² To date, no randomized clinical trials have compared nal-iri/5FU to FOLFIRI, so it is unknown whether one regimen is clinically superior to the other.

Preclinical data demonstrate a 5-fold higher intratumoral concentration of the active irinotecan metabolite SN-38 after nal-iri administration compared to conventional irinotecan.³ This raises the intriguing possibility that nal-iri may be preferentially taken up by tumor cells, thereby increasing tumor cell killing while sparing normal cells from the toxic effects of SN-38. However, the available data suggest FOLFIRI may achieve survival outcomes similar to the more expensive nal-iri/5FU regimen. The increased cost of nal-iri/5FU could be justified if shown to have superior efficacy or significantly less toxicity than conventional irinotecan. Therefore, we sought to address this gap in clinical knowledge.

We retrospectively reviewed medical records of adult patients with locally advanced or metastatic pancreatic cancer who received either nal-iri/5FU or FOLFIRI after a gemcitabine-based therapy from October 2015 to August 2018.⁴ The primary outcome of our study was progression-free survival (PFS), with secondary endpoints that included time to treatment failure (TTF), overall survival (OS), frequency of dose reductions or treatment delays, and frequency of adverse effects. We also incorporated a cost analysis using estimates based on data available from the Centers for Medicare and Medicaid Services (CMS).

To account for potential differences between groups, we utilized inverse probability of treatment weighting (IPTW) based on baseline characteristics, and applied IPTW adjustment to all outcomes. We did not conduct any statistical hypothesis tests since the study hypothesis was non-inferiority of FOLFIRI and the limited sample size did not provide adequate power for formal tests of non-inferiority.

A total of 82 patients were screened for inclusion, and patients were excluded for not having received prior gemcitabine (n = 5) or not having received a study treatment (n = 2). Of the remaining 75 patients, 35 received nal-iri/5FU and 40 received FOLFIRI. After IPTW adjustment, treatment groups were balanced with regard to all baseline characteristics. Nearly all patients (88%) had metastatic disease, with 71% of those patients having hepatic involvement. More than half of patients in each group received at least 2 prior systemic therapies. Approximately one-third (n=23) of patients had prior exposure to irinotecan, mostly in the neoadjuvant setting (7 of 10 nal-iri/5FU patients and 11 of 13 FOLFIRI patients).

The primary outcome of PFS was similar between treatment groups, with a median of 4.1 months for nal-iri/5FU and 3.1 months for FOLFIRI. OS was also similar (7.1 vs 6.7 months), while TTF was nearly 2 months longer for nal-iri/5FU (4.1 months) com-pared to FOLFIRI (2.2 months). Treatment delays were common in the nal-iri/5FU group (66% vs 36%), whereas dose reductions occurred more frequently in the FOLFIRI group (48% vs 39%). Granulocyte colony-stimulating factor (G-CSF) use was similar between both groups (16% vs 15%), but atropine for the management of acute diarrhea (we do not regularly utilize atropine for primary prophylaxis) was used in nearly twice as many patients in the FOLFIRI group (70% vs 36%). There were no distinct differences in the frequency of grade 3 or 4 adverse effects. The cost analysis based on CMS data estimated a total treatment cost of $52,834 for nal-iri/5FU and $1,809 for FOLFIRI.

These results in a real-world patient population demonstrate a similar PFS and OS for advanced pancreatic cancer patients treated with either nal-iri/5FU or FOLFIRI. In the absence of formal statistical testing, visual inspection of the time-to-event curves did not demonstrate a clear survival advantage for nal-iri/5FU. Although this was a small, single-center study, our survival outcomes were similar to those published in previous trials.^1,5-7 In addition, patients experienced adverse effects with a similar frequency in both groups, which does not seem to support the hypothesis that the liposomal formulation of nal-iri spares healthy cells from exposure to irinotecan or its metabolites in a clinically meaningful way. FOLFIRI patients were more likely to need atropine, but this did not translate into a clear difference in the reported rates or severity of diarrhea.

The difference in overall toxicity management, with FOLFIRI patients more likely to have a dose reduction while nal-iri/5FU patients were more often delayed, was an interesting contrast that we hypothesize could be a result of oncology team familiarity with each regimen. Since FOLFIRI has been utilized for decades in many different GI malignancies, oncologists and pharmacists might be more comfortable determining an appropriate dose reduction might be for a given patient, whereas they may opt for a treatment delay for the newer and less-familiar nal-iri/5FU regimen.

The decision to select one treatment over another involves several factors, including efficacy and safety, and may also include considerations for cost or convenience. After FDA approval of nal-iri, no institutional protocols or guidelines encouraged providers to select one treatment over the other in any specific scenario. Therefore, the decision to treat with nal-iri/5FU or FOLFIRI at our institution was based on provider- and patient-specific factors and determined on a case-by-case basis.

This study did not demonstrate an obvious difference in either survival outcomes or adverse effect frequencies. Our cost analysis, with an acknowledgement of its inherent limitations for applicabil-ity to a health system with complex payment and reimbursement models, undoubtedly shows treatment with nal-iri/5FU is significantly more expensive than treatment with FOLFIRI.

Together, these factors support consideration of FOLFIRI in place of nal-iri/5FU for the treatment of advanced pancreatic cancer. Of course, a well-powered randomized controlled trial would be able to more definitively answer the question of non-inferiority. The oncology clinician may at least take comfort that these data do not suggest we do our patients a disservice by electing for treatment with FOLFIRI for advanced pancreatic cancer, particularly when the costs of treatment are of concern.

REFERENCES

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