First- and Second-Line Treatments for Advanced Pancreatic Cancer

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The two standards of care for patients with advanced pancreatic cancer are FOLFIRINOX and nab-paclitaxel plus gemcitabine. These agents were approved based on findings from large studies that demonstrated extensions in overall survival. However, at this point, head-to-head data are not available comparing these treatments.

The phase II/III PRODIGE study, conducted in France, looked at FOLFIRINOX compared with gemcitabine in patients with an ECOG performance status (PS) of 0-1. The median overall survival was 11.1 months in the FOLFIRINOX arm compared with 6.8 months for gemcitabine; corresponding improvements in progression-free survival (PFS) and tumor response were reported. FOLFIRINOX has inherent side effects, such as gastrointestinal toxicity, myelosuppression, infection, neuropathy, and fatigue. To compensate for these adverse events, FOLFIRINOX is often modified to preserve efficacy while ameliorating toxicity.

The phase III MPACT trial introduced the combination of nab-paclitaxel and gemcitabine for patients with advanced pancreatic cancer. In this trial, the median OS was 8.5 months with nab-paclitaxel plus gemcitabine compared with 6.7 for gemcitabine alone.

Slight differences in the patient populations enrolled in each study affected the results to some extent. In contrast to the PRODIGE trial where the upper age limit was 76 years, there was no age limit in the MPACT study. MPACT also included patients with ECOG PS 2, whereas PRODIGE enrolled only ECOG PS 0-1. Patient selection may have had a significant impact on outcomes; however, for the control arms, OS was similar in both studies.

Although FOLFIRINOX appears to be superior on the surface, notes Eileen O’Reilly, MD, the efficacy of the two regimens is comparable when the differences between the patient populations are taken into account. Moreover, treatment is not straightforward, when considering practical/logistic issues, and patient preferences. When deciding between the two treatments, the conversation generally centers on whether the patient prefers a weekly treatment versus the need for a Mediport and an infusion schedule, and whether alopecia is a concern for a patient, adds O’Reilly.

The practical issues for choosing which regimen to use comes down to patient preference and toxicity, and, to some extent, the degree of supportive care required afterward, according to Philip Philip, MD, PhD. The side effect profile for the gemcitabine and nab-paclitaxel combination appears to be more favorable, Philip notes. However, both regimens should be used with caution in patients with abnormal liver function tests.

Gastrointestinal side effects are limiting, particularly in the second-line setting with FOLFIRINOX, warranting dose modifications, states Philip. Strategies include omitting the 5-FU bolus, reducing the dosage of irinotecan, reducing the dosages of the individual components of FOLFIRINOX, and giving FOLFOX or XELOX. It is important to recognize that the median dose intensity delivered in the phase II/III trial was 80%, O’Reilly emphasizes.

The approach to second-line therapy, or for those who cannot tolerate the first regimen, is typically to switch to whichever regimen hasn’t previously been given. The majority of patients will experience early progression of their disease, warranting the further investigation of new therapies. Patients with a good performance status and organ function should be considered for a clinical trial.

Novel second-line agents are currently in development. The JAK inhibitor ruxolitinib in combination with capecitabine demonstrated promising findings in a phase II study for patients with metastatic pancreatic cancer. Additionally, second-line treatment with MM-398 (nal-IRI) plus 5-FU and leucovorin extended OS, PFS, and overall response rate compared with 5-FU and leucovorin alone for patients with metastatic pancreatic cancer. In November 2014, the FDA granted MM-398 plus 5-FU and leucovorin a Fast Track designation as a second-line treatment for patients with metastatic pancreatic cancer, based on these findings.