FOLFIRINOX Plus IPI-926 for Advanced Pancreatic Adenocarcinoma

Pancreatic adenocarcinoma (PDAC) represents the fourth leading cause of cancer-related mortality in the United States, with an estimated 36,800 deaths attributable to PDAC in 2010.(1) Over 90% of patients have inoperable disease at presentation, at which point systemic therapy becomes the primary form of treatment. Single agent gemcitabine became the standard of care for advanced pancreatic cancer a decade ago since demonstrating improved survival when compared with fluorouracil. Since then, a number of phase III trials have evaluated the benefit of adding additional cytotoxic or targeted agents to gemcitabine, as shown in the table below. The PA.3 trial(2), which led to the approval of erlotinib in advanced pancreatic cancer, was a landmark study in that it represented the first positive phase III study of a combination regimen for this disease indication; however, while erlotinib represents both an important proof of principle and a welcome addition to our therapeutic armamentarium, it has failed to gain significant traction in this disease, as many in the oncology community consider the marginal absolute improvement in median overall survival to be of questionable clinical significance.

FOLFIRINOX: A new standard of care for advanced PDAC? At the 2010 American Society of Clinical Oncology Annual Meeting (ASCO), a French cooperative group presented results of a potentially practice-changing phase III clinical trial (PRODIGE 4/ACCORD 11).(18) In this study, 342 patients with previously untreated metastatic pancreatic cancer were randomized to receive either gemcitabine monotherapy or the combination of biweekly infusional 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) (ref). The investigators reported statistically significant improvements for the FOLFIRINOX arm in the primary endpoint, overall survival (median of 11.1 months vs 6.8 months, P < .0001); as well as 1-year survival rate (48.4% vs. 20.6%), median progression-free survival (6.4 vs. 3.3 months; P < .0001), and objective response rate (CR+PR, 31.6% vs. 9.4%; P = .0001)). Not surprisingly, the more complex FOLFIRINOX regimen was associated with higher rates of grade 3/4 toxicities, including neutropenia (45.7% vs 18.7%), febrile neutropenia (5.4% vs. 0.6%), fatigue (23.2% vs. 14.2%), and diarrhea (12.7% vs. 1.2%). Notably, while primary prophylaxis with growth factor support was not mandated in this trial, 42.5% of patients did ultimately receive such support. Moreover, most patients enrolled in this trial had non-pancreatic head tumors (approximately 64%) which is the opposite distribution of what one might expect in a representative pancreatic cancer population. Thus, it is conceivable that the FOLFIRINOX regimen, with its high rates of neutropenia, may lead to unacceptable rates of infectious complications (eg, ascending cholangitis and biliary sepsis), in patients with pancreatic head tumors with indwelling endobiliary stents.

Nevertheless, this strikingly positive survival benefit, with a median overall survival approaching one year in a purely metastatic cohort, has never before been observed in any previous study, which raises the question of whether FOLFIRINOX should become the newly adopted standard of care, at least in patients with preserved performance status (patients on this trial were required to have an ECOG performance score of 0-1).

HEDGEHOG SIGNALING The Hedgehog(19) signaling pathway is important for normal mammalian embryonic development and for adult tissue remodeling. Recent reports have demonstrated that aberrant activation of the Hh pathway is associated with many types of cancer, including basal cell carcinoma (BCC), medulloblastoma, pancreatic adenocarcinomas, small-cell lung cancer (SCLC), metastatic prostate cancer, glioma, breast cancer, hepatocellular cancer, and hematologic malignancies. High levels of Hh pathway activation, either through mutation of pathway components or through constitutive expression of Hh pathway genes, appear to be involved in both the initiation of cancer and tumor cell survival, as well as tumor growth and metastasis. Given the therapeutic potential of Hh pathway inhibition in cancer, Infinity has developed IPI-926, a potent and specific antagonist of the Hh pathway that binds Smoothened (Smo), a key signaling transmembrane protein in this pathway, thereby diminishing downstream promoters of cellular proliferation.

Pancreatic adenocarcinomas are an ideal tumor class in which to evaluate the activity of a Hh pathway inhibitor, as multiple lines of evidence support a role for Hedgehog signaling in pancreatic tumorigenesis:

- Aberrant expression of Sonic hedgehog (SHH) and its associated signaling components (patched (PTC) and smoothened (SMO)) are frequently found in pancreatic cancer specimens.(20-27)

- Pharmacologic inhibition of hedgehog signaling produces antitumor effects in pancreatic cancer cell lines27 and orthotopic xenograft models.(28,29) Studies involving global sequencing analysis have identified this pathway as one of the central elements undergoing transformation in nearly all pancreatic cancers.(21)

- Hedgehog signaling may play an important role in maintenance of pancreatic cancer stem cells.(30-32)

- The dense desmoplastic mesenchymal network that constitutes the stroma of pancreatic adenocarcinomas coupled with poor vascularity may present a major challenge to effective delivery of intravenous chemotherapy to the bulk of pancreatic tumor cell burden. Recent evidence in a genetically engineered mouse model of pancreatic cancer demonstrated that IPI-926 can deplete tumor-associated stromal tissue and increase intratumoral mean vessel density, resulting in enhanced delivery of concurrently administered systemic agents such as gemcitabine, decreased tumor burden, and prolonged survival.(33)