Randomized Phase Ib/II Study of Gemcitabine Plus Placebo or Vismodegib, a Hedgehog Pathway Inhibitor, in Patients With Metastatic Pancreatic Cancer

INTRODUCTION

Pancreatic cancer (PC) is the fourth leading cause of cancer mortality in the United States, with 38,460 deaths annually.¹ Five-year survival for all stages combined is only 6%. Gemcitabine had beenthe backbone treatment for years in advanced disease,² until the introduction of FOLFIRINOX (fluorouracil, leucovorin, irinotecan, and oxaliplatin)³ and gemcitabine plus albumin-bound nab-paclitaxel⁴ regimens, both reported after initiation of our trial. Despite numerous attempts, most gemcitabine combinations with molecularly targeted therapies have failed to demonstrate a significant improvement in overall survival (OS),^5–8 with the exception of gemcitabine plus erlotinib, which has demonstrated a statistically significant but clinically modest benefit.⁹

Vismodegib (Erivedge; Genentech, South San Francisco, CA), a synthetic small-molecule inhibitor of smoothened (SMO) in the hedgehog (Hh) pathway,^10,11 has demonstrated clinical benefit in basal cell carcinoma and medulloblastoma—both harboring recurrent Hh pathway mutations in SMO or protein patched homolog 1 (PTCH1).^12,13 Vismodegib is US Food and Drug Administration approved for the treatment of patients with advanced basal cell carcinoma. Trials applying various SMO inhibitors to other tumors harboring genomic activation of the Hh signaling pathway are under way, some within novel clinical trial designs.¹⁴ However, no single-agent activity was observed in early phase I studies within molecularly unselected patients with advanced and pretreated PC.^15,16

Nevertheless, the Hh pathway has been reported to be critical for tumor progression in preclinical PC models^17,18 and has been considered a potential therapeutic target.^19–21 Sonic Hh (SHH) is overexpressed in approximately 70% of PCs and has been shown to be an early and late mediator of PC tumorigenesis.^22–24 Tumor-derived SHH has influenced and promoted tumor growth in preclinical PC systems by activating Hh signaling in stroma.^25–28 This paracrine Hh signaling may establish and maintain the desmoplastic stroma observed in PC, creating a barrier for proper drug penetration.²⁹ Hh pathway inhibition with IPI-269609, an SMO inhibitior,^30–32 reportedly led to increased tumor perfusion, enhanced tumor delivery of gemcitabine when coadministered, and improvement in survival in a genetically engineered murine PC model,²⁹ forming the rationale for human clinical trials in PC.

Given this background, we hypothesized that inhibition of the Hh pathway would be synergistic with gemcitabine and would lead to improved progression-free survival (PFS) compared with gemcitabine alone for metastatic PC.³³ This article reports the final results of a phase Ib (n = 7) and multicenter randomized phase II trial (n = 106) comparing gemcitabine plus vismodegib (GV) with gemcitabine plus placebo (GP) in patients with advanced PC; there were no significant differences in overall response rate (ORR), PFS, or OS between these two groups. To further investigate the putative biologic mechanisms of SMO inhibition, we used two autochthonous PC models (Kras^G12D; p16/p19^fl/fl; Pdx1-Cre [KPP] and Kras^G12D; p53^R270H/wt; Pdx1-Cre [KR]) to recapitulate the phase II clinical trial. In contrast to recent reports with IPI-926 (saridegib),^29,34–36 our preclinical and clinical results with vismodegib are concordant and demonstrate no statistically significant differences with respect to tumor growth, drug delivery, or treatment efficacy.

PATIENTS AND METHODS

The Data Supplement provides detailed information on methods.

RESULTS

DISCUSSION

Effective molecularly targeted treatment for advanced PC remains an unmet need. When we began this trial, extensive preclinical evidence provided rationale for the clinical evaluation of Hh pathway inhibition along with concurrent gemcitabine treatment.^{19,22,24,25,29,32}

The addition of vismodegib to gemcitabine in this clinical study was well tolerated, no unexpected toxicities were observed, and there were no significant toxicity differences compared with the GP arm (Table 2). Unfortunately, this trial failed to meet its primary objective of a statistically significant improvement in median PFS, achieving a median PFS of 4.0 and 2.5 months in the GV and GP arms, respectively (HR, 0.83; 95% CI, 0.55 to 1.23). It should be noted, however, that the study was powered (85%) to detect an HR of 0.6, and therefore, a smaller effect, if present, may not have been detectable. Similarly, there were no differences between arms in median OS (6.9 v 6.1 months) or disease control rate (58% v 51%).

Despite a recent report suggesting that serum SHH levels were decreased in patients with PC compared with age-matched controls, we did not observe this association.⁴² Moreover, we hypothesized that serum SHH might change over time, potentially differentially with or without exposure to vismodegib, but as noted, this was not observed either. Consistent with these findings, Kim et al⁴³ recently reported no change in tumor SHH protein expression in matched biopsies from patients treated for 3 weeks with vismodegib.

To investigate the discrepancy between our clinical data and previous reports,^24,25,29 we sought to assess baseline primary pancreatic tumor perfusion and its association with response to therapy. Perfusion CT is a clinical technique used to provide regional maps and obtain quantitative measurements of hemodynamic parameters on the basis of the linear relationship between CT enhancement and iodinated contrast material concentration.^44,45 Whole-organ perfusion of the pancreas using dynamic contrast-enhancement imaging revealed significantly lower perfusion in the tumor compared with adjacent normal pancreatic tissue.⁴⁶ In addition, enhancement patterns of PCs on conventional dynamic multidetector row CT correlated with degree of angiogenesis, and these patterns were reportedly modified by degree of fibrosis.⁴⁷ However, we did not observe a correlation between higher baseline tumor perfusion and improved treatment response to gemcitabine (pooled analysis, GV + GP) in this univariable analysis of a small exploratory cohort. Because there were no significant differences in clinical outcomes between the GV and GP arms, evaluation of serial changes in perfusion over time was not performed.

Much of the preclinical work supporting Hh inhibition for PC was performed with IPI-296 (saridegib).^29,31 It is noteworthy that a randomized phase II trial of saridegib in PC, conducted simultaneously with our trial, was halted at interim analysis in January 2012 because of worse median PFS and median OS compared with the placebo arm.³⁶ A recent report attempting to discern the preclinical²⁹ to clinical³⁶ discrepancy suggested that prolonged exposure to IPI-296 before frank tumor development (PanIN stage) ultimately led to tumors with undifferentiated histology, increased vascularity, and heightened proliferation.³⁴ Importantly, clinical correlates to confirm the original²⁹ or newly reported³⁴ preclinical findings, including increased vascularity, improved drug delivery, and worsened disease resulting from IPI-296 treatment, are still lacking or unreported. Subsequently, a similar preclinical study evaluating vismodegib treatment, also at the tumor precursor stage (PanIN), reported accelerated tumor progression.³⁵ Here, further support for the critical role of stroma early in pancreatic tumor formation was provided with elegant studies, where SHH was genetically deleted coincident with tumor suppressor loss and oncogene activation. In the absence of epithelial-derived SHH secretion, the resulting pancreatic tumors were phenotypically distinct, devoid of desmoplastic stroma, more vascularized, and more proliferative than controls.^34,35 The early treatment design of these experiments is consistent with a large body of work describing the preventive nature of stroma in early tumor formation,^48–50 but it does little to reconcile the preclinical and clinical discrepancy with Hh inhibition in established pancreatic tumors. The discordance between the preclinical²⁹ (benefit) and clinical³⁶ (detriment) results with IPI-926 in established tumor scenarios may be a result of overinterpretation of the preclinical gemcitabine model data,²⁹ because small yet statistically significant effects do not ensure a biologically meaningful effect in patients. This lack of predictive correlation contrasts the strong predictive value of preclinical work in models harboring mutationally driven Hh pathway signaling.⁵¹ Patient-derived xenograft models may also promote better understanding in the future.

Patients with PC frequently present with advanced disease, so to model the clinical treatment scenario, we treated two independent, genetically engineered PC models when defined, measurable tumors were readily detectable. Not only did SHH pathway inhibition not improve survival, no measurable changes in gemcitabine delivery or tumor growth rate were observed in either murine model. An increase in vascular density was not observed with vismodegib treatment, in contrast to IPI-926.²⁹ In our study, HhAntag treatment showed a significant or trending decrease in microvessel density, depending on the marker used, which is consistent with previous work in preclinical tumor models where vismodegib treatment reduced tumor growth and mean vessel density.⁴¹

It is also possible that the preclinical efficacy differences may be attributed to unique molecular properties of the agents, given that IPI-926 is a cyclopamine derivative, whereas GDC-0449 (vismodegib) is a synthetic inhibitor of SMO. For example, although both molecules occupy a similar pocket within the transmembrane domain of SMO, they may mechanistically diverge, because cyclopamine treatment leads to accumulation of SMO in the primary cilium, whereas vismodegib prevents it.^52,53 Moreover, cyclopamine has been shown to have off-target effects that may lead to enhanced toxicity and/or potentially cause the stromal effects observed. Notably, a clinical trial with IPI-926 in PC was stopped because of worse survival outcome in the investigational arm.³⁶ In our study, we did not observe increased toxicity or a detriment in survival with GV. Nevertheless, neither molecule demonstrated statistically significant improvement when combined with gemcitabine in PC.

In conclusion, we found no benefit in adding vismodegib to gemcitabine in this randomized phase II trial of molecularly unselected patients with metastatic PC; we corroborated these findings in two independent genetic murine PC models (KPP and KR). Given the discrepant results between the two tested SMO inhibitors, their selectivity may uniquely diverge, where off-target effects might explain altered outcomes. Importantly, our preclinical findings were ultimately concordant with the outcome of our clinical trial. Given that newer chemotherapy regimens have demonstrated benefit over gemcitabine, a number of ongoing trials are evaluating the role vismodegib in PC using these more active cytotoxic backbones.⁵⁴

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Disclosures provided by the authors are available with this article at www.jco.org.

AUTHOR CONTRIBUTIONS

Conception and design: Daniel V.T. Catenacci, Melissa R. Junttila, Theodore Karrison, Naoko Takebe, Ravi Salgia, Walter M. Stadler, Frederic J. de Sauvage, Hedy L. Kindler

Financial support: Daniel V.T. Catenacci, Ravi Salgia, Walter M. Stadler, Hedy L. Kindler

Administrative support: Walter M. Stadler

Provision of study materials or patients: Daniel V.T. Catenacci, Nathan Bahary, Margit N. Horiba, Sreenivasa R. Nattam, Robert Marsh, James Wallace, Mark Kozloff, Lakshmi Rajdev, Deirdre Cohen, James Wade, Bethany Sleckman, Heinz-Josef Lenz, Patrick Stiff, Pankaj Kumar, Hedy L. Kindler

Collection and assembly of data: Daniel V.T. Catenacci, Melissa R. Junttila, Nathan Bahary, Margit N. Horiba, Sreenivasa R. Nattam, Robert Marsh, James Wallace, Mark Kozloff, Lakshmi Rajdev, Deirdre Cohen, James Wade, Bethany Sleckman, Heinz-Josef Lenz, Patrick Stiff, Pankaj Kumar, Peng Xu, Les Henderson, Naoko Takebe, Xi Wang, Hedy L. Kindler

Data analysis and interpretation: Daniel V.T. Catenacci, Melissa R. Junttila, Theodore Karrison, Nathan Bahary, Les Henderson, Naoko Takebe, Ravi Salgia, Xi Wang, Walter M. Stadler, Frederic J. de Sauvage, Hedy L. Kindler

Manuscript writing: All authors

Final approval of manuscript: All authors

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST