Emerging Systemic and Targeted Therapies

Fig. 10.1

Development of new drugs and regimens in the treatment of pancreatic cancer. Drugs or regimen activity demonstrated in a phase III study. Not all agents are approved by the FDA

FOLFIRINOX

In a phase II/III French study, 342 patients with metastatic pancreatic cancer and good performance status (ECOG 0 or 1) were randomly assigned to FOLFIRINOX (oxaliplatin, 85 mg/m²; irinotecan, 180 mg/m², leucovorin, 400 mg/m², and 5-FU 400 mg/m² bolus followed by 2400 mg/m² given as a 46-h continuous infusion, every 2 weeks) or gemcitabine at a standard dose and schedule. The median overall survival was significantly longer in the FOLFIRINOX group of 11.1 months as compared with 6.8 months in the gemcitabine group (HR, 0.57, 95 % CI, 0.45–0.73, p < 0.001). Similarly median progression-free survival was 6.4 months in FOLFIRINOX arm and 3.3 months in gemcitabine group (HR for disease progression, 0.47, 95 % CI 0.37–0.59; p < 0.001). Incidence of grade 3 or 4 neutropenia, febrile neutropenia, thrombocytopenia, diarrhea, and sensory neuropathy were significantly higher in the FOLFIRINOX group [8]. There are no mature randomized trials that have evaluated FOLFIRINOX in locally advanced pancreatic cancer or in resectable localized disease.

Nanoparticle Albumin-Bound Paclitaxel (Nab-Paclitaxel) and Gemcitabine

The combined antitumor activity of nab-paclitaxel with gemcitabine was evaluated in a large phase III clinical trial. Eight hundred and sixty-one patients with metastatic pancreatic cancer were randomized to receive gemcitabine plus nab-paclitaxel or gemcitabine alone. The median overall survival was 8.5 months in the nab-paclitaxel plus gemcitabine arm compared to 6.7 months in the gemcitabine arm (HR for death 0.72; 95 % CI 0.62–0.83, p < 0.001). The progression-free survival was 5.5 months in the combination group vs. 3.7 months in the single agent gemcitabine group (HR for disease progression or death 0.69, 95 % CI 0.58–0.82, P < 0.001). As to be expected there were more febrile neutropenia and peripheral neuropathy in the combination group [10]. Based on this clinical trial, nab-paclitaxel plus gemcitabine was approved by the FDA and was established as a standard of care alongside FOLFIRINOX in patients with advanced pancreatic cancer. There is no head-to-head comparison between the two regimens in advanced disease. The Nab-paclitaxel/gemcitabine regimen is currently being investigated in patients with resected pancreatic cancer in a Phase III trial versus single agent gemcitabine.

TH-302 and Gemcitabine

As tumors grow, it rapidly outgrows its blood supply resulting in a hypoxic environment within the tumor. The hypoxic microenvironment in many solid tumors including pancreatic cancer induces alterations in tumor biology, promoting invasion, angiogenesis, drug resistance, and metastases. Conventional cytotoxic agents typically target actively dividing cells near the tumor vasculature. Tumor cells within the hypoxic region of tumors are relatively quiescent making them resistant to conventional chemotherapy and radiotherapy. Traditional cytotoxic drugs have poor penetrance into the hypoxic regions of the tumor, resulting in decrease concentration of these cytotoxic agents within that microenvironment leading to treatment failure. TH-302 (evofosfamide) is a hypoxia-activated cytotoxic prodrug currently being developed for the treatment of advanced pancreatic cancer and other solid tumors. Evofosfamide is a 2-nitroimidazole prodrug designed to release DNA cross-linker bromo-iphosphoramide mustard (Br-IPM) when reduced by intracellular reductase in the setting of severe hypoxia. Once released, Br-IPM also diffuses to adjacent cells in normoxic regions of the tumor. In a phase II study, 214 patients with locally advanced or metastatic pancreatic cancer were randomized to receive gemcitabine alone, gemcitabine plus TH 302 (240 mg/m²) or gemcitabine plus TH-302 (340 mg/m²). Median PFS was 5.6 vs. 3.6 months (HR, 0.61; 95 % CI, 0.43–0.87; P = 0.005). Median OS was 7.6 vs. 6.3 months for metastatic disease and 13.1 vs. 15 months for locally advanced disease with the combinations compared with gemcitabine alone [11]. Based on this trial, a global phase III clinical trial (MAESTRO; NCT01746979) comparing gemcitabine plus TH-302 at 340 mg/m² vs. gemcitabine plus placebo was recently completed to evaluate efficacy with the primary end point being overall survival.

Liposomal Irinotecan (MM-398) and 5-FU/Leucovorin

MM-398 (liposomal irinotecan) is a nanoliposomal encapsulated prodrug of irinotecan with approximately 80,000 molecules of irinotecan stably encapsulated in a 100 nm liposome. This liposomal encapsulation extends the plasma half-life of the drug and improves normal tissue/tumor biodistribution resulting in improved antitumor activity with lesser toxicity [12]. Based on a phase II study showing moderate antitumor activity against gemcitabine refractory metastatic pancreatic cancer [13], a large multicenter phase III study NAPOLI-1 was completed. In this three-arm study, patients with metastatic pancreatic cancer previously treated with gemcitabine-based therapy were randomized to M-398 (iv 120 mg/m² every 3 weeks) (n = 118), 5-FU and leucovorin alone (iv 2000/200 mg/m² weekly × 4 every 6 weeks) (n = 119), and the combination of MM-398 [(iv 80 mg/m²) plus 5-FU/LV (2400/400 mg/m²) every 2 weeks] (n = 117). The overall survival in the MM-398 plus 5-FU/LV was 6.1 months (95 % CI 4.8–8.9) (stratified HR for death 0.57 (95 % CI 0.41–0.80), p = 0.009). Similarly, median PFS was 3.1 months (95 % CI 2.7–4.2) vs. 1.5 months, (95 % CI 1.4–1.8), p = 0.0001 in the MM-398 plus 5-FU/LV group vs. 5-FU/LV respectively. There was no significant difference in overall survival between MM-398 alone vs. 5-FU/LV alone group. The most common grade 3 or more adverse effects were fatigue 14 %, diarrhea (13 %), and vomiting (11 %). The most common grade 3 or more hematologic adverse effects was neutropenia (20 %) [14]. Currently, MM-398 is pending FDA approval for second-line therapy after gemcitabine-based therapy failures. There is no data on the comparative effectiveness of MM-398 versus regular irinotecan.

Targeted Agents

Targeting HER and IGF-1R Pathways

Several studies have reported that overexpression of HER2/neu or gene amplification in 11–16 % of metastatic pancreatic ductal adenocarcinoma [15, 16]. Trastuzumab is a humanized IgG kappa monoclonal antibody that selectively binds with extracellular domain of epidermal growth factor receptor protein, HER2, causing inhibition of the proliferation of human tumor cells that overexpresses HER2. Trastuzumab in combination with capecitabine and gemcitabine has been evaluated in phase II clinical trials in patients with advance pancreatic cancer. Addition of trastuzumab with capecitabine or gemcitabine did not significantly improve OS or PFS as compared to single agent capecitabine or gemcitabine [15, 16].

Insulin-like growth factor-1 (IGF-1) activates its receptor IGF-1R leading to activation of the PI3 kinase pathway which leads to cell growth and proliferation, as well as, provide antiapoptotic signals to premalignant and malignant cells [17]. In pancreatic cancer, IGF-1 and its receptor are aberrantly expressed or activated [18–20]. AMG 479 (ganitumab) is a human monoclonal antibody against IGF-1R that has shown additive antitumor activities in combination with gemcitabine against malignant pancreatic cancer cells both in vitro and in vivo [21]. Conatumumab (AMG655) is a human monoclonal antibody against the TRAIL receptor 2 (tumor necrosis factor-related apoptosis-inducing ligand) that induces apoptosis [22]. In a randomized, placebo-controlled phase II study, ganitumab and conatumumab were evaluated in combination with gemcitabine in patients with metastatic pancreatic cancer. Both ganitumab and conatumumab demonstrated trends toward an improved survival at 6 months [23]. Based on this trial result, a phase III placebo control clinical trial (clinical trial: NCT01231347) was conducted utilizing combination AMG 479 (ganitumab) and gemcitabine. Based on preplanned interim analysis, the data monitoring committee decided to stop the trial. The data monitoring committee concluded that the addition of ganitumab to gemcitabine was unlikely to significantly improve overall survival.

Erlotinib , an oral EGFR tyrosine kinase inhibitor was tested in a phase III double-blind, placebo-controlled study in patients with locally advanced or metastatic pancreatic cancer. Erlotinib 100 mg/day was combined with gemcitabine and resulted in a significantly longer overall survival when compared to gemcitabine alone (HR = 0.82, p = 0.038). However, the benefit was deemed clinically less meaningful because of a very marginal improvement in the median survival (6.24 vs. 5.91 months) and 1-year survival rate (23 % vs. 17 %) [24]. Increased toxicity and cost, as well as, the lack of a clinical biomarker that could identify responsive patients have made the use of erlotinib obsolete. Erlotinib in combination with gemcitabine was also tested in patients with pancreatic cancer after complete resection. This phase III study did not show any survival advantage for patients receiving erlotinib plus gemcitabine compared to gemcitabine alone in the adjuvant setting [25]. Similarly, the use of erlotinib was tested in patients with LAPC in the LAP 07 study. The addition of erlotinib to gemcitabine did not show survival advantage [26]. The monoclonal antibody cetuximab has also been investigated in patients with advanced pancreatic cancer in combination with gemcitabine. In a large phase III clinical trial involving 745 patients with locally advanced or metastatic pancreatic adenocarcinoma, efficacy of cetuximab in combination with gemcitabine (n = 372) vs. gemcitabine (n = 372) alone was investigated. This study found that there was no difference in median survival (6.3 vs. 5.9 months, HR 1.06; 95 % CI 0.91–1.23, p = 0.23) between the combination arms vs. gemcitabine alone. Despite, 92 % of the patients having EGFR positive tumors, there were no differences in median survival in either arm (median OS 6 months, HR 0.98; 95 % CI 0.83–1.17; p = 0.42) [27]. Overall, targeting EGFR in patients with localized or advanced pancreatic cancer without patient selection is not a valid therapeutic strategy.

Targeting Vascular Endothelial Growth Factor/Receptor Pathway

The Vascular endothelial growth factor/receptor (VEGF/VEGFR) pathway was actively investigated in patients with advanced pancreatic cancer. This included testing of anti-VEGF and anti-VEGFR treatment strategies with drugs added to a backbone of chemotherapy consisting of gemcitabine. Addition of bevacizumab in combination with erlotinib and gemcitabine or gemcitabine in patients with metastatic pancreatic cancer has failed to demonstrate a survival benefit [28]. Axitinib is a tyrosine kinase inhibitor of VEGF receptors used in treatment of metastatic renal cell carcinoma. The addition of axitinib to gemcitabine has not improved overall survival in advanced pancreatic cancer [23]. Sorafenib is a multi-targeted kinase inhibitor of vascular endothelial growth factor receptors (VEGFRs) and platelet-derived growth factor (PDGF) receptor and RAF kinase. It is currently approved for the treatment for advanced renal cell carcinoma and hepatocellular carcinoma. In a placebo-controlled, double-blind phase III study, the efficacy of gemcitabine plus sorafenib (n = 52) compared to gemcitabine and placebo (n = 52) was evaluated in patients with advanced pancreatic cancer. The addition of sorafenib to gemcitabine did not improve response rate or overall survival [29]. This negative result was consistent with a phase II study conducted by El-Khoueiry comparing combination of gemcitabine plus sorafenib with sorafenib alone [30]. Aflibercept is a VEGF inhibitor that binds with circulating VEGFs causing failure of initiation of VEGF-ligand-dependent signaling pathway. In a preclinical and phase I study, aflibercept demonstrated antitumor activity and was well tolerated [31, 32]. The efficacy of aflibercept was tested in patients with metastatic pancreatic cancer in combination with gemcitabine. In a large phase III double-blind clinical trail, 546 patients with metastatic pancreatic cancer were randomized to aflibercept plus gemcitabine group (n = 271) or gemcitabine plus placebo (n = 275). Preplanned interim analysis conducted on 427 patients failed to show a survival benefit for the aflibercept group and the study was terminated early [33].

At this time, targeting the VEGF/VEGFR pathway is considered to be a failed therapeutic strategy, partly explained by the poorly vascularized nature of pancreatic cancer.

Targeting NOTCH and JAK/STAT Pathway

Global genomic analysis of pancreatic cancer has revealed that pancreatic cancers contain an average of 63 genetic alterations, majority of them are point mutations in a core set of 12 cellular signaling pathways. The WNT/Notch pathway is dysregulated in 100 % of pancreatic cancers [34]. The Notch signaling pathway plays an important role in the embryonic development of the pancreas [35] and the Notch targeted genes are upregulated in invasive pancreatic cancers, and are involved in the progression of pancreatic cancer from pancreatic intraepithelial neoplasia (PIEN) [36–38]. MRK-003 is a potent gamma-secretase inhibitor, which downregulates the nuclear Notch 1 intracellular domain resulting in the inhibition of cellular growth. Preclinical studies in mice demonstrated that MRK-003 in combination with gemcitabine prolongs survival [39]. Janus kinase (JAK) and the activation of downstream signal transducer and activator of transcription 3 (STAT3) play important roles in the progression of pancreatic cancer [40, 41]. Inhibition of STAT3 activities with Janus Kinase-specific inhibitor AG490 suppresses the growth of pancreatic cancer cells [42]. A recent preclinical study has shown that targeting Notch and JAK2/STAT3 signaling pathways with gamma-secretase inhibitor IX and AG-490 concurrently is superior in inhibiting pancreatic cancer progression, then a single inhibitor alone [43].

Ruxolitinib is a selective inhibitor of Janus Kinase (JAK1 and JAK2) tyrosine kinase. It is currently approved for the treatment of myelofibrosis with mutation of JAK2V617F and provides significant improvement in cytokines-mediated symptoms [44]. Given patients with advance pancreatic cancer have evidence of systemic inflammations as evident by cachexia, muscle loss, and poor performance status, a phase II study was conducted in patients with metastatic pancreatic cancer that were refractory to chemotherapy. Patients were randomized to ruxolitinib plus capecitabine (n = 64) or capecitabine plus placebo (n = 63). Multivariate analysis of overall survival in subgroups of patients with CRP (c-reactive protein) more than 13 g/mL showed survival advantage in the ruxolitinib combination group as compared to placebo group with HR for death of 0.47 (95 % CI 0.26–0.85); p = 0.01 [45]. Based on this trial, a randomized, double-blind phase III study is underway evaluating ruxolitinib or placebo in combination with capecitabine in patients with advanced pancreatic cancer with serum CRP levels of ≥10 g/mL (NCT02119663).

Targeting DNA Repair-Deficient Cells

Recent work has identified DNA repair-deficient pancreatic cancers such as those with BRCA mutations to be susceptible to cell kill by platinum compounds and also by PARP inhibitors. Ongoing clinical trials are investigating these treatment strategies in patients with advanced pancreatic cancers.

Degrading Hyaluronan

Hyaluronan is the component of the stroma that is considered to establish a barrier to the effective delivery of cytotoxic drugs to tumor cells in addition to other biological functions promoting carcinogenesis and tumor progression. Preclinical studies have demonstrated that targeting the hyaluronan with hyaluronidase would increase the killing of tumor cells and improve survival of mice treated with gemcitabine. Pegylated hyaluronidase is currently being tested in two major randomized clinical trials in patients with metastatic pancreatic cancer in combination with either gemcitabine/nab-paclitaxel (supported by Halozyme) or FOLFIRINOX (supported by the Southwest Oncology Group). Interim data from the ongoing study with gemcitabine and nab-paclitaxel suggested a benefit of the pegylated hyaluronidase in patients who have high tumoral expression levels of hyaluronan measured by immunohistochemistry.

Immunotherapy

The benefits of immunotherapy have long been appreciated in hematologic malignancies and the graft versus leukemia effect of donor transfusion lymphocytes is a well-established knowledge [46]. Recent advances of immunotherapy in solid tumors are showing promising results such as Sipuleucel-T for prostate cancer [47], and ipilimumab for melanoma [48]. The recent evolution of cancer vaccines has been encouraging. GVAX is an irradiated allogeneic granulocyte-macrophage colony-stimulating factor (GM-CSF)-secreting pancreatic tumor vaccine [49]. It is administered 24 h after treatment with low-dose cyclophosphamide with intention to regulate CD8+ T cells. GVAX activates CD8+ T cells against various antigens of pancreatic cancer and mesothelin [50]. Activation of mesothelin-specific CD8-T cells has been correlated with improved disease-free survival [51]. CRS-207 is a recombinant live-attenuated, Listeria monocytogenes that has been engineered to express human cancer antigen mesothelin that get processed and get presented to major histocompatibility complex class I and class II [52]. GVAX and CRS-207 have been evaluated in pancreatic cancer in a phase II study in patients with metastatic pancreatic cancer. The use of cyclophosphamide followed by GVAX as priming vaccines and CRS-207 as a booster resulted in improved overall survival with minimum toxicity [53]. Based on this promising result, a phase 2b ECLIPSE trial has been designed for patient with metastatic pancreatic cancer with the intention to recruit 300 patients [54]. At this time the activity of immune checkpoint inhibitors have not been established in pancreatic cancer.

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