SYSTEMIC THERAPY AND NOVEL AGENTS IN THE TREATMENT OF PANCREAS CANCER

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1 SYSTEMIC THERAPY AND NOVEL AGENTS IN THE TREATMENT OF PANCREAS CANCER Eileen M. O REILLY, Maeve A. LOWERY, Andrew EPSTEIN Ghassan K. ABOU-ALFA Introduction Adenocarcinoma of the pancreas is arguably the most challenging of human malignancies. Approximately 42,000 new cases of pancreatic cancer and around 36,000 pancreatic cancer related deaths are estimated in the US in It remains the fourth most common cause of cancer death in contrast to its tenth position on the list of leading causes of cancer incidence. The understanding of the molecular pathogenesis of pancreatic adenocarcinoma has significantly improved over the last two decades and it is clear that invasive pancreatic cancer has acquired many genetic alterations by the time of clinical presentation [1-2] (Figure 1). New data in 2010 has provided a new cytotoxic option for initial therapy of advanced disease and multiple agents exploiting the genetic complexity of pancreas adenocarcinoma are in development. This review articles summarizes the state-of-the-art regarding cytotoxic and new targeted agents in the treatment of pancreas adenocarcinoma. Cytotoxic Therapy Gemcitabine was approved by the US food and drugs administration (FDA) as first-line therapy for advanced pancreatic cancer in 1997, based on a phase III trial demonstrating an improved clinical benefit rate and palliation of symptoms when compared to 5FU chemotherapy, but also demonstrating an improved median and 9-fold increased one-year survival [3]. Several classes of drugs have been evaluated in combination with gemcitabine; however, erlotinib is the only targeted agent to have received FDA approval to date for use in advanced pancreatic adenocarci-noma [4]. Several trials have evaluated the addition of platinum containing regimens to gemcitabine. Meta-analyses have shown a survival benefit to the addition of platinum compounds in selected patients [5-6]; however, a recently reported phase III trial of 400 patients with advanced pancreatic cancer treated with gemcitabine monotherapy vs. gemcitabine and cisplatin showed no overall or progression-free survival benefit to the combination arm. Gemcitabine in combination with multiple other cytotoxic agents including 5FU, pemetrexed, docetaxel, exatecan and irinotecan have similarly failed to show a significant survival benefit in advanced disease. Several possible mechanisms accounting for the relative chemotherapy resistance of pancreatic adenocarcinoma have been suggested, including increased DNA repair, alterations in apoptotic pathways, enhanced inactivation of active drug metabolites and abnormal membrane receptor transport. Department of Medicine Section of Gastrointestinal Oncology Memorial Sloan-Kettering Cancer Center New York, NY, USA New Directions in Cytotoxic Therapy Agents targeting both the stroma and malignant cells have an obvious attraction in pancreas adenocarcinoma. Nab-paclitaxel (Abraxane, ABI-007) an albumin-bound nanoparticle form of paclitaxel, is such a drug. SPARC (secreted protein rich in cysteine) is expressed on the surface of both pancreatic cancer cells and in the stromal matrix and is associated with worse clinical outcomes. Von Hoff and colleagues have reported their recent phase I-II experience of nab-paclitaxel combined with gemcitabine in 63 patients with previously untreated metastatic pancreas cancer [7]. Results are interesting with significant activity seen by conventional response S20

2 ED UC ATI ONAL CON FER EN CE Embryo Pdx-1 Sonic hedgehog Serine/threonin e kinase 11 PANIN-1 K-ras Telomere shortening P21 Her2/neu Mucin 1 (MUC 1) MUC 6 Trefoil factor 1(TTF 1) P16 S100A11 MUC5AC S100A6 PANIN-2 Cyclin D1 COX-2 Hes 1 (Hair and enhancer of split 1) Notch 1 Pepsinogen C Kruppel-like factor 4 HOXA5 GATA5 Gastrin Villin-1 Villin-2 Cellular retinoic acid binding protein PANIN-3 P53 SMAD4 BRCA2 S100P SHH SialyT Maspin MUC4 TCLC1 FAP Adapted from: Ghaneh P, Costello E, Neoptolemos JP: Biology and management of pancreatic cancer, Gut 2007; 56 (8): FIGURE 1. Key molecular events in the development of pancreatic adenocarcinoma. assessment, PET imaging and with Ca 19-9 biomarker profiling. In particular, SPARC positive tumors appear to benefit more from this drug although SPARC negativity did not preclude benefit with median progression-free survivals of 6.2 and 4.8 months reported respectively. For all patients the median overall survival was over 9 months. These results have led to an ongoing randomized phase III trial of gemcitabine and nab-paclitaxel compared to gemcitabine alone in untreated S21

3 metastatic pancreas adenocarcinoma. Results are anticipated in 2011/12. In the second-line setting (following-gemcitabine progression), nab-paclitaxel met its phase II primary endpoint of 6-month overall survival (median 7.2 months) in 20 advanced pancreas cancer patients, whose SPARC correlative analysis is ongoing [8]. Another paclitaxel formulation is the cationic liposome Endo-Tag-1, which targets activated negatively charged tumor cells and has demonstrated both cytotoxic and vascular effects in a European phase II [9]. Further development in either a randomized phase II or phase III setting is planned. Arguably the most striking pancreas cancer trial results ever reported were presented at the 2010 American Society of Clinical Oncology meeting. The PRODIGE 4/ACCORD 11 trial compared FOLFIRINOX to gemcitabine in the previously untreated metastatic disease setting [10]. Patients with an ECOG performance status of 0-1 (38% ECOG 0), were randomized to either FOLFIRINOX (oxaliplatin 85 mg/m 2, irinotecan 180 mg/m 2, and leucovorin 400 mg/m 2 on day 1 of a biweekly cycle, followed by a bolus of 400 mg/m 2 and a 46-hour continuous 5-FU infusion at 2,400 mg/m 2 ) or standard dose gemcitabine. Three hundred and forty-two patients were enrolled. At a planned interim analysis after 167 events (death), the data and safety monitoring board closed the study as the primary study endpoint was met. In the FOLFIRINOX arm, the response rate was 31.6% (versus 9.4% for gemcitabine), progression-free survival was 6.4 months (versus 3.3 months), and the median overall survival was 11.1 months versus 6.8 months, HR = 0.57, p < Grade 3-4 fatigue and gastrointestinal side effects were more common in the FOLFIRINOX arm. Additionally, grade 3-4 neutropenia occurred in 46% of the combination arm versus 19% in gemcitabine-treated patients, and febrile neutropenia rates were 5.4% and 0.6%, respectively, both statistically significant. FOLFIRINOX is therefore the first non-gemcitabine containing regimen to demonstrate statistically significant response rate, progression-free survival and overall survival benefit over single-agent gemcitabine in pancreas cancer, and for selected patients can be considered a standard option. Further development of this regimen is ongoing in the adjuvant and gemcitabine-refractory disease settings. At a national level in the US, a randomized phase II trial is planned to evaluate the comparative efficacy and safety of FOLFIRINOX and several emerging gemcitabine based combinations. Such a trial will provide important insights into usability of this regimen in a prospective US-based setting. Targeted Approaches for Pancreatic Cancer Jones et al. in their analysis of 24 human pancreas genomes have provided important information pertaining to the molecular signature of pancreas adenocarcinoma [11]. Twelve common signaling pathways involved in cellular repair mechanisms, metabolism, cell-cycle regulation, genomic repair, metastasis, apoptosis, etc., are affected in over two-thirds of pancreas cancer genomes. An average of 63 genetic alterations per each cancer was observed, mostly point mutations, however, it is estimated that only 8-15 of these mutations are driver mutations. Current therapeutic approaches have attempted to exploit some of these vulnerabilities. Selected targets and agents in development are highlighted in Table I. S22

4 TABLE 1 SELECTED THERAPEUTIC TARGETS/AGENTS IN DEVELOPMENT IN PANCREAS ADENOCARCINOMA Target Drug Class Drug RAS Farnesyl transferase inhibitor Tipifarnib Oncolytic virus Reovirus EGFR Antibody to EGFR Cetuximab Tyrosine kinase inhibitor Erlotinib Her-2/neu Antibody to HER-2 Trastuzumab Lapatinib IGF1-R Antibody to IGF1-R AMG 479 MK 0646 Tyrosine kinase inhibitor PQIP Hedgehog Small molecule inhibitor GDC-0449 LDE 225 Angiogenesis VEGF Bevacizumab Sorafenib Aflibercept Axitinib Vatalanib Vandetanib SRC SRC/Bcr-Abl inhibitor Dasatinib AZD 0530 TRAIL DR4, 5 antibody AMG 655 Mapatumumab Poly ADP Ribose PARP inhibitor AZD 2281 Polymerase (PARP) ABT-888 BS1-201 NF-kB/IkB Inhibitor Curcumin Genestein Phy906 Ras The majority of pancreas adenocarcinomas, up to 90%, have a mutated k-ras oncogene. A mutated K-ras causes persistent activation of the membrane-bound k-ras oncoprotein and relative insensitivity to ras-mediated signals. For many years targeting ras has been a relatively unproductive with monotherapy and combination studies of farnesyl protein transferase inhibitors having shown limited activity [12]. However, newer generations of anti-ras agents (e.g., salirasib, reovirus) are in development given the ubiquity and attractiveness of this target. Reovirus (respiratory enteric orphan virus) is a relatively benign human pathogen. Cells with an activated ras pathway are unable to respond to a reovirus infection with consequent viral replication and cell lysis. In vitro and in vivo studies provide support for this approach and clinical trials of reovirus in combination with systemic therapy in advanced pancreas cancer are commencing [13]. S23

5 EGFR Two classes of drugs interfering with EGFR activation have been evaluated in pancreatic cancer. Firstly, monoclonal antibodies which bind to the extracellular domain of the EGFR, interfering with ligand binding and thereby preventing activation, and secondly small molecules which bind competitively to the intracellular ATP binding site of the tyrosine kinase domain, thereby preventing activation of downstream signals. Cetuximab is a chimeric monoclonal antibody with high affinity and specificity for the extracellular domain of the EGFR receptor. A phase II study of gemcitabine and cetuximab for metastatic and locally advanced pancreatic cancer reported interesting activity (12.2% PR, 63.4% SD) with a median time to tumor progression of 3.8 months and a median overall survival of 7.1 months [14]. A subsequent phase III trial, SWOG S0205 study, randomized 766 patients with metastatic or locally advanced pancreatic cancer to gemcitabine alone or gemcitabine plus cetuximab [15]. This study failed to show a statistically significant benefit for the addition of cetuximab to gemcitabine. Median overall survival was six months in the gemcitabine arm and 6.5 months in the gemcitabine plus cetuximab arm (p = 0.14, HR 1.09). Erlotinib, a small molecule tyrosine kinase inhibitor, has demonstrated more promising results in clinical trials, leading to FDA approval in 2005 for treatment of locally advanced, unresectable or metastatic pancreatic carcinoma. The NCIC CTG PA.3 was a double-blind, placebo-controlled, phase III trial of erlotinib plus gemcitabine in 569 patients with stage III or IV disease [4]. Overall survival was statistically significantly longer in the erlotinib and gemcitabine arm versus gemcitabine and placebo arm with median survival 6.24 months versus 5.91 months and one-year survival rates of 23% and 17% respectively (p =.023). Given the very modest differences in outcomes between the two arms, many have argued regarding the overall clinical significance of these results. However, it is clear that for patients who experienced a significant rash, substantial benefit accrued, with the median survival for this subgroup recorded at over 10 months. A retrospective analysis in the 20% of patients in whom tissue was available indicated a non-statistical trend for benefit in favor of wild-type k-ras status [16]. Anti-vascular Agents A phase II trial of gemcitabine in combination with bevacizumab in selected 52 patients with metastatic pancreatic cancer and ECOG 0-1 reported a median overall survival of 8.8 months, with a median progression-free survival of 5.4 months [17]. These provocative results led to a randomized phase III trial of gemcitabine plus bevacizumab or placebo, CALGB 80303, in 602 patients with advanced pancreatic cancer. No benefit was seen with the addition of bevacizumab to gemcitabine; median overall survival was 5.2 vs. 5.8 months, with median progression free survival 4.8 vs. 4.3 months [18]. Pre-clinical data has also suggested synergy between combined EGFR and VEGF inhibition; however, a phase III trial of gemcitabine, erlotinib and bevacizumab demonstrated an improvement in progressionfree survival but no benefit in overall survival to the addition of bevacizumab [19-20]. Similarly a phase III trial of the anti-angiogenic agent axitinib, a dual inhibitor of PDGF and VEGF, was recently discontinued due to lack of efficacy as S24

6 was a phase III trial of gemcitabine with or without VEGF-trap (aflibercept), which was also stopped early by the Data and Safety monitoring board. The collective interpretation of these four phase III trials of anti-vascular therapy in the front-line is that despite compelling preclinical data, anti-vascular therapy has no role in treating pancreas cancer. Hedgehog and Embryonic Pathways The hedgehog proteins are a family of signaling proteins involved in embryonic and organ development [21]. Altered functioning of the hedgehog signaling pathway has been observed in pancreas adenocarcinoma and in pancreas cell lines [22-23]. IPI-926, a semi-synthetic cyclopamine derivative, has been assessed in mouse models of gemcitabine-resistant pancreas adenocarcinoma and results in altered tumor vascular density and reduced desmoplastic tumor stroma facilitating improved gemcitabine delivery to tumor [24]. GDC-0449, an oral small molecule inhibitor of hedgehog signaling by blockade of patched and smoothened, has been assessed in a phase I trial of 33 patients [22]. In diseases where embryonic signaling pathways are important, e.g., basal cell cancer and medulloblastoma, significant activity with this drug has been observed [25]. Pancreas cancer is an obvious target and trials are underway with this drug and related compounds to ascertain the role of targeting embryonic pathways in these disease. PARP Inhibition Poly (ADP ribose) polymerase (PARP) is a family of enzymes involved in cellular signaling and act as a cellular sensitizer for DNA breaks and facilitate repair using base excision repair (BER), homologous recombination repair and non-homologous end-joining (NHEJ) pathways. Increased PARP activity confers tumor cell resistance to DNA-damaging agents. BRCA 1 and 2 proteins are involved in DNA repair and maintain the integrity of the genome. PARP inhibitors may have single agent activity in tumors with identified DNA repair defects, e.g., BRCA mutations, leading to gross genetic instability and cell death, a concept known as synthetic lethality and such cells are extremely sensitive to PARP inhibitors [26-27]. Five- 7% of patients with pancreas adenocarcinoma may harbor a BRCA mutation, particularly BRCA-2 [28]. Increased sensitivity to DNA cross-linking agents, e.g., cisplatin, mitomycin, has been demonstrated in other BRCA-associated malignancies; anecdotal reports indicate that this may also be true for BRCA-associated pancreatic cancer. Several early trials are underway evaluating the role of PARP inhibition in a broader population of patients with pancreas cancer. Conclusions The last decade in pancreas cancer research has established the value of gemcitabine as a therapy for all stages of pancreas adenocarcinoma. For selected patients gemcitabine-based cytotoxic combinations have a role. To date, the track record for targeted agents in pancreatic cancer has been disappointing, despite extensive evaluation of many classes of agents. Currently, erlotinib, combined with gemcitabine, remains the only targeted therapy licensed for treatment of pancreatic cancer. FOLFIRINOX is an active non-gemcitabine-containing cytotoxic regi- S25

7 men that is a new option for selected good performance status patients and there is considerable hope that gemcitabine combined with nab-paclitaxel may establish itself as a standard option. Jone et al. have provided insights into the molecular pathogenesis of pancreas cancer and have resulted in a re-reflection on therapeutic approaches currently employed in the treatment of pancreas cancer [11]. It is clear that targeting a single-pathway in isolation is of limited value; however, selective combinations of cytotoxics combined with new agents may provide some incremental gains over the next several years. References 1. Ghaneh P, Costello E, Neoptolemos JP. Biology and management of pancreatic cancer. Gut Aug 2007 ; 56 (8) : Maitra A, Kern S, Hruban R. Molecular pathogenesis of pancreatic cancer. Best Practice & Research Clinical Gastroenterology 2006 ; 20 (2) : Burris HA, Moore MJ, Andersen J et al. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer : A randomized trial. Journal of Clinical Oncology Jun 1997 ; 15 (6) : Moore MJ, Goldstein D, Hamm J et al. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer : a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol May ; 25 (15) : Heinemann V, Boeck S, Hinke A, Labianca R, Louvet C. Meta-analysis of randomized trials : evaluation of benefit from gemcitabine-based combination chemotherapy applied in advanced pancreatic cancer. Bmc Cancer 2008 ; 8 : Sultana A, Smith CT, Cunningham D, Starling N, Neoptolemos JP, Ghaneh P. Metaanalyses of chemotherapy for locally advanced and metastatic pancreatic cancer. J Clin Oncol Jun ; 25 (18) : Von Hoff DD, Ramanathan R, Borad M et al. SPARC correlation with response to gemcitabine (G) plus nab-paclitaxel (nab-p) in patients with advanced metastatic pancreatic cancer: A phase I/II study. J Clin Oncol (Meeting Abstracts) 2009 May 20 ; 27 (15S) : Hosein PJ, Lopes GD, Jr., Gomez CM et al. A phase II trial of nab-paclitaxel (NP) in patients with advanced pancreatic cancer (PC) who have progressed on gemcitabine (G)-based therapy. J Clin Oncol (Meeting Abstracts) 2010 May 20 ; 28 (15S) : Loehr M, Bodoky G, Folsch U et al. Cationic liposomal paclitaxel in combination with gemcitabine in patients with advanced pancreatic cancer: A phase II trial. J Clin Oncol (Meeting Abstracts) May 20 ; 27 (15S) : Conroy T, Desseigne F, Ychou M et al. Randomized phase III trial comparing FOLFIRINOX (F: 5FU/leucovorin [LV], irinotecan [I], and oxaliplatin [O]) versus gemcitabine (G) as first-line treatment for metastatic pancreatic adenocarcinoma (MPA) : Preplanned interim analysis results of the PRODIGE 4/ACCORD 11 trial. J Clin Oncol (Meeting Abstracts) May 20 ; 28 (15S) : Jones S, Zhang X, Parsons DW et al. Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science (New York, N.Y. Sep ; 321 (5897) : Van Cutsem E, van de Velde H, Karasek P et al. Phase III trial of gemcitabine plus tipifarnib compared with gemcitabine plus placebo in advanced pancreatic cancer. J Clin Oncol 2004 Apr 15 ; 22 (8) : Kelly K, Nawrocki S, Mita A, Coffey M, Giles FJ, Mita M. Reovirus-based therapy S26

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