November marks Pancreatic Cancer Awareness Month. According to the American Cancer Society, more than 44,000 new cases of pancreatic cancer will be diagnosed in the U.S. and over 37,000 deaths are expected from the disease in 2011. It has the highest mortality rate of all major cancers; 74% of patients die within the first year of diagnosis and 94% of patients die within five years[i]. Out of the top 15 cancer sites, pancreatic cancer is the only one with a five-year relative survival rate in the single digits [6%][ii].
Visibility for the disease is on the rise following the recent deaths of Apple, Inc. (AAPL) co-founder Steve Jobs and Ralph Steinman, a cell biologist who died several days before being named one of three winners for the 2011 Nobel Prize in Medicine. While awareness is increasing, there is an urgent need for more effective treatments and diagnostics to detect the disease earlier due to the fact that the number of new pancreatic cancer cases is projected to increase by 55% from 2010 to 2030[iii].
The disease remains one of the most difficult to treat due to its extreme resistance to treatment and few early symptoms. At the time of initial diagnosis, 50% of patients have distant metastases to the liver or peritoneal surface, and more than 80% of the remaining patients have locally advanced tumors [confined to the pancreas but unresectable][iv]. The majority of pancreatic tumors [95%] are adenocarcinomas that mainly develop from exocrine cells in the tissues of the pancreas[v]. The tumors are characterized by an aggressive behavior with a fast progression rate that makes them highly metastatic. In contrast, neuroendocrine tumors of pancreatic origin [pancreatic NET, also known as islet cell tumors] are not as common [<2%] and are considered less deadly[vi].
Illustrating the difference between the two, Hollywood actor Patrick Swayze was diagnosed with stage IV pancreatic exocrine cancer that had already spread to the liver in March 2008 and lost his battle with the disease in September 2009 at the age of 57. Apple’s Steve Jobs underwent surgery for pancreatic NET in 2004 and didn’t succumb to the disease until October 2011 at the age of 56.
Treatment for Organ Confined Disease
In terms of treatment, surgical removal of the tumor represents the best option for pancreatic cancer patients without invasion into surrounding organs or distant metastasis. Unfortunately, only 15–20% of all patients are candidates for potentially curative surgery[vii]. Depending on the tumor localization, pancreaticoduodenectomy [Whipple procedure], distal, or total pancreatectomy can be performed. However, even with an optimal curative surgery, metastases often occur. Median survival time without evidence of recurrent disease is 21.2 months after surgical resection[viii].
Treatment for Locally Advanced/Metastatic Disease
For locally advanced or metastatic disease, an effective single agent for pancreatic cancer remains elusive and treatment is still palliative rather than curative. Since its approval in 1997, Eli Lilly’s (LLY) Gemzar® [gemcitabine] is the only single agent that improves symptoms and overall survival [OS] in patients with locally advanced or metastatic pancreatic exocrine cancer. However, gemcitabine is associated with a modest median OS of 5.7 months and one-year probability of survival rate of 18%[ix]. No confirmed objective tumor responses were observed in the pivotal study.
Beyond Single Agent Gemcitabine
At least 35 Phase II trials of gemcitabine-containing regimens and 11 randomized Phase III trials have been performed to improve the efficacy of gemcitabine alone, but the progress to date has been incremental at best[x]. In these 46 trials, overall response rates ranged from 5% to 58% in the Phase II studies and 4.4% to 38.5% in the Phase III studies. Median OS ranged from 4 months to 13.1 months in the Phase II studies and 5.4 months to 9 months in the Phase III studies. Inclusion of heterogeneous patient populations in many of these studies may have confounded the results, as the median survival time for patients with metastatic disease and locally advanced disease is 3–6 and 9-13 months, respectively[xi]. The only successful combination approved by the FDA in 2005 is gemcitabine plus Roche/Astellas Pharma’s Tarceva® [erlotinib], which modestly increased the median OS to 6.4 months and one-year survival to 23%.
Hope on the Horizon
Despite the long list of past failures, drug developers continue to explore new options for treating pancreatic cancer and more than a dozen new treatments are currently being evaluated in clinical trials [see Table 1]. One product was recently approved and several programs have demonstrated encouraging results with data from pivotal trials due in the next 6-12 months. While a comprehensive review of investigational pancreatic cancer therapies is beyond the scope of this article, we briefly highlight some of the more high profile pancreatic treatments below:
Amgen, Inc. (AMGN)
Amgen is developing AMG 479, an investigational fully human monoclonal antibody that targets type 1 insulin-like growth factor receptor [IGF-1R], which plays an important role in the regulation of cell growth and survival. At the 2010 American Society of Clinical Oncology [ASCO] Annual Meeting, Amgen announced results from a Phase 2 study demonstrating that the addition of AMG 479 to gemcitabine resulted in an OS rate at six months of 56.6% versus 50.1% with gemcitabine alone[xii]. Median OS was 7.3 months versus 6.2 months in the gemcitabine arm. Amgen initiated a Phase III trial with AMG 479 for metastatic pancreatic cancer in the second quarter of 2011 with data expected in late 2013 or 2014 [ClinicalTrials.gov identifier NCT01231347]. This trial focuses on metastatic disease and therefore should represent a homogeneous patient population where the median OS is expected to be 3–6 months in the control arm.
Celgene Corporation (CELG)
Historically known more for its franchise in treating blood cancers, Celgene moved into the realm of solid tumors through its 2010 acquisition of Abraxis BioScience, Inc. for $2.9 billion. As a result, Celgene is now developing Abraxane® [paclitaxel protein-bound particles for injectable suspension] for the treatment of metastatic pancreatic cancer. Abraxane is currently approved for the treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy[xiii].
In October 2011, positive Phase I/II study results with Abraxane in combination with gemcitabine in 67 patients with advanced pancreatic cancer were published in the Journal of Clinical Oncology[xiv]. In the Phase II component of the study, the overall response rate was 48% [21/44 patients], median OS was 12.2 months, and the one-year survival rate for patients was 48%. This compares favorably with the median OS of 5.7 months and one-year probability of survival rate of 18% with single-agent gemcitabine.
The combination of Abraxane and gemcitabine is now the treatment arm of an ongoing, international, randomized Phase III clinical trial for patients with metastatic pancreatic cancer [ClinicalTrials.gov identifier NCT00844649]. Importantly, this study specifically excludes patients with only locally advanced disease and therefore represents a homogeneous patient population where the median OS is expected to be 3–6 months in the control arm.
Clovis Oncology, Inc. (private)
In November 2009, Clovis licensed rights from Clavis Pharma for CO-101 in the U.S., E.U., and select other countries. CO-101 is an investigational, lipid-conjugated derivative of gemcitabine, currently in a pivotal Phase II randomized, open-label, multicenter study comparing CO-101 with gemcitabine as first-line therapy in patients with metastatic pancreatic adenocarcinoma [ClinicalTrials.gov identifier NCT01124786]. CO-101 is designed to improve upon the efficacy of gemcitabine by enabling the drug to enter cancer cells without requiring membrane expression of transporter proteins. As a hydrophilic molecule, the entry of gemcitabine into tumor cells is dependent upon the expression of specific membrane transporter proteins, particularly human equilibrative nucleoside transporter 1 [hENT1]. Data from the pivotal Phase II trial are expected in the first half of 2012 and the inclusion criteria for only Stage IV patients [metastatic] represents a homogeneous population to study in this trial.
In April 2010, Clovis Oncology, Inc. and Ventana Medical Systems, Inc. entered into a collaboration for the development of a hENT1 immunohistochemistry [IHC] assay, which will be used in Clovis' CO-101 clinical trials to identify patients with low level tumor expression of hENT1 protein. Approximately 50% of pancreatic cancer patients have been shown to have low tumor expression of hENT1 and low levels of tumor hENT1 expression have been shown to correlate with poor survival outcomes after gemcitabine therapy[xv]. These observations support the hypothesis that limited tumor uptake of gemcitabine in hENT1-low patients is responsible for a poor treatment effect in many patients and is an excellent example of a biomarker-driven clinical strategy.
Novartis AG (NVS)
In May 2011, the FDA approved Afinitor® (everolimus) by Novartis AG (NVS) for the treatment of progressive pancreatic NET in patients with unresectable, locally advanced or metastatic disease. Afinitor is an allosteric inhibitor of mammalian target of rapamycin [mTOR], a serine-threonine kinase, downstream of the PI3K/AKT pathway that is dysregulated in several human cancers. Approval of Afinitor represents the first new therapy for pancreatic NET in the US in nearly 30 years[xvi]. The approval was based on Phase III data from the RADIANT-3 [RAD001 In Advanced Neuroendocrine Tumors] trial, showing treatment with Afinitor plus best supportive care more than doubled median progression-free survival [PFS], or time without tumor growth, from 4.6 to 11.0 months and reduced the risk of cancer progression by 65% when compared with placebo in patients with advanced pancreatic NET.
Threshold Pharmaceuticals, Inc. (THLD)
At the 2011 ASCO Gastro Intestinal Cancers Symposium, Threshold Pharmaceuticals presented results with its hypoxia-activated prodrug, TH-302, in combination with gemcitabine in 47 patients with previously untreated, locally advanced, unresectable or metastatic pancreatic adenocarcinoma[xvii]. Of the 43 evaluable patients, one patient [2%] demonstrated a complete response as measured by RECIST [Response Evaluation Criteria In Solid Tumors] and 8 patients [19%] had a partial response. In the gemcitabine plus TH-302 treatment arms, median OS was 8.5 months. While this compares favorably with the median OS of 5.7 months with single-agent gemcitabine, recall that in 35 Phase II trials of gemcitabine-containing regimens in heterogeneous patient populations the median OS ranged from 4 months to 13.1 months.
In June 2011, Threshold Pharmaceuticals completed enrollment of patients with first-line, locally advanced, unresectable or metastatic pancreatic adenocarcinoma. The company expanded the study’s enrollment target from the original 165 patients to at least 200 patients. As mentioned earlier, inclusion of a heterogeneous patient population may confound the study results [expected before the end of 2011], as the median OS for patients with metastatic disease and locally advanced disease is different.
As we approach Pancreatic Cancer Awareness Month, visibility for the disease is on the rise following recent high-profile deaths. Despite numerous late-stage failures, more than a dozen products are currently in clinical trials with key data expected in the next 6-12 months. Going forward, early detection using biomarkers, more effective treatments, and novel drug targets could provide new hope for the treatment of this deadly disease.
NOTE: For more information, please visit the Pancreatic Cancer Action Network [http://www.pancan.org], a national organization creating hope in a comprehensive way through research, patient support, community outreach and advocacy for a cure.
Table 1. Baker’s Dozen in Active Clinical Development for Pancreatic Cancer
|Aduro BioTech, Inc. (private)||Cancer Vaccines CRS-207 and GVAX Pancreas||Immunotherapy||Phase II|
|Amgen (AMGN)||AMG 479 (ganitumab)||Immunotherapy||Phase III|
|Celgene (CELG)||Abraxane||Chemotherapy||Phase III|
|Celgene (CELG) and GlobeImmune (private)||GI-4000||Immunotherapy||Phase II|
|Clovis Oncology||CO-101||Chemotherapy||Phase II|
|Immunomedics (IMMU)||90Y-hPAM4||Radiopharmaceutical||Phase Ib|
|Infinity Pharma (INFI)||IPI-926||Signal transduction inhibitor||Phase Ib/II|
|NewLink Genetics (private)||HyperAcute®-Pancreas (Algenpantucel-L)||Immunotherapy||Phase III|
|Novartis AG (NVS) and Bayer Schering Pharma AG (BAYRY.PK)||Vatalanib (PTK787/ZK-222584)||Kinase inhibitor||Phase I/II|
|Oncolytics Biotech (ONCY)||Reolysin®||Reovirus||Phase II|
|Pharmacyclics (PCYC)||PCI-27483||Signal transduction inhibitor||Phase II|
|Seattle Genetics (SGEN)/Astellas Pharma (ALPMY.PK)||ASG-5ME||Immunotherapy – drug conjugate||Phase I|
|Threshold Pharmaceuticals (THLD)||TH-302||Chemotherapy||Phase II|
[ii] SEER Cancer Statistics Review, 1975-2007, National Cancer Institute. Bethesda, MD. Altekruse SF, Kosary CL, Krapcho M, et al (eds). http://seer.cancer.gov/csr/1975_2007/, based on November 2009 SEER data submission, posted to the SEER web site, 2010.
[iii] Future of cancer incidence in the United States: burdens upon an aging, changing nation. Smith BD, Smith GL, Hurria A, Hortobagyi GN, Buchholz TA. J Clin Oncol. 2009 Jun 10;27(17):2758-65. Epub 2009 Apr 29.
[iv] Pancreatic adenocarcinoma. Howard TJ. Curr Probl Cancer. 1996 Sep-Oct;20(5):281-328.
[v] PET and PET-CT of malignant tumors of the exocrine pancreas [Article in German]. Reske SN. Radiologe. 2009 Feb;49(2):131-6.
[vi] Population-based study of islet cell carcinoma. Yao JC, Eisner MP, Leary C, Dagohoy C, Phan A, Rashid A, Hassan M, Evans DB. Ann Surg Oncol. 2007 Dec;14(12):3492-500. Epub 2007 Sep 26.
[vii] Pancreatic Cancer. U.S. News and World Report Health. http://health.usnews.com/health-conditions/cancer/pancreatic-cancer/treatment
[viii] Outcomes following resection of pancreatic adenocarcinoma: 20-year experience at a single institution. Helm JF, Centeno BA, Coppola D, Druta M, Park JY, Chen DT, Hodul PJ, Kvols LK, Yeatman TJ, Carey LC, Karl RC, Malafa MP. Cancer Control. 2008 Oct;15(4):288-94.
[x] Cytotoxic chemotherapy for pancreatic cancer: Advances to date and future directions. Xiong HQ, Carr K, Abbruzzese JL. Drugs. 2006;66(8):1059-72. Review.
[xi] Efficacy and factors affecting outcome of gemcitabine concurrent chemoradiotherapy in patients with locally advanced pancreatic cancer.
Huang PI, Chao Y, Li CP, Lee RC, Chi KH, Shiau CY, Wang LW, Yen SH. Int J Radiat Oncol Biol Phys. 2009 Jan 1;73(1):159-65. Epub 2008 May 26.
[xii] A placebo-controlled, randomized phase II study of conatumumab (C) or AMG 479 (A) or placebo (P) plus gemcitabine (G) in patients (pts) with metastatic pancreatic cancer (mPC). H. L. Kindler, D. A. Richards, J. Stephenson, L. E. Garbo, C. S. Rocha Lima, H. Safran, J. S. Wiezorek, E. G. Feigal, S. Bray, C. Fuchs. J Clin Oncol 28:15s, 2010 (suppl; abstr 4035).
[xiii] Abraxane prescribing information at http://www.abraxane.com/docs/Abraxane_PrescribingInformation.pdf
[xiv] Gemcitabine Plus nab-Paclitaxel Is an Active Regimen in Patients With Advanced Pancreatic Cancer: A Phase I/II Trial. Von Hoff DD, Ramanathan RK, Borad MJ, Laheru DA, Smith LS, Wood TE, Korn RL, Desai N, Trieu V, Iglesias JL, Zhang H, Soon-Shiong P, Shi T, Rajeshkumar NV, Maitra A, Hidalgo M. J Clin Oncol. 2011 Oct 3. [Epub ahead of print]
[xv] Human equilibrative nucleoside transporter 1 levels predict response to gemcitabine in patients with pancreatic cancer. Farrell JJ, Elsaleh H, Garcia M, Lai R, Ammar A, Regine WF, Abrams R, Benson AB, Macdonald J, Cass CE, Dicker AP, Mackey JR. Gastroenterology. 2009 Jan;136(1):187-95. Epub 2008 Oct 7.
[xvi] Company press release May 6, 2011 - Novartis gains FDA approval for Afinitor® as first new treatment in nearly three decades for patients with advanced pancreatic NET
[xvii] Clinical benefits TH-302, a tumor-selective, hypoxia-activated prodrug, and gemcitabine in first-line pancreatic cancer (PanC). M. J. Borad, E. G. Chiorean, J. R. Molina, A. C. Mita, J. R. Infante, W. R. Schelman, A. M. Traynor, G. Vlahovic, D. S. Mendelson, S. G. Reddy. J Clin Oncol 29: 2011 (suppl 4; abstr 265).
by Michael D. Becker and Janet L. Dally
MD Becker Partners, LLC
STOCKHOLM, SWEDEN –One of the goals of personalized medicine is that genomic sequencing of a patient’s tumor may identify actionable/druggable targets, and therapies aimed at those targets will improve outcomes and possibly cure for cancers. There have been some spectacular successes in personalized medicine – most notably Herceptin for HER2-positive breast cancer and Gleevec for chronic myelogenous leukemia and gastrointestinal stromal tumor (GIST).
But, according to Gordon Mills, MD, Institute for Personalized Cancer Therapy, M.D. Anderson Cancer Center, Houston TX, “The number of successes, and in most cases these are only found in small subpopulations of patients and are transient, are far outnumbered by spectacular failures…. We are far from overcoming the hurdles associated with the implementation of personalized cancer therapy.”
At the recently held European Multidisciplinary Cancer Congress (EMCC) in Stockholm, Sweden, Dr. Mills reviewed the many hurdles investigators face in personalized medicine research including:
After reviewing these challenges in some depth, Dr. Mills described a pilot program initiated at the M.D. Anderson Cancer Center on personalized medicine. The program services about 30,000 patients per year in which a patient’s tumor undergoes genomic sequencing to identify actionable/druggable genetic aberration, and then if a drug is available for the identified target, a clinical trial of 1 is undertaken.
Mass array testing of 44 genes was undertaken in 996 patients to search for actionable mutations. The investigators identified 457 cancer-associated genes and discovered that 122 of them are frequently found in epithelial tumors. However, according to the investigators, most of the mutations were rare and less than 25% of those identified were actionable. Dr. Mills said this percentage is much lower than has been reported in the literature.
The most common mutation was p53, but there is no targeted therapy for this aberration, he said. Fifteen percent of mutations were RAS, which are associated with resistance. He pointed out that most patients with advanced disease have the p53 mutation; but that most mutations are not “drivers,” but rather “passengers”. Investigators at M.D. Anderson are working on methods of distinguishing between passenger and driver mutations.
Dr. Mills also emphasized the difficulty in finding actionable mutations. For instance, out of the 16 most common mutations in acute myelogenous leukemia and the 237 most common mutations in lung cancer, less than 6 from both groups are actionable.
In addition, once an actionable/druggable target is identified, costs of targeted therapy can be quite high. Given that most targeted therapies achieve short-lived responses in a small subpopulation of patients, value for dollar spent becomes questionable for payers. Even though the cost of genomic sequencing has come down to under $10,000 per patient, the costs of bioinformatics or data storage and handling can be more expensive than the sequencing itself.
“It is estimated that even the eventual $1,000 genome sequencing will cost $100,000 to manage and interpret,” Dr. Mills stated.
He cautioned about all the hype surrounding personalized medicine and the false hopes this has created for patients. While there is incredible excitement about the potential implementation of personalized cancer therapy, he said “it is easy to contend that the excitement is massively overblown.”
Studies at EMCC Further Reflect the Challenges of Personalized Medicine
Several presentations with failed or suboptimal results reflected the inherent challenges in personalized medicine. In one study of patients with renal cell carcinoma, genomic sequencing and identification of single nucleotide polymorphisms (SNPs) failed to identify a subset of patients who would benefit from therapy with axitinib and also failed to show an effect on hypertension, which is a marker for response to axitinib. Axitinib is a selective inhibitor of VEGF receptors 1, 2, and 3. (Abstract #7103, presented by Bernard Escudier, MD, Institut Gustave Roissy, Villejuif, France)
The PICCOLO study of patients with chemoresistant colorectal cancer found that the benefit of anti-EGFR therapy with panitumumab was not universal in patients with wild-type KRAS (the subset who should derive treatment benefit), because 29% of patients with wild-type KRAS were found to have other mutations that conferred resistance to the drug. These disappointing findings led study author Matt Seymour, MD, University of Leeds, U.K., to say, “There was no benefit and maybe even harm of anti-EGFR therapy in patients selected for therapy by KRAS wild-type status.” This study is an example of activation of compensatory pathways when a specific mutation is targeted, which appears to explain emergence of resistance. (Abstract #6007)
BOLERO-2, a large Phase III trial of postmenopausal women with estrogen receptor-positive breast cancer resistant to the aromatase inhibitors letrozole or anastrozole, showed that everolimus added to another aromatase inhibitor, exemestane, was able to overcome hormonal resistance. Supposedly, the cross talk between everolimus (an mTOR inhibitor) and exemestane (an aromatase inhibitor) explains this result. (Presented by Jose Baselga, MD, Massachusetts General Hospital, Harvard Medical School, Boston, MA; Abstract #9LBA)
Further support of this thesis comes from another study presented at the meeting by G.S. Bhattacharyya, MD, Orchid Nursing Home, Kolata, India, showing that sirolimus (another mTOR inhibitor) given with tamoxifen overcomes resistance to tamoxifen alone (Abstract #16LBA).
In a separate study of sorafenib, a multi-targeted tyrosine kinase inhibitor (LBA27), enrichment of the study population for KRAS mutational status did not improve outcomes. Outcomes were similar for wild-type KRAS and mutated KRAS in patients with stage III or IV non small-cell lung cancer (NSCLC). (Presented by A.M. Dingemans, MD, Maastricht University Medical Center, The Netherlands)
In a separate presentation on sarcoma, Jean-Yves Blay, MD, University of Lyon, France, explained that at least five genetic subtypes of sarcoma have been identified, along with complex genetic alterations. He said that, so far no targeted therapy has made substantial inroads in extending survival. However, the search continues. “Molecular subtypes will drive therapy [of sarcoma],” he predicted.
Similarly, genetic insights into ovarian cancer have led to improved understanding of the biology of ovarian cancer, but to date, no targets for small molecule inhibitors have been identified, said Michael Bookman, MD, University of Arizona Cancer Center, Tucson, AZ.
By Alice Goodman
Though oncologists are well aware of molecular-level testing, the concept may be new for patients. When clinicians discuss treatment plans, patients often focus on little beyond the word “cancer” because their attention is focused on their fear, anxiety, and uncertainty. After diagnosis, patients often call their clinician’s office to rehash the conversation because they don’t remember what was said. Also, few patients clearly understand the technologies and how they can lead to personalized treatments. A new website, www.IsMyCancerDifferent.com, helps in patient understanding by providing expert information on molecular-level testing in a consumer-friendly, patient-driven format.
We discussed this new website with Dr. April Latrice Speed, a breast specialist at Dekalb Medical Hillandale in Lithonia, GA. She explained that the site empowers patients to drive the conversation about their individualized cancer treatment plan. For oncologists, this website helps to communicate to patients the concepts of molecular-level testing and how this testing can provide crucial information to guide diagnosis, prognosis, and treatment planning.
“The website helps to reinforce the office discussion in the comfort of your own home. You don’t plan for cancer. You can’t process and wrap your head around it. It allows you to have a friend at your house and basically rehash what your clinician just told you. It’s a format that is compassionate, comprehensive, and not intimidating,” said Dr. Speed.
The advice on www.IsMyCancerDifferent.com is delivered from the patient’s perspective, while providing interface with experts. It is patient-friendly and has consumer-driven content. The majority of other websites have a format that is driven by clinicians or else they are strictly consumer driven without expert interface.
This website “puts the power in patient’s hands. It’s a game changer,” stated Dr. Speed. Patients can access information at low impact to their wallet since no travel or time off of work is needed. The information equalizes the potential for patients to get good treatment, even when they do not live in an area with top-notch facilities nearby.
“The website puts the patient behind the wheel,” said Dr. Speed.
The website is sponsored by Clarient, which is a GE Healthcare Company, and by N-of-One. The content is reviewed for accuracy by the president of N-of-One, Jennifer Levin Carter, MD, MPH, and is also reviewed by the legal and regulatory team from Clarient/GE Healthcare.
Clarient provides comprehensive, cancer-diagnostic laboratory services, and is developing proprietary companion diagnostic tests for therapeutics in breast, prostate, lung, and colon cancer, along with leukemia/lymphoma. N-of-One provides access to cutting-edge technologies for cancer patients and their physicians.
by Kathy Bolz, PhD