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Thread: Two cancer drugs keep rare pancreatic tumors in check

  1. #1
    Distinguished Community Member gpawelski's Avatar
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    Default Two cancer drugs keep rare pancreatic tumors in check

    But both Sutent and Afinitor double the amount of time that cancers remain in check, compared with placebos, according to two studies in today's New England Journal of Medicine.

    That's significant, because patients with advanced disease live a median of only about two years, says James Yao, lead author of the Afinitor study.

    The only known drug for this cancer, approved decades ago, is very toxic and doesn't work very well; many doctors don't even try it, says Yao of Houston's M.D. Anderson Cancer Center.

    "This is very good news for patients," he says. "It's very encouraging to have two drugs come along at the same time."

    Both drugs, already on the market for kidney cancer, controlled tumors for about 11 months. Patients taking placebos saw their tumors begin growing again in 4˝ to 5˝ months, according to the studies, paid for by the drugs' manufacturers.

    Still, the two drugs did cause some serious side effects. Sutent increased the risk of high blood pressure and a loss of infection-fighting blood cells. Afinitor increased the risk of anemia, diarrhea, mouth sores and high blood sugar, the studies say.

    Doctors don't know how long patients can live on the drugs, Yao says. The Afinitor trial, involving 410 patients from 18 countries, hasn't gone on long enough to tell, he says.

    The Sutent study, with 171 patients from 11 countries, ended early because Sutent patients were doing so much better than those on placebos that an ethics committee decided to offer the drug to everyone. By that time, 10% of the Sutent patients had died, compared with 25% of those on placebo, the study says.

    The new drugs are a big step forward for patients, who haven't had many options until now, says Richard Goldberg, a professor at the University of North Carolina-Chapel Hill and an expert on neuroendocrine tumors.

    The study results offer patients hope that other new drugs might work in this disease, as well, Goldberg says, or that patients might do even better if they combine them.

    Given the current state of the art, cell-based in vitro drug sensitivity testing (with functional profiling) could be of significant clinical value. One aspect of a functional profiling assay is that microvascular viability can measure dead microvascular cells in tissue, fluid and peripheral blood specimens to identify potential responders to anti-angiogenic drugs, Avastin (bevacizumab), Nexavar (sorafenib), Sutent (sunitinib), Torisel (temsirolimus), Votrient (pazopanib) and Afinitor (everolimus). The AngioRx Assay has significant clinical value.

    But the findings leave many questions unanswered, write researchers Robert Jensen and Gianfranco Delle Fave in an accompanying editorial. For example, since the drugs appear to stabilize the disease rather than cure it, will patients have to take the drugs indefinitely? If so, will patients, who are often symptom-free, even with advanced disease, agree to accept side effects for years?

    Literature Citation:
    Functional profiling with cell culture-based assays for kinase and anti-angiogenic agents Eur J Clin Invest 37 (suppl. 1):60, 2007
    Functional Profiling of Human Tumors in Primary Culture: A Platform for Drug Discovery and Therapy Selection (AACR: Apr 2008-AB-1546)
    Gregory D. Pawelski

  2. #2
    Distinguished Community Member gpawelski's Avatar
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    Default Sutent for the Treatment of Pancreatic Neuroendocrine Tumors

    Sutent (sunitinib malate) for the Treatment of Pancreatic Neuroendocrine Tumors

    Eric Raymond, M.D., Ph.D., Laetitia Dahan, M.D., Ph.D., Jean-Luc Raoul, M.D., Ph.D., Yung-Jue Bang, M.D., Ivan Borbath, M.D., Ph.D., Catherine Lombard-Bohas, M.D., Juan Valle, M.D., Peter Metrakos, M.D., C.M., Denis Smith, M.D., Aaron Vinik, M.D., Ph.D., Jen-Shi Chen, M.D., Dieter Hörsch, M.D., Pascal Hammel, M.D., Ph.D., Bertram Wiedenmann, M.D., Ph.D., Eric Van Cutsem, M.D., Ph.D., Shem Patyna, Ph.D., Dongrui Ray Lu, M.Sc., Carolyn Blanckmeister, Ph.D., Richard Chao, M.D., and Philippe Ruszniewski, M.D.

    N Engl J Med 2011; 364:501-513February 10, 2011

    Background

    The multitargeted tyrosine kinase inhibitor sunitinib has shown activity against pancreatic neuroendocrine tumors in preclinical models and phase 1 and 2 trials.

    Methods

    We conducted a multinational, randomized, double-blind, placebo-controlled phase 3 trial of sunitinib in patients with advanced, well-differentiated pancreatic neuroendocrine tumors. All patients had Response Evaluation Criteria in Solid Tumors–defined disease progression documented within 12 months before baseline. A total of 171 patients were randomly assigned (in a 1:1 ratio) to receive best supportive care with either sunitinib at a dose of 37.5 mg per day or placebo. The primary end point was progression-free survival; secondary end points included the objective response rate, overall survival, and safety.

    Results

    The study was discontinued early, after the independent data and safety monitoring committee observed more serious adverse events and deaths in the placebo group as well as a difference in progression-free survival favoring sunitinib. Median progression-free survival was 11.4 months in the sunitinib group as compared with 5.5 months in the placebo group (hazard ratio for progression or death, 0.42; 95% confidence interval [CI], 0.26 to 0.66; P<0.001). A Cox proportional-hazards analysis of progression-free survival according to baseline characteristics favored sunitinib in all subgroups studied. The objective response rate was 9.3% in the sunitinib group versus 0% in the placebo group. At the data cutoff point, 9 deaths were reported in the sunitinib group (10%) versus 21 deaths in the placebo group (25%) (hazard ratio for death, 0.41; 95% CI, 0.19 to 0.89; P=0.02). The most frequent adverse events in the sunitinib group were diarrhea, nausea, vomiting, asthenia, and fatigue.

    Conclusions

    Continuous daily administration of sunitinib at a dose of 37.5 mg improved progression-free survival, overall survival, and the objective response rate as compared with placebo among patients with advanced pancreatic neuroendocrine tumors.

    Funded by Pfizer; ClinicalTrials.gov number, NCT00428597
    Gregory D. Pawelski

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    Distinguished Community Member gpawelski's Avatar
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    Default Afinitor (everolimus) for Advanced Pancreatic Neuroendocrine Tumors

    Afinitor (everolimus) for Advanced Pancreatic Neuroendocrine Tumors

    James C. Yao, M.D., Manisha H. Shah, M.D., Tetsuhide Ito, M.D., Ph.D., Catherine Lombard Bohas, M.D., Edward M. Wolin, M.D., Eric Van Cutsem, M.D., Ph.D., Timothy J. Hobday, M.D., Takuji Okusaka, M.D., Jaume Capdevila, M.D., Elisabeth G.E. de Vries, M.D., Ph.D., Paola Tomassetti, M.D., Marianne E. Pavel, M.D., Sakina Hoosen, M.D., Tomas Haas, Ph.D., Jeremie Lincy, M.Sc., David Lebwohl, M.D., and Kjell Öberg, M.D., Ph.D. for the RAD001 in Advanced Neuroendocrine Tumors, Third Trial (RADIANT-3) Study Group

    N Engl J Med 2011; 364:514-523February 10, 2011

    Background

    Everolimus, an oral inhibitor of mammalian target of rapamycin (mTOR), has shown antitumor activity in patients with advanced pancreatic neuroendocrine tumors, in two phase 2 studies. We evaluated the agent in a prospective, randomized, phase 3 study.

    Methods

    We randomly assigned 410 patients who had advanced, low-grade or intermediate-grade pancreatic neuroendocrine tumors with radiologic progression within the previous 12 months to receive everolimus, at a dose of 10 mg once daily (207 patients), or placebo (203 patients), both in conjunction with best supportive care. The primary end point was progression-free survival in an intention-to-treat analysis. In the case of patients in whom radiologic progression occurred during the study, the treatment assignments could be revealed, and patients who had been randomly assigned to placebo were offered open-label everolimus.

    Results

    The median progression-free survival was 11.0 months with everolimus as compared with 4.6 months with placebo (hazard ratio for disease progression or death from any cause with everolimus, 0.35; 95% confidence interval [CI], 0.27 to 0.45; P<0.001), representing a 65% reduction in the estimated risk of progression or death. Estimates of the proportion of patients who were alive and progression-free at 18 months were 34% (95% CI, 26 to 43) with everolimus as compared with 9% (95% CI, 4 to 16) with placebo. Drug-related adverse events were mostly grade 1 or 2 and included stomatitis (in 64% of patients in the everolimus group vs. 17% in the placebo group), rash (49% vs. 10%), diarrhea (34% vs. 10%), fatigue (31% vs. 14%), and infections (23% vs. 6%), which were primarily upper respiratory. Grade 3 or 4 events that were more frequent with everolimus than with placebo included anemia (6% vs. 0%) and hyperglycemia (5% vs. 2%). The median exposure to everolimus was longer than exposure to placebo by a factor of 2.3 (38 weeks vs. 16 weeks).

    Conclusions

    Everolimus, as compared with placebo, significantly prolonged progression-free survival among patients with progressive advanced pancreatic neuroendocrine tumors and was associated with a low rate of severe adverse events.

    Funded by Novartis Oncology; RADIANT-3 ClinicalTrials.gov number, NCT00510068
    Gregory D. Pawelski

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    Distinguished Community Member gpawelski's Avatar
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    Default Different classes of drugs that target VEGF

    There are a number of new classes of drugs that target VEGF, at the protein level (Avastin), at the tyrosine kinase level (Nexavar, Sutent) and at the intracellular metabolic pathway mTOR (Afinitor, Torisel).

    However, responses to any individual mechanism occurs in the miniority of patients. It is unclear why some patients repond to these interventions while others fail. In cell function analysis, it has found unexpectedly good response to conventional cytotoxic drugs following a failure to respond to these targeted agents.

    This reinforces the need for cancer therapies to be individualized. It remines us that it is the good outcome of the patient not the therapy applied that constitute successful therapy.

    The FDA does not have the legal authority to regulate the practice of the medicine and the physician may prescribe a drug off-label. Some drugs are used more frequently off-label than for their original, FDA-approved indications. Frequently, the standard of care for a particular type or stage of cancer involves the off-label use of one or more drugs.

    The FDA wants to alter rules for cancer drug cocktails. Rather than mixing and matching approved drugs, scientists want to develop combinations designed to work in tandem to block cancer. Some have suggested to use assays to identify a potential targeted population of ovarian cancer patients that it thinks will benefit from any of the above drugs, singularly or in combination.
    Gregory D. Pawelski

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