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From: Ian@SI	2/8/2012 4:25:28 PM
	of 892

XGEVA 12-1 vote against expanding use. Seems neutral with respect to cabo... ??? +++++++++++++ A federal advisory panel rejected a proposal Wednesday by Amgen Inc. to expand the use of its bone drug Xgeva in men with prostate cancer that has not spread to the bones. Xgeva is currently approved to delay fractures and other bone injuries in patients whose cancer has already spread to the bones. The company is seeking approval from the Food and Drug Administration for the use of Xgeva to prevent the spread of prostate cancer that has not responded to other therapies, or essentially to give the drug at an earlier time point in the disease. Xgeva was reviewed Wednesday by the FDA's oncologic drugs advisory committee which is made up of non-FDA medical experts. The panel voted negatively 12 to 1 on whether Xgeva "demonstrated a favorable risk/benefit evaluation" in men with prostate cancer who are at high risk of having the cancer spread to the bones. The vote amounts to a recommendation that FDA not approve Xgeva for that use. The FDA isn't required to follow the recommendation but usually follows the advice of its advisory panels. "This isn't a question of whether this drug works," said Wyndam Wilson, the panel's chairman and the chief of the lymphoma therapeutics division at the National Cancer Institute. "The question is when is the most effective time to give it." Amgen conducted a study of Xgeva in 1,432 men with prostate cancer that hadn't responded to previous therapies, but had not spread to the bones. Many types of cancer spread to the bones and cause tumors to grow, destroying the bone around the tumor, and causing fractures and other problems. Half of the men were treated with Xgeva while the other half received a placebo. The study examined the time until men developed bone metastases or died, whichever occurred first. The study showed Xgeva prolonged median bone metastatis-free survival by 4.2 months compared to patients in the placebo group. While the FDA said the study met its primary objective, the agency said it was unclear whether the results were "clinically meaningful" given that there was no difference in overall survival between the two patient groups. The agency said the risk-benefit ratio of Xgeva must also take into account the overall toxicity of the drug. One of the side effects includes a risk of developing osteonecrosis of the jaw, or ONJ, a rare jaw-decay problem, which was seen in about 5% of patients taking Xgeva in the clinical study. Michael Severino, Amgen's vice president of research and development, said in an interview on Monday that the company believes Xgeva does provide a clinically meaningful benefit because it delays the spread of cancer to the bone, which causes significant pain and other problems such as incontinence. Xgeva is also sold under the brand name Prolia as an osteoporosis treatment but is administered at a lower dose and less often than used to treat cancer-related bone complications. Xgeva's and Prolia's combined sales in 2011 topped $550 million. The drugs target a protein called RANK Ligand, which helps regulate cells called osteoclasts that break down bone.

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From: tnsaf	2/11/2012 12:08:54 AM
	of 892

Exelixis Announces Pricing of $60.5 Million Public Offering of Common StockSOUTH SAN FRANCISCO, Calif.--(BUSINESS WIRE)-- Exelixis, Inc. (Nasdaq: EXEL - News) today announced the pricing of its underwritten public offering of 11,000,000 shares of newly issued common stock at a price to the public of $5.50 per share. Exelixis also granted the underwriters a 30-day option to purchase up to an additional 1,650,000 shares of its common stock in connection with the offering. All of the shares in the offering are being sold by Exelixis. The shares will be issued pursuant to a prospectus supplement filed as part of a shelf registration statement previously filed with the Securities and Exchange Commission (SEC) on Form S-3. Exelixis anticipates that its aggregate net proceeds from the offering will be $56.5 million after deducting the underwriting discount and estimated offering expenses payable by Exelixis (assuming no exercise of the underwriters' option to purchase additional shares of common stock). Goldman, Sachs & Co. is acting as sole book running manager, and Cowen and Company, LLC is acting as co-manager of the offering. Exelixis expects to close the offering on or about February 15, 2012, subject to customary closing conditions. This announcement does not constitute an offer to sell or a solicitation of an offer to buy, nor shall there be any sale of these securities in any state or jurisdiction in which such offer, solicitation or sale would be unlawful prior to registration or qualification under the securities laws of any such state or jurisdiction. This press release is being issued pursuant to and in accordance with Rule 134 under the Securities Act of 1933, as amended. Any offer, if at all, will be made only by means of a prospectus supplement and accompanying prospectus forming a part of the effective registration statement. Copies of the prospectus supplement and accompanying prospectus relating to the offering may be obtained, when available, from Goldman, Sachs & Co. (200 West Street, New York, New York 10282, Attn: Prospectus Department, Phone: 1-866-471-2526, Fax: 212-902-9316, Email: prospectus-ny@ny.email.gs.com) or from Cowen and Company, LLC (c/o Broadridge Financial Services., 1155 Long Island Avenue, Edgewood, NY,11717, Attn: Prospectus Department, Phone: 631-274-2806, Fax: 631-254-7140). Exelixis intends to file a final prospectus supplement relating to the offering with the SEC, which will be available along with the prospectus filed with the SEC in connection with the shelf registration statement, on the SEC's website at www.sec.gov.

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From: IRWIN JAMES FRANKEL	2/24/2012 3:54:42 PM
	of 892

Dual Inhibition of MET and VEGF Signaling With Cabozantinib Blocks Tumor Invasiveness and Metastasis-- Preclinical data published in Cancer Discovery support clinical development program evaluating cabozantinib’s potential in multiple oncology indications SOUTH SAN FRANCISCO, Calif.--(BUSINESS WIRE)-- Exelixis, Inc. (NASDAQ: EXEL - News) today announced the company’s lead compound, cabozantinib, is highlighted in a new peer-reviewed publication demonstrating that simultaneous inhibition of MET and VEGF signaling reduces tumor invasiveness and metastasis in preclinical models of pancreatic cancer. The research, led by Dr. Donald M. McDonald at theUniversity of California, San Francisco (UCSF), showed that selective inhibition of VEGF signaling with a neutralizing antibody against VEGF or with a small molecule kinase inhibitor resulted in more invasive and metastatic tumors than from placebo-treated mice. Importantly, this effect was accompanied by increased expression of MET. The researchers went on to show that treatment with cabozantinib (which targets both MET and VEGF signaling), or with a combination of selective inhibitors targeting both pathways, reduced these malignant processes. The researchers also reported that cabozantinib prolonged survival compared with all other treatment combinations examined. The preclinical data will be published in the March 1, 2012 issue of Cancer Discovery and are also discussed in a press release issued by the American Association for Cancer Research, the journal’s publisher. Starting today, the article will be available at cts.businesswire.com Researchers at Exelixis collaborated on the studies with UCSF. “These data provide important insights into the potential clinical benefits of simultaneously inhibiting the MET and VEGF signaling pathways with cabozantinib, and add to the scientific rationale for our ongoing clinical investigation of the compound,” said Michael M. Morrissey, Ph.D., president and chief executive officer at Exelixis. “To date, cabozantinib has shown activity in 12 of 13 tumor types studied, including particularly encouraging interim results in castration-resistant prostate, medullary thyroid, renal, liver, ovarian, non-small cell lung, and breast cancers, as well as melanoma. These results suggest that, in many types of tumors, cabozantinib may have a potentially differentiated activity profile as compared to compounds that inhibit only VEGF or MET.” In the research described in Cancer Discovery, tumor-bearing mice were treated with an anti-VEGF antibody or with sunitinib, which inhibits multiple tyrosine kinases including VEGF receptors. These treatments were tested alone or in combination with an inhibitor of MET. Separate groups of animals were treated with cabozantinib. Key findings include: Cabozantinib reduced tumor invasiveness compared with VEGF inhibition alone, through a mechanism consistent with MET inhibition.Liver metastases were completely absent in animals treated with cabozantinib.Overall survival was longest in cabozantinib-treated animals. All animals treated with cabozantinib survived until the end of the study, whereas most or all animals in all other treatment groups did not survive until the end of the study."Inhibition of VEGF signaling has become a mainstay of cancer therapy, and its ability to delay disease progression and prolong survival in certain cancers has been extensively documented. However, there is a growing body of evidence suggesting that VEGF inhibition on its own can lead to increased tumor aggressiveness in some preclinical models and in at least one human cancer,” said Donald M. McDonald, M.D., Ph.D., a member of the Helen Diller Comprehensive Cancer Center and the Cardiovascular Research Institute and professor of anatomy at UCSF. “These new preclinical findings suggest that upregulation of MET contributes to the evasive response of tumors to anti-VEGF therapy, and that simultaneous inhibition of MET and VEGF signaling can confer the benefits associated with VEGF inhibition while significantly reducing, and in some cases reversing, invasion and metastasis. Additional preclinical and clinical evaluation of combined MET and VEGF inhibition are clearly warranted.” About Cabozantinib Cabozantinib is a potent, dual inhibitor of MET and VEGFR2. Cabozantinib is an investigational agent that provides coordinated inhibition of metastasis and angiogenesis to kill tumor cells while blocking their escape pathways. The therapeutic role of cabozantinib is currently being investigated across several tumor types. MET is upregulated in many tumor types, thus facilitating tumor cell escape by promoting the formation of more aggressive phenotypes, resulting in metastasis. MET-driven metastasis may be further stimulated by hypoxic conditions in the tumor environment, which are often exacerbated by selective VEGF-pathway inhibitors. In preclinical studies, cabozantinib has shown powerful tumoricidal, antimetastatic and antiangiogenic effects, including: Extensive apoptosis of malignant cellsDecreased tumor invasiveness and metastasisDecreased tumor and endothelial cell proliferationBlockade of metastatic bone lesion progressionDisruption of tumor vasculatureAbout Exelixis Exelixis, Inc. is a biotechnology company committed to developing small molecule therapies for the treatment of cancer. Exelixis is focusing its proprietary resources and development efforts exclusively on cabozantinib (XL184), its most advanced product candidate, in order to maximize the therapeutic and commercial potential of this compound. Exelixis believes cabozantinib has the potential to be a high-quality, broadly-active, differentiated pharmaceutical product that can make a meaningful difference in the lives of patients. Exelixis has also established a portfolio of other novel compounds that it believes have the potential to address serious unmet medical needs, many of which are being advanced by partners as part of collaborations. For more information, please visit the company's web site at www.exelixis.com. Forward-Looking Statements This press release contains forward-looking statements, including, without limitation, statements related to: the continued development and clinical, therapeutic and commercial potential of, and opportunities for, cabozantinib; the belief that the referenced research and data support the cabozantinib clinical development program; the belief that interim results in various cancers are encouraging and suggest that cabozantinib may have a potentially differentiated activity profile compared to compounds that inhibit only VEGF or MET; the potential benefits of simultaneous inhibition of MET and VEGF; and the belief that additional preclinical and clinical evaluation of combined MET and VEGF inhibition are clearly warranted. Words such as “support,” “potential,” “ongoing,” “encouraging,” “suggest,” “may,” “can,” “warranted,” “believes,” and similar expressions are intended to identify forward-looking statements. These forward-looking statements are based upon Exelixis' current plans, assumptions, beliefs and expectations. Forward-looking statements involve risks and uncertainties. Exelixis' actual results and the timing of events could differ materially from those anticipated in such forward-looking statements as a result of these risks and uncertainties, which include, without limitation: risks related to the potential failure of cabozantinib to demonstrate safety and efficacy in clinical testing; Exelixis' ability to conduct clinical trials of cabozantinib sufficient to achieve a positive completion; the availability of data at the referenced times; the sufficiency of Exelixis' capital and other resources; the uncertain timing and level of expenses associated with the development of cabozantinib; the uncertainty of the FDA approval process; market competition; and changes in economic and business conditions. These and other risk factors are discussed under "Risk Factors" and elsewhere in Exelixis' annual report on Form 10-K for the fiscal year ended December 30, 2011 and Exelixis' other filings with the Securities and Exchange Commission. Exelixis expressly disclaims any duty, obligation or undertaking to release publicly any updates or revisions to any forward-looking statements contained herein to reflect any change in Exelixis' expectations with regard thereto or any change in events, conditions or circumstances on which any such statements are based.

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From: DonShimoda

3/3/2012 4:21:11 PM

of 892

Cabozantinib (XL184) inhibits prostate tumor growth and bone lesion development

Abstract Number:	2851

Presentation Time:	Monday, Apr 02, 2012, 1:00 PM - 5:00 PM

Author Block:	Jinlu Dai1, Honglai Zhang1, Andreas Karatsinides1, Dana Aftab2, Frauke Schimmoller2, Evan T. Keller1. 1Univ. of Michigan Comp. Cancer Ctr., Ann Arbor, MI; 2Exelixis, Inc, South San Francisco, CA
Abstract Body:	Over 80% of advanced prostate cancers (PCa) metastasize to bone resulting in primarily osteoblastic bone lesions. Cabozantinib (CABO) is a multi-kinase inhibitor that targets MET and vascular endothelial growth factor receptor-2 (VEGFR2). Administration of CABO to men with PCa bone metastases has been shown to induce a marked resolution of lesions on bone scan as well as regression of measurable disease. Modulation of prostate specific antigen (PSA) appeared to be independent of changes in other parameters such as target lesions and bone scan. The current study was designed to determine mechanisms underlying CABO activity in PCa. Expression of MET and VEGFR2 or modulation of their activity were verified in PCa cell lines such as PC-3 or the pre-osteoblast cell line MC3T3-E1. To evaluate if CABO impacts PCa neoplastic phenotypes, PCa cell lines LNCaP, C4-2B and PC-3 were treated. CABO inhibited cell viability, migration and invasive ability and promoted apoptosis in LNCaP, C4-2B and PC-3 cells. To determine if CABO could directly modulate PSA expression, LNCaP (androgen dependent) and C4-2B (androgen independent) cells were incubated in the presence or absence of CABO. CABO increased both PSA and androgen receptor (AR) mRNA and protein expression in the LNCaP cells but did not modulate PSA expression in C4-2B cells. MC3T3-E1 and ST2 cells were treated with CABO to evaluate impact on osteoblastogenesis. CABO decreased cell viability and modulated osteocalcin levels in MC3T3-E1 and ST2 cells. ACE-1 canine osteoblastic PCa cells were injected into the tibia and treatment with CABO was started after tumors had developed to determine the impact on PCa growth in vivo. CABO decreased both ACE-1 tumor burden and tumor-induced osteoblastic activity in bone. In contrast, when PC-3 cells (osteolytic) were injected subcutaneously or into the tibiae of mice, which were treated with CABO or vehicle once tumors were established, CABO slowed the growth of PC-3 tumors in the soft tissue but not in bone. These findings indicate that CABO inhibits prostate tumor growth and tumor-induced bone lesion development through direct targeting of both PCa cells and osteoblasts. These studies provide a strong rationale to further elucidate the effect of CABO on osteoblastogenesis and PSA modulation.

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From: DonShimoda	3/5/2012 10:39:43 AM
	of 892

Exelixis Announces Initiation of Investigator-Sponsored Clinical Trial Combining Cabozantinib and Abiraterone in Men With Castration-Resistant Prostate Cancer SOUTH SAN FRANCISCO, Calif.--(BUSINESS WIRE)--Mar. 5, 2012-- Exelixis Inc. (NASDAQ:EXEL) today announced the initiation of a phase 1 dose-finding trial of cabozantinib in combination with abiraterone in men with metastatic castration-resistant prostate cancer (CRPC) who have disease progression following treatment with up to two prior chemotherapy regimens. The study is designed to define the maximum tolerated dose (MTD) of cabozantinib in combination with abiraterone and prednisone. Abiraterone was approved by the FDA in April 2011 and is indicated in combination with prednisone for the second-line treatment of CRPC in men who have received prior chemotherapy containing docetaxel. The study is being led by Dr. Chris Sweeney at the Dana-Farber Cancer Institute. The Massachusetts General Hospital and Beth Israel Deaconess Medical Center will also participate in accrual to the study. “The Exelixis clinical development strategy for cabozantinib in CRPC is designed to rationally exploit the compound’s unique activity profile as both a single-agent and in combination with other therapies,” said Michael M. Morrissey, Ph.D., president and chief executive officer of Exelixis. “This investigator-sponsored trial is designed to provide important insight into the potential clinical utility of a combination of cabozantinib and abiraterone as a second-line regimen. Based on the extensive preclinical and clinical data generated to date for both compounds, we believe that a combination regimen of cabozantinib and abiraterone may provide CRPC patients with improved outcomes. Additional cabozantinib combination studies with other therapies are planned for the near future.” Rationale for Combination Approach Clinical and preclinical evidence suggest that inhibition of androgen receptor signaling (a consequence of treatment with androgen synthesis inhibitors such as abiraterone) leads to upregulation of MET signaling, which may contribute to the survival and invasiveness of prostate cancer cells. Cabozantinib is a potent inhibitor of MET, and may therefore enhance the activity of abiraterone by blocking this putative resistance mechanism. Additionally, the high level of activity that cabozantinib has demonstrated against both soft tissue and bone lesions in men with CRPC may complement the clinical activity of abiraterone. “Based on our increasing understanding of the biology and pathogenesis of CRPC, we now have the opportunity to impact the course of disease in this debilitating and deadly cancer. We are hopeful that the combination of two active agents with different mechanisms of action may meaningfully improve the outcome for men with metastatic prostate cancer,” said Philip Kantoff, M.D., Chief Clinical Research Officer and Director of the Lank Center for Genitourinary Oncology at the Dana-Farber Cancer Institute and Professor of Medicine, Harvard Medical School. “Although the recent approval of several new agents for the treatment of metastatic CRPC has helped to improve the treatment and outcomes for men with this disease, this is an indication that still has significant unmet medical need,” said Christopher Sweeney, M.D., Clinical Director of the Lank Center for Genitourinary Oncology at the Dana-Farber Cancer Institute and Associate Professor of Medicine, Harvard Medical School, and principal investigator of the trial. “Bone metastases occur in approximately 90% of CRPC patients, and these lesions are the primary cause of morbidity and mortality in this patient population. The combination of cabozantinib and abiraterone may improve control of both soft tissue and bone lesions. Data from this study will provide a foundation on which to explore the clinical benefit this combination regimen may provide to men with CRPC.” Trial Design The study will enroll men with progressive metastatic CRPC who have received up to two prior chemotherapy regimens; patients who have received prior MET or VEGFR inhibitors or prior CYP17A1 inhibitor therapy are not eligible to participate (although prior ketoconazole therapy is allowed if treatment was completed more than 120 days prior to study entry). The study will be conducted in two parts. Part A is a dose-escalation study in which patients will receive cabozantinib (20 mg, 40 mg, or 60 mg) in combination with 1000 mg of abiraterone daily and 5 mg of prednisone twice daily. This part of the study is a standard “3 plus 3” dose-escalation design in which 3 patients are initially accrued at each dose level. If none of the patients experiences a dose-limiting toxicity (DLT) in the first 4 weeks of treatment, dose escalation will proceed to the next dose level. If 1 patient experiences a DLT, 3 additional patients will be accrued at that dose. If 2 or more patients experience a DLT, that dose will be considered as exceeding the MTD. In Part B of the study, the dose levels identified as safe and tolerable in Part A will be expanded to include up to 12 patients. The primary endpoint is the rate of dose limiting toxicity (DLT) in the first 4 weeks of therapy when abiraterone is combined with escalating doses of cabozantinib. The secondary objective is to define a dosing regimen of abiraterone and cabozantinib suitable for further evaluation based on long-term toxicity and efficacy data. This objective comprises several secondary endpoints, including DLT incidence, impact on soft tissue disease per RECIST, time to disease progression, time to skeletal-related events, impact on bone scan, and changes in a variety of biomarkers. The Significance of Bone Metastases in CRPC The primary cause of morbidity and mortality in patients with CRPC is metastasis to the bone, which occurs in about 90% of cases. Bone metastases cause local disruption of normal bone remodeling, with lesions generally showing a propensity for an osteoblastic (bone-forming) phenotype on imaging. These lesions often lead to increased skeletal fractures, spinal cord compression, and severe bone pain. Osteoblastic lesions are typically visualized in CRPC patients by bone scan, which detects rapid incorporation of 99mTc-labeled methylene-diphosphonate radiotracer into newly forming bone. In addition, increased blood levels of ALP and CTx, markers for osteoblast and osteoclast activity, respectively, are often observed in CRPC patients with bone metastases, and are associated with shorter overall survival. About Cabozantinib Cabozantinib is a potent, dual inhibitor of MET and VEGFR2. Cabozantinib is an investigational agent that provides coordinated inhibition of metastasis and angiogenesis to kill tumor cells while blocking their escape pathways. The therapeutic role of cabozantinib is currently being investigated across several tumor types. MET is upregulated in many tumor types, thus facilitating tumor cell escape by promoting the formation of more aggressive phenotypes, resulting in metastasis. MET-driven metastasis may be further stimulated by hypoxic conditions in the tumor environment, which are often exacerbated by selective VEGF-pathway inhibitors. In preclinical studies, cabozantinib has shown powerful tumoricidal, antimetastatic and antiangiogenic effects, including: - Extensive apoptosis of malignant cells - Decreased tumor invasiveness and metastasis - Decreased tumor and endothelial cell proliferation - Blockade of metastatic bone lesion progression - Disruption of tumor vasculature About Exelixis Exelixis, Inc. is a biotechnology company committed to developing small molecule therapies for the treatment of cancer. Exelixis is focusing its proprietary resources and development efforts exclusively on cabozantinib (XL184), its most advanced product candidate, in order to maximize the therapeutic and commercial potential of this compound. Exelixis believes cabozantinib has the potential to be a high-quality, broadly-active, differentiated pharmaceutical product that can make a meaningful difference in the lives of patients. Exelixis has also established a portfolio of other novel compounds that it believes have the potential to address serious unmet medical needs, many of which are being advanced by partners as part of collaborations. For more information, please visit the company's web site at www.exelixis.com.

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From: Ian@SI	4/2/2012 4:41:06 PM
	of 892

SOUTH SAN FRANCISCO, Calif. (Business Wire) -- Exelixis, Inc. (NASDAQ:EXEL) announced today that its lead compound, cabozantinib, will be the subject of nine separate data presentations at the upcoming Annual Meeting of the American Society of Clinical Oncology (ASCO). The meeting will be held June 1-5, 2012, in Chicago, Illinois. Clinical data for cabozantinib will be featured in four oral presentations, four poster discussion presentations, and one general poster presentation. For the first time, investigators will present data from EXAM, the pivotal trial of cabozantinib in medullary thyroid cancer. Initial positive top-line results from EXAM were announced in October 2011. "The nine data presentations at this year's ASCO Annual Meeting are indicative of the growing depth and breadth of cabozantinib's global clinical development program," said Michael M. Morrissey, Ph.D., president and chief executive officer of Exelixis. "As the data across multiple tumor types for cabozantinib continues to mature, its unique activity profile is increasingly being recognized broadly across the oncology community. We look forward to sharing these exciting data at ASCO later this year." The full roster of cabozantinib data presentations expected at the meeting (all times Central Daylight Time): Oral Presentations "Activity of cabozantinib (XL184) in hepatocellular carcinoma: Results from a phase II randomized discontinuation trial (RDT)" (Abstract #4006)Dr. Chris Verslype, Hepatology, University Hospitals Gasthuisberg, BelgiumOral Abstract Session: Gastrointestinal (Noncolorectal) CancerSaturday, June 2; 3:00 p.m. - 6:00 p.m. "Efficacy of cabozantinib (XL184) in patients (pts) with metastatic, refractory renal cell carcinoma (RCC)" (Abstract #4504)Dr. Toni K. Choueiri, Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute/Brigham and Women's Hospital, Harvard Medical School, Boston, MAOral Abstract Session: Genitourinary Cancer (Nonprostate)Saturday, June 2; 3:00 p.m. - 6:00 p.m. "An international, double-blind, randomized, placebo-controlled phase III trial (EXAM) of cabozantinib (XL184) in medullary thyroid carcinoma (MTC) patients (pts) with documented RECIST progression at baseline" (Abstract #5508)Dr. Patrick Schoffski, Department of General Medical Oncology, Catholic University Leuven, BelgiumClinical Science Symposium: Targeting Therapeutics for Thyroid CancersMonday, June 4; 11:30 a.m. - 1:00 p.m. "Cabozantinib (XL184) in chemotherapy-pretreated metastatic castration resistant prostate cancer (mCRPC): Results from a phase II nonrandomized expansion cohort (NRE)" (Abstract #4513)Dr. Matthew R. Smith, Massachusetts General Hospital Cancer Center, Boston, MAOral Abstract Session: Genitourinary Cancer (Prostate)Tuesday, June 5; 9:45 a.m. - 12:45 p.m. Poster Discussion Presentations "Activity of cabozantinib (XL184) in metastatic breast cancer (MBC): Results from a phase II randomized discontinuation trial (RDT)" (Abstract #535)Dr. Eric P. Winer, Dana-Farber Cancer Institute, Boston, MAPoster Discussion Session: Breast Cancer-HER2/ERSaturday, June 2; 1:15 p.m. - 5:45 p.m. "Activity of cabozantinib (XL184) in metastatic melanoma: Results from a phase II randomized discontinuation trial (RDT)" (Abstract #8531)Dr. Michael S. Gordon, Pinnacle Oncology Hematology, Scottsdale, AZPoster Discussion Session: Melanoma/Skin CancersSaturday, June 2; 1:15 p.m. - 5:45 p.m. "Investigator sponsored trial of efficacy and tolerability of cabozantinib (cabo) at lower dose: A dose-finding study in men with castration-resistant prostate cancer (CRPC) and bone metastases" (Abstract #4566)Dr. Richard J. Lee, Massachusetts General Hospital Cancer Center, Boston, MAPoster Discussion Session: Genitourinary (Prostate) CancerMonday, June 4, 8:00 a.m. - 12:30 p.m. "Activity of cabozantinib (XL184) in metastatic NSCLC: Results from a phase II randomized discontinuation trial (RDT)" (Abstract #7514)Dr. Beth A. Hellerstedt, US Oncology Research, LLC, McKesson Specialty Health, The Woodlands, TX, and Texas Oncology, Central Austin Cancer Center, Austin, TXPoster Discussion Session: Lung Cancer - Non-small Cell MetastaticTuesday, June 5; 8:00 a.m. - 12:30 p.m. Poster Presentation "Antitumor activity of cabozantinib (XL184) in a cohort of patients (pts) with differentiated thyroid cancer (DTC)" (Abstract #5547)Dr. Maria E. Cabanillas, University of Texas M. D. Anderson Cancer Center, Houston, TXGeneral Poster Session: Head and Neck CancerSaturday, June 2; 1:15 p.m. - 5:15 p.m. About Cabozantinib Cabozantinib is a potent, dual inhibitor of MET and VEGFR2. Cabozantinib is an investigational agent that provides coordinated inhibition of metastasis and angiogenesis to kill tumor cells while blocking their escape pathways. The therapeutic role of cabozantinib is currently being investigated across several tumor types. MET is upregulated in many tumor types, thus facilitating tumor cell escape by promoting the formation of more aggressive phenotypes, resulting in metastasis. MET-driven metastasis may be further stimulated by hypoxic conditions in the tumor environment, which are often exacerbated by selective VEGF-pathway inhibitors. In preclinical studies, cabozantinib has shown powerful tumoricidal, antimetastatic and antiangiogenic effects, including: Extensive apoptosis of malignant cells Decreased tumor invasiveness and metastasis Decreased tumor and endothelial cell proliferation Blockade of metastatic bone lesion progression Disruption of tumor vasculature About Exelixis [snip]

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From: IRWIN JAMES FRANKEL

4/16/2012 8:13:02 PM

of 892

onclive.com

Study Supports Combining c-MET Targeted Therapies With Angiogenesis Inhibitors
Jane de Lartigue
Published Online: Monday, April 16th, 2012

Donald M. McDonald, MD, PhD
Professor
Department of Anatomy
Helen Diller Family Comprehensive Cancer Center
University of California
San Francisco

Agents that target the c-MET pathway may prove to have significant benefit when combined with inhibitors of angiogenesis, particularly vascular endothelial growth factor (VEGF) inhibitors, according to a study published in Cancer Discovery, an American Association for Cancer Research journal.

The findings suggest future implications for treatment regimens involving drugs that target VEGF, such as bevacizumab (Avastin, Genentech), which has been controversial in metastatic breast cancer. Donald M. McDonald, MD, PhD, led a research group at the University of California, San Francisco, that explored single VEGF and dual inhibition strategies in preclinical mouse models of neuroendocrine pancreatic tumors.

Their results confirmed that targeting VEGF alone led to increased invasion and metastasis. They further demonstrated that one of the potential mechanisms for this increased tumor aggressiveness was an increase in the activation of MET receptor signaling in these tumor cells.

The key finding, however, was that the subsequent addition of MET receptor inhibitors to VEGF-targeted agents blocks invasion and metastasis, as does the use of a combined inhibitor of VEGF and MET receptors.

The dual inhibition strategy turned aggressive tumors in the mice into tiny balls with few or no metastases.

“These findings do not exclude the involvement of mechanisms of evasive resistance other than upregulation of c-MET, but they do provide proof of concept that certain types of resistance that develop in response to angiogenesis inhibitors that inhibit VEGF signaling can be overcome therapeutically,” McDonald said in an e-mail interview.

Specifically, investigators examined the effects of using an anti-VEGF neutralizing antibody or sunitinib (Sutent, Pfizer), which inhibits VEGF receptors and other receptor tyrosine kinases, including platelet-derived growth factor receptor and KIT.

They tested these agents alone or in combination with the investigational MET receptor inhibitors crizotinib (PF-02341066) and PF-04217903 (both from Pfizer), in addition to testing a dual inhibitor of VEGF and MET receptors, cabozantinib (XL184, Exelixis).

“It’s the combination of approaches—there’s a synergy between the two,” McDonald said in a press release, explaining the benefits that researchers observed.

Angiogenesis, one of the six hallmarks of cancer, allows cancer cells to obtain the oxygen and nutrients necessary for sustaining their growth. Most angiogenesis inhibitors, including bevacizumab, target the VEGF ligand or its receptor. The FDA has approved bevacizumab for the treatment of metastatic colorectal cancer, advanced nonsquamous non-small cell lung cancer, metastatic kidney cancer, and glioblastoma. However, the agency revoked the drug’s indication in metastatic breast cancer in 2011 due to a lack of data showing improved survival, and the potential for serious adverse events.

Study Details

Human agents investigated
Tumor-bearing RIP-Tag2 transgenic mice
Cancer control
Sunitinib
PF-04217903
Crizotinib (PF-02341066)
Cabozantinib (XL184)

A number of research groups have been investigating the reasons for poor response to antiangiogenic agents and have discovered that although they slow tumor growth, they also increase the aggressiveness of the tumor by promoting invasion and metastasis.

Further observation has revealed that treatment with agents that blocked both VEGF receptors and other receptor tyrosine kinases (including c-MET) do not have this effect, and inhibit both angiogenesis and invasion and metastasis. Given the role of c-MET in these cellular processes, researchers hypothesized that the concurrent inhibition of c-MET by these multitargeted inhibitors may be responsible for the reduction in invasiveness and metastasis.

This study suggests that activation of the MET receptor signaling is one of the mechanisms responsible for increased aggressiveness of tumors following inhibition of angiogenesis, and that concurrent targeting of the MET receptor may help to avoid this effect and achieve optimal patient outcomes. Clinical trials are already underway to test this approach in patients with various tumor types.

Sennino B, Ishiguro-Oonuma T, Wei Y, et al. Suppression of tumor invasion and metastasis by concurrent inhibition of c-Met and VEGF signaling in pancreatic neuroendocrine tumors. Cancer Discovery. 2012; 2(3): OF1-OF18.

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From: Ian@SI	4/27/2012 5:37:24 PM
	of 892

I would have expected a better response from EXEL today... 1:22AM Amgen receives Complete Response Letter From FDA for XGEVA sBLA for prevention of bone metastases (AMGN) 70.79 : Co announces the FDA has issued a Complete Response Letter for the supplemental Biologics License Application for XGEVA to treat men with castration-resistant prostate cancer at high risk of developing bone metastases. The Complete Response Letter states that FDA cannot approve the application in its present form. The FDA determined that the effect on bone metastases-free survival was of insufficient magnitude to outweigh the risks (including osteonecrosis of the jaw) of XGEVA in the intended population, and requested data from an adequate and well-controlled trial demonstrating a favorable risk-benefit profile for XGEVA that is generalizable to the U.S. population. In reference to this, co states: "The FDA's action today does not impact the approved indication of XGEVA in the prevention of skeletal-related events in men with bone metastases from prostate cancer, which was acknowledged by the FDA and the advisory committee members who discussed the application."

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From: IRWIN JAMES FRANKEL

5/2/2012 6:19:01 PM

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From YM:

ASCO Abstracts 1-May-12 09:49 pm

A search on the ASCO website shows these eight abstracts for XL-184. There are three oral presentations, one Clinical Science Symposium, and four poster presentations. The search also showed that there may be three additional abstracts for XL-184 that have not been updated on the website yet (maybe late breaking?).

Full abstracts will be released on the ASCO.org website on May 16 at 6:00 PM (EDT)

Saturday, Jun 2 | 1:15 PM - 5:15 PM
Session Type: Poster Discussion Session (Display)

Abstract #8531
Activity of cabozantinib (XL184) in metastatic melanoma: Results from a phase II randomized discontinuation trial (RDT).
Michael S. Gordon, MD
Poster Board: #20

Abstract #535
Activity of cabozantinib (XL184) in metastatic breast cancer (MBC): Results from a phase II randomized discontinuation trial (RDT).
Eric P. Winer, MD
Poster Board: #25

Abstract #5547
Antitumor activity of cabozantinib (XL184) in a cohort of patients (pts) with differentiated thyroid cancer (DTC).
Maria E. Cabanillas, MD
Poster Board: #22G

Saturday, Jun 2 | 3:00 PM - 6:00 PM
Session Type: Oral Abstract Session

Abstract #4007
5:15 PM - 5:30 PM
Activity of cabozantinib (XL184) in hepatocellular carcinoma: Results from a phase II randomized discontinuation trial (RDT).
Chris Verslype

Abstract #4504
4:15 PM - 4:30 PM
Efficacy of cabozantinib (XL184) in patients (pts) with metastatic, refractory renal cell carcinoma (RCC).
Toni K. Choueiri

Monday, Jun 4 | 11:30 AM - 1:00 PM
Session Type: Clinical Science Symposium

Abstract #5508
11:30 AM - 11:45 AM
An international, double-blind, randomized, placebo-controlled phase III trial (EXAM) of cabozantinib (XL184) in medullary thyroid carcinoma (MTC) patients (pts) with documented RECIST progression at baseline.
Patrick Schoffski, MD, MPH

Tuesday, Jun 5 | 8:00 AM - 12:00 PM
Session Type: Poster Discussion Session (Display)

Abstract #7514
Activity of cabozantinib (XL184) in metastatic NSCLC: Results from a phase II randomized discontinuation trial (RDT).
Beth A. Hellerstedt, MD
Poster Board: #4

Tuesday, Jun 5 | 9:45 AM - 12:45 PM
Session Type: Oral Abstract Session

Abstract #4513
11:00 AM - 11:15 AM
Cabozantinib (XL184) in chemotherapy-pretreated metastatic castration resistant prostate cancer (mCRPC): Results from a phase II nonrandomized expansion cohort (NRE).
Matthew R. Smith

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