On October 7, 2016 Myriad Genetics, Inc. (NASDAQ:MYGN), a leader in molecular diagnostics and personalized medicine, reported that four poster presentations will be featured at the 2016 European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) annual meeting, October 7-11, 2016 in Copenhagen, Denmark (Press release, Myriad Genetics, OCT 7, 2016, View Source [SID:SID1234515650]).

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"Myriad is a pioneer in personalized medicine and is committed to improving the prevention, detection and treatment of cancer," said Jerry Lanchbury, Ph.D., chief scientific officer, Myriad Genetics. "We are excited to present these new studies at ESMO (Free ESMO Whitepaper) that highlight and advance the science of our next-generation companion diagnostics to help inform and improve the treatment of cancer patients."

Please visit the Myriad booth #408 at ESMO (Free ESMO Whitepaper) for more information. Abstracts are available online at: View Source Follow Myriad on Twitter via @MyriadGenetics to stay informed about news and updates from the Company.

Poster Presentations
Title: Outcomes of clinical testing for tumor BRCA1 and BRCA2 gene analysis for 354 patients: First experience with tumor companion diagnostic for PARP inhibitors.
Presenter: Karen Copeland, M.S.
Date: Saturday, Oct. 8, 2016. 1:00-2:00 p.m.
Location: Poster 874P (Abstract 4031). Hall E.

This study assessed 354 patients with ovarian cancer undergoing BRCA1 and BRCA2 full sequencing and large rearrangement DNA analysis using the Tumor BRACAnalysis CDx test. The results show that, of the 354 samples analyzed, 93 (26.3 percent) tested positive for a pathogenic mutation; 57 were found in BRCA1 and 37 in BRCA2. Of the pathogenic mutations detected, 93.6 percent were sequencing variants and 6.4 percent were large rearrangements. These findings highlight the utility of the Tumor BRACAnalysis CDx test to accurately detect BRCA mutations in patients with ovarian cancer.

Title: The molecular landscape of genome instability in prostate cancer.
Presenter: Kirsten Timms, Ph.D.
Date: Monday, Oct. 10, 2016. 1:00-2:00 p.m.
Location: Poster 115P (Abstract 3247). Hall E.

In this study, DNA from 95 prostate cancer (PC) tumors was analyzed to generate homologous recombination deficiency (HRD) and Microsatellite instability (MSI) and cell cycle progression (CCP) scores. Additionally, 45 DNA damage repair (DDR) genes were sequenced and were considered non-functional if both alleles were mutated and/or deleted. If the second allele was intact, these genes were considered defective but functional. The results showed that non-functional DDR genes (CDK12, PALB2, RPA1, ATM, and BRCA2) were observed in seven tumors and DDR gene defects in eight genes were observed in 11 tumors. Importantly, the HRD score was significantly associated with DDR mutation status, Gleason score and CCP score. A significant proportion of aggressive prostate tumors carry molecular signatures associated with response to therapies targeting DDR deficiencies or to immune-therapeutics. This study demonstrates the importance of assessing both alleles when identifying prostate tumors with DDR gene mutations. In the study, an HRD score of ≥20 identified three times as many potential responders to HRD-dependent therapies compared to non-functional DDR gene mutations.

Title: Characteristics of homologous recombination deficiency (HRD) in paired primary and recurrent high-grade serous ovarian cancer.
Presenter: Jai Patel.
Date: Monday, Oct. 10, 2016. 1:00-2:00 p.m.
Location: Poster 113P (Abstract 3290). Hall E.

In this study, the myChoice HRD test was used to evaluate paired primary and recurrent tumors from 54 patients with high-grade serous ovarian cancer (HGSOC), the vast majority of whom were treated with adjuvant carboplatin and paclitaxel. The objective was to determine if changes in the genomic profile of primary and recurrent tumors might impact the myChoice HRD score. The results showed that there were no significant differences in the genomic markers evaluated between primary and recurrent tumors. Importantly, the myChoice HRD test was not impacted by changes in the genomic profile. This finding suggests that testing recurrent HGSOC tumors would not alter treatment strategies relative to analysis of the primary tumor.

Title: Homologous recombination deficiency (HRD) score shows superior association with outcome compared to its individual score components (LOH, TAI, and LST scores) in platinum treated serous ovarian cancer.
Presenter: Jerry Lanchbury, Ph.D.
Date: Monday, Oct. 10, 2016. 1:00-2:00 p.m.
Location: Poster 112P (Abstract 2504). Hall E.

The myChoice HRD score is the sum of three independent measures of HRD, including loss of heterozygosity (LOH), telomeric-allelic imbalance (TAI) and large-scale state transitions (LST). This study compared the myChoice HRD score to its individual score components (LOH, TAI, and LST). The results showed that the myChoice HRD score is a superior prognostic marker of HR deficiency than the individual scores. There were a significant number of discrepancies between the myChoice HRD score and the individual component, which demonstrated a risk of both false positives and negatives. These findings support the use of myChoice HRD, rather than the individual biomarkers, to inform treatment decisions for patients.

About Tumor BRACAnalysis CDx
Tumor BRACAnalysis CDx is a companion diagnostic test for identifying both germline and somatic cancer-causing mutations in the BRCA1 and BRCA2 genes. Currently, Tumor BRACAnalysis CDx is a CE-marked genomic test designed to detect the presence of a BRCA1 or BRCA2 gene mutation in ovarian tumor tissue. Additionally, Myriad is actively collaborating with leading pharmaceutical companies and academic centers to further develop Tumor BRACAnalysis CDx as a companion diagnostic for use with certain PARP inhibitors, platinum-based drugs and other chemotherapeutic agents.

On October 7, 2016 Kite Pharma, Inc. (Nasdaq:KITE) reported updated results from the Phase 1 portion of Kite’s ZUMA-1 clinical trial of its lead product candidate, KTE-C19, in patients with chemorefractory, aggressive non-Hodgkin lymphoma (NHL) (Press release, Kite Pharma, OCT 7, 2016, View Source [SID:SID1234515649]). The results were provided in an oral presentation at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) annual congress. KTE-C19 is an investigational therapy in which a patient’s T cells are genetically modified to express a chimeric antigen receptor (CAR) that is designed to target the antigen CD19, a protein expressed on the cell surface of B-cell lymphomas and leukemias.

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"These data complement our recently reported interim topline results from ZUMA-1 Phase 2 and support the potential for KTE-C19 to be a breakthrough therapy for chemorefractory, aggressive NHL," said David Chang, M.D., Ph.D., Executive Vice President, Research and Development, and Chief Medical Officer of Kite. "We are encouraged that the complete remission rate of 43 percent in the Phase 1 portion of the study continues through month 12 and look forward to reporting additional data on the durability of response to KTE-C19 from the Phase 2 portion of ZUMA-1 in 2017."

A summary of the 12-month follow-up data from the Phase 1 portion of the ZUMA-1 study is provided below.

Ongoing complete remissions in phase 1 of ZUMA-1: a phase 1-2 multi-center study evaluating the safety and efficacy of KTE-C19 (anti-CD19 CAR T cells) in patients with refractory aggressive B cell non-Hodgkin Lymphoma (NHL). Abstract 1048O; Presenter: Frederick Locke, M.D., Moffitt Cancer Center, Tampa, FL; Friday, October 7, 2016: 4:00-5:30pm CEST; Proffered Paper session: Immunotherapy of Cancer (SITC) (Free SITC Whitepaper); Location: Copenhagen.

Phase 1 of ZUMA-1 treated a total of 7 patients with chemorefractory, diffuse large B-cell lymphoma (DLBCL)
KTE-C19 related adverse events consisted predominantly of cytokine release syndrome (CRS) and neurotoxicity which were generally reversible
Grade 3 or higher CRS was observed in 14 percent and neurotoxicity in 57 percent; all were reversible except in one patient with dose-limiting toxicity
KTE-C19 achieved rapid and durable responses in patients with chemorefractory disease (objective response rate 71 percent, complete remission rate 57 percent)
Ongoing complete remissions were observed in 3 of 7 patients as of 12-month study follow-up
Three additional posters relating to KTE-C19 clinical trials in progress will also be presented at ESMO (Free ESMO Whitepaper) 2016.

ZUMA-1: A phase 2 multi-center study evaluating anti-CD19 chimeric antigen receptor (CAR) T cells in patients with refractory aggressive non-Hodgkin lymphoma (NHL). Abstract 943TiP; Saturday, October 8, 2016: 1:00-2:00pm CEST; Poster Display session; Location: Hall E.

ZUMA-2: A phase 2 multi-center study evaluating the efficacy of KTE-C19 (Anti-CD19 CAR T cells) in patients with relapsed/refractory Mantle cell lymphoma (R/R MCL). Abstract 945TiP; Saturday, October 8, 2016: 1:00-2:00pm CEST; Poster Display session; Location: Hall E.

ZUMA-3: A phase 1/2 multi-center study evaluation the safety and efficacy of KTE-C19 anti-CD19 CAR T cells in adult patients with relapsed/refractory B precursor acute lymphoblastic leukemia (R/R ALL). Abstract 415TiP; Monday, October 10, 2016: 1:00-2:00pm CEST; Poster Display session; Location: Hall E.

About KTE-C19

Kite Pharma’s lead product candidate, KTE-C19, is an investigational therapy in which a patient’s T cells are engineered to express a CAR to target the antigen CD19, a protein expressed on the cell surface of B-cell lymphomas and leukemias, and redirect the T cells to kill cancer cells. KTE-C19 has been granted Breakthrough Therapy Designation status for diffuse large B-cell lymphoma (DLBCL), transformed follicular lymphoma (TFL), and primary mediastinal B-cell lymphoma (PMBCL) by the U.S. Food and Drug Administration and Priority Medicines (PRIME) regulatory support for DLBCL in the EU.

On October 7, 2016 Exelixis, Inc. (NASDAQ:EXEL) reported results from a phase 1 trial of cabozantinib in combination with nivolumab in patients with previously treated genitourinary tumors (Press release, Exelixis, OCT 7, 2016, View Source;p=RssLanding&cat=news&id=2210053 [SID:SID1234515648]). The findings will be presented during a poster discussion session (Abstract #774PD) on October 9 at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) 2016 Congress, which is being held in Copenhagen, October 7 – 11, 2016.

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"The treatment landscape for advanced, intractable cancers such as metastatic urothelial carcinoma is continuously evolving and the use of combination therapies may improve outcomes for patients in need of new options," said Andrea Apolo, M.D., Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, the principal investigator of the trial. "Our previous correlative studies have demonstrated that cabozantinib has immunomodulatory properties that may counteract tumor-induced immunosuppression, providing the rationale for this trial.1,2 These promising early stage clinical findings support further investigation of cabozantinib in combination with nivolumab in a number of genitourinary tumors."

Between July 2015 and September 2016, 24 patients were accrued with metastatic urothelial carcinoma (n=7), urachal adenocarcinoma (n=4), squamous cell carcinoma of the bladder or urethra (n=3), germ cell tumor (n=4), castration-resistant prostate cancer (n=4), renal cell carcinoma (n=1), or trophoblastic tumor (n=1) and were treated in Part I of the study, which evaluated the combination of cabozantinib and nivolumab at four dose levels. The median number of prior systemic therapies was 3, and 10 patients had received 4 or more prior therapies. The objective response rate was 43 percent among the 23 patients who were evaluable for response, with one complete response and nine partial responses. Four of six patients (67 percent) with urothelial cancer achieved a response. The recommended doses for the ongoing expansion cohorts were determined to be cabozantinib at 40 mg daily and nivolumab at 3 mg/kg once every 2 weeks. Part II of the phase 1 trial examining the use of the triplet combination of cabozantinib, nivolumab, and ipilimumab is also ongoing.

"Cabozantinib has demonstrated clinical activity as a single agent in several tumors, and we are interested in further examining its potential in combination with immunotherapies to treat a variety of genitourinary and other cancers," said Michael M. Morrissey, Ph.D., president and chief executive officer of Exelixis. "We are encouraged by these preliminary phase 1 data and look forward to results from the ongoing expansion cohorts in this trial in patients with metastatic urothelial carcinoma and renal cell carcinoma."

Common grade 1/2 adverse events observed in more than 30 percent of patients were fatigue, diarrhea, anorexia, dysgeusia, hoarseness, and oral mucositis. Grade 3 adverse events observed in more than 10 percent of patients, included neutropenia, fatigue, and thromboembolic events. There was one grade 4 adverse event of lipase elevation. No grade 5 toxicities were observed.

In addition to Part I, the study also has enrolled 15 patients in Part II, which is evaluating the triplet combination of cabozantinib, nivolumab, and ipilimumab. Expansion cohorts assessing cabozantinib and nivolumab are currently being accrued with bladder, renal and rare genitourinary cancer patients. Data from these patients will be reported at a later date.

About Genitourinary Cancers

Genitourinary cancers are those that affect the urinary tract, bladder, kidneys, ureter, prostate, testicles, penis or adrenal glands — parts of the body involved in reproduction and excretion — and include renal cell carcinoma and urothelial carcinoma.3

Kidney cancer is among the top ten most commonly diagnosed forms of cancer among both men and women in the U.S., according to the American Cancer Society’s 2016 statistics.4 Clear cell renal cell carcinoma is the most common type of kidney cancer in adults.5 If detected in its early stages, the five-year survival rate for RCC is high; for patients with advanced or late-stage metastatic RCC, however, the five-year survival rate is only 12 percent, with no identified cure for the disease.4 Approximately 30,000 patients in the U.S. and 68,000 globally require treatment.6

Prostate cancer is the second most common cause of cancer death in men, behind only skin cancer.7 There is a high survival rate for patients when prostate cancer is detected early, but once the disease has spread to other parts of the body the five-year survival rate is just 28 percent.8 Approximately 2,850,000 men were living with prostate cancer in the U.S. in 2013,9 and 180,000 new cases are diagnosed each year.7

Urothelial cancers encompass carcinomas of the bladder, ureter and renal pelvis at a ratio of 50:3:1, respectively.10 Urothelial carcinoma occurs mainly in older people, with 90 percent of patients aged 55 or older.11 Bladder cancer is the fourth most common cancer in men and accounts for about five percent of all new cases of cancer in the U.S. each year.11 In 2013, an estimated 587,426 people were living with bladder cancer in the U.S.12

About CABOMETYX (cabozantinib)

CABOMETYX is the tablet formulation of cabozantinib. Its targets include MET, AXL and VEGFR-1, -2 and -3. In preclinical models, cabozantinib has been shown to inhibit the activity of these receptors, which are involved in normal cellular function and pathologic processes such as tumor angiogenesis, invasiveness, metastasis and drug resistance.

CABOMETYX is available in 20 mg, 40 mg or 60 mg doses. The recommended dose is 60 mg orally, once daily.

On April 25, 2016, the FDA approved CABOMETYX tablets for the treatment of patients with advanced renal cell carcinoma who have received prior anti-angiogenic therapy. On September 9, 2016, the European Commission approved CABOMETYX tablets for the treatment of advanced renal cell carcinoma in adults who have received prior vascular endothelial growth factor (VEGF)-targeted therapy in the European Union, Norway and Iceland. On February 29, 2016, Exelixis and Ipsen jointly announced an exclusive licensing agreement for the commercialization and further development of cabozantinib indications outside of the United States, Canada and Japan.

U.S. Important Safety Information

Hemorrhage: Severe hemorrhage occurred with CABOMETYX. The incidence of Grade ≥3 hemorrhagic events was 2.1% in CABOMETYX-treated patients and 1.6% in everolimus-treated patients. Fatal hemorrhages also occurred in the cabozantinib clinical program. Do not administer CABOMETYX to patients that have or are at risk for severe hemorrhage.

Gastrointestinal (GI) Perforations and Fistulas: Fistulas were reported in 1.2% (including 0.6% anal fistula) of CABOMETYX-treated patients and 0% of everolimus-treated patients. GI perforations were reported in 0.9% of CABOMETYX-treated patients and 0.6% of everolimus-treated patients. Fatal perforations occurred in the cabozantinib clinical program. Monitor patients for symptoms of fistulas and perforations. Discontinue CABOMETYX in patients who experience a fistula that cannot be appropriately managed or a GI perforation.

Thrombotic Events: CABOMETYX treatment results in an increased incidence of thrombotic events. Venous thromboembolism was reported in 7.3% of CABOMETYX-treated patients and 2.5% of everolimus-treated patients. Pulmonary embolism occurred in 3.9% of CABOMETYX-treated patients and 0.3% of everolimus-treated patients. Events of arterial thromboembolism were reported in 0.9% of CABOMETYX-treated patients and 0.3% of everolimus-treated patients. Fatal thrombotic events occurred in the cabozantinib clinical program. Discontinue CABOMETYX in patients who develop an acute myocardial infarction or any other arterial thromboembolic complication.

Hypertension and Hypertensive Crisis: CABOMETYX treatment results in an increased incidence of treatment-emergent hypertension. Hypertension was reported in 37% (15% Grade ≥3) of CABOMETYX-treated patients and 7.1% (3.1% Grade ≥3) of everolimus-treated patients. Monitor blood pressure prior to initiation and regularly during CABOMETYX treatment. Withhold CABOMETYX for hypertension that is not adequately controlled with medical management; when controlled, resume CABOMETYX at a reduced dose. Discontinue CABOMETYX for severe hypertension that cannot be controlled with anti-hypertensive therapy. Discontinue CABOMETYX if there is evidence of hypertensive crisis or severe hypertension despite optimal medical management.

Diarrhea: Diarrhea occurred in 74% of patients treated with CABOMETYX and in 28% of patients treated with everolimus. Grade 3 diarrhea occurred in 11% of CABOMETYX-treated patients and in 2% of everolimus-treated patients. Withhold CABOMETYX in patients who develop intolerable Grade 2 diarrhea or Grade 3-4 diarrhea that cannot be managed with standard antidiarrheal treatments until improvement to Grade 1; resume CABOMETYX at a reduced dose. Dose modification due to diarrhea occurred in 26% of patients.

Palmar-Plantar Erythrodysesthesia Syndrome (PPES): Palmar-plantar erythrodysesthesia syndrome (PPES) occurred in 42% of patients treated with CABOMETYX and in 6% of patients treated with everolimus. Grade 3 PPES occurred in 8.2% of CABOMETYX-treated patients and in <1% of everolimus-treated patients. Withhold CABOMETYX in patients who develop intolerable Grade 2 PPES or Grade 3 PPES until improvement to Grade 1; resume CABOMETYX at a reduced dose. Dose modification due to PPES occurred in 16% of patients.

Reversible Posterior Leukoencephalopathy Syndrome (RPLS): RPLS, a syndrome of subcortical vasogenic edema diagnosed by characteristic finding on MRI, occurred in the cabozantinib clinical program. Perform an evaluation for RPLS in any patient presenting with seizures, headache, visual disturbances, confusion, or altered mental function. Discontinue CABOMETYX in patients who develop RPLS.

Embryo-fetal Toxicity: CABOMETYX can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with CABOMETYX and for 4 months after the last dose.

Adverse Reactions: The most commonly reported (≥25%) adverse reactions are: diarrhea, fatigue, nausea, decreased appetite, PPES, hypertension, vomiting, weight decreased, and constipation.

Drug Interactions: Strong CYP3A4 inhibitors and inducers: Reduce the dosage of CABOMETYX if concomitant use with strong CYP3A4 inhibitors cannot be avoided. Increase the dosage of CABOMETYX if concomitant use with strong CYP3A4 inducers cannot be avoided.

Lactation: Advise a lactating woman not to breastfeed during treatment with CABOMETYX and for 4 months after the final dose.

Reproductive Potential: Contraception―Advise females of reproductive potential to use effective contraception during treatment with CABOMETYX and for 4 months after the final dose. Infertility ―CABOMETYX may impair fertility in females and males of reproductive potential.

Hepatic Impairment: Reduce the CABOMETYX dose in patients with mild (Child-Pugh score [C-P] A) or moderate (C-P B) hepatic impairment. CABOMETYX is not recommended for use in patients with severe hepatic impairment.

Please see full Prescribing Information at View Source

On October 7, 2016 Exelixis, Inc. (NASDAQ:EXEL) reported that its collaborator Genentech, a member of the Roche Group, will present preliminary results from a phase 1b clinical trial evaluating the safety and clinical activity of the triple combination of cobimetinib, vemurafenib, and atezolizumab in patients with previously untreated BRAF V600 mutation-positive advanced melanoma (Press release, Exelixis, OCT 7, 2016, View Source;p=RssLanding&cat=news&id=2210054 [SID:SID1234515647]). The results will be the subject of a poster discussion presentation (Abstract #1109PD) at the European Society of Medical Oncology (ESMO) (Free ESMO Whitepaper) 2016 Congress, which is being held October 7-11 in Copenhagen, Denmark. Patrick Hwu, M.D., chair of the Department of Melanoma Medical Oncology at the University of Texas M.D. Anderson Cancer Center, Houston, Texas, will present the results during a session on Monday, October 10, 2016, beginning at 11:00 a.m. CEST.

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"Cobimetinib and vemurafenib is FDA-approved to treat specific forms of BRAF V600 mutation-positive unresectable or metastatic melanoma and has been associated with significant improvements in progression-free survival, overall survival and objective response rate as compared to vemurafenib alone," said Michael M. Morrissey, Ph.D., president and chief executive officer of Exelixis. "The preliminary results to be presented at the ESMO (Free ESMO Whitepaper) Congress suggest that adding atezolizumab to the combination regimen is associated both with a manageable safety profile and promising antitumor activity."

The primary objective of the phase 1b trial is the evaluation of the safety and tolerability of the triple combination. Secondary endpoints include progression-free survival (PFS), overall survival (OS), objective response rate (ORR), best overall response, and duration of response, as well as additional exploratory objectives. Patients in the trial receive the triple combination of cobimetinib, vemurafenib, and atezolizumab after a 28-day run-in cycle of combination cobimetinib and vemurafenib. Atezolizumab is administered intravenously at 800 mg every two weeks.

As of the June 15, 2016 data cut-off, 30 patients with previously untreated BRAF V600 mutation-positive unresectable or advanced melanoma who had received at least one dose of atezolizumab were evaluable for safety. The median follow-up for safety was 3.9 months, with a range of 0.7 to 16.8 months. All-grade AEs occurring in greater than 20 percent of patients and reported as related to cobimetinib and/or vemurafenib and/or atezolizumab included elevated liver enzymes, fatigue, arthralgia, diarrhea, flu-like symptoms, photosensitivity, increased blood alkaline phosphatase, fever and pyrexia. Twelve patients had cobimetinib- and/or vemurafenib and/or atezolizumab-related grade 3/4 AEs during the triple combination period; all resolved after appropriate intervention.

Twenty-nine patients had received at least one dose of atezolizumab and undergone at least one on-treatment, post baseline tumor assessment. The ORR, a secondary endpoint, was 83 percent with 24 patients achieving a response (fifteen of which were confirmed as of the data cutoff). Three patients (10 percent) achieved complete responses and 21 patients had partial responses (72 percent). All but one subject in the trial had a reduction of tumor burden. Median duration of response and PFS were not evaluable as a result of limited follow-up time.

Immune biomarkers potentially predictive of clinical responses were evaluated in this phase 1b trial. Increases in CD8+ T cells in the tumor were observed following cobimetinib and vemurafenib treatment during the run-in period.

A pivotal placebo-controlled phase 3 trial evaluating the combination of cobimetinib, vemurafenib and atezolizumab compared to cobimetinib, vemurafenib and placebo was recently posted on ClinicalTrials.gov. Sponsored by Roche, the full title of study NCT02908672 is "A Study of Atezolizumab Plus Cobimetinib and Vemurafenib Versus Placebo Plus Cobimetinib and Vemurafenib in Previously Untreated BRAFv600 Mutation-Positive Participants With Metastatic or Unresectable Locally Advanced Melanoma." Exelixis expects to share additional details of this trial as they become available from its collaborator Roche.

Cobimetinib is a selective inhibitor of MEK that was discovered by Exelixis and is the subject of a worldwide collaboration agreement between Exelixis and Genentech. Cobimetinib is approved in multiple countries to treat specific forms of BRAF V600 mutation-positive unresectable or metastatic melanoma, in combination with vemurafenib. Atezolizumab is an anti-PD-L1 antibody developed by Genentech that received FDA approval to treat previously treated bladder cancer in May 2016.

Additional Cobimetinib Data Presented at the ESMO (Free ESMO Whitepaper) 2016 Congress

The poster discussion presentation in advanced melanoma is one of seven cobimetinib abstracts being presented at the ESMO (Free ESMO Whitepaper) 2016 Congress. Additional data presentations include studies of cobimetinib in combination with other therapies to treat metastatic colorectal cancer and triple-negative breast cancer and BRAF-mutant melanoma. For full logistical information on these other presentations, please see Exelixis’ ESMO (Free ESMO Whitepaper) announcement press release issued on August 31, 2016, available online here.

About the Cobimetinib Development Collaboration

Exelixis discovered cobimetinib internally and advanced the compound to investigational new drug (IND) status. In late 2006, Exelixis entered into a worldwide collaboration agreement with Genentech, under which Exelixis received initial upfront and milestone payments for signing the agreement and submitting the IND. Following the determination of the maximum tolerated dose in phase 1 by Exelixis, Genentech exercised its option to further develop cobimetinib.

Under the terms of the collaboration, Exelixis is entitled to an initial equal share of U.S. profits and losses, which will decrease as sales increase, and shares U.S. commercialization costs. In November 2013, Exelixis exercised its option to co-promote cobimetinib in the United States and fields 25 percent of the U.S. sales force, closely coordinating its efforts with Genentech. Outside of the United States, Exelixis is eligible to receive royalties on any sales.

Cobimetinib is now approved in multiple countries, including the United States, European Union, Switzerland, Canada, Australia and Brazil, to treat specific forms of BRAF mutation-positive unresectable or metastatic melanoma, in combination with vemurafenib. The trade name for cobimetinib is COTELLIC. Further country approvals are anticipated in 2016 and beyond. Cobimetinib is also the subject of a clinical development program aimed at evaluating its potential in combination with a variety of investigational and approved therapies in disease settings including metastatic melanoma, triple-negative breast cancer and advanced solid tumors.

COTELLIC Indication

COTELLIC (cobimetinib) is a prescription medicine that is used with the medicine Zelboraf (vemurafenib), to treat a type of skin cancer called melanoma that has spread to other parts of the body or cannot be removed by surgery, and that has a certain type of abnormal "BRAF" gene.

A patient’s healthcare provider will perform a test for the BRAF gene to make sure that COTELLIC is right for them. It is not known if COTELLIC is safe and effective in children under 18 years of age.

COTELLIC Important Safety Information

Patients should avoid sunlight during treatment with COTELLIC and Zelboraf. COTELLIC and Zelboraf can make a patient’s skin sensitive to sunlight. They may burn more easily and get severe sunburns. When a patient goes outside, they should wear clothes that protect their skin, including their head, face, hands, arms and legs. They should use lip balm and a broad-spectrum sunscreen with SPF 30 or higher.

COTELLIC and Zelboraf may cause serious side effects, including risk of new skin cancers, risk of other cancers, bleeding problems, heart problems, allergic reactions, severe rash and other severe skin reactions, eye problems, changes in the electrical activity of the heart (QT prolongation), liver problems or liver injury, muscle problems (rhabdomyolysis), skin sensitivity to sunlight (photosensitivity), worsening side effects from radiation treatment, and kidney injury.

Patients should tell their doctor if they are pregnant or plan to become pregnant, as COTELLIC and Zelboraf can harm an unborn baby. Females who are able to become pregnant should use effective birth control during treatment with COTELLIC and Zelboraf and for two weeks after the final dose of COTELLIC or Zelboraf (whichever is taken later).

Patients should not breastfeed during treatment and for two weeks after the final dose of COTELLIC or Zelboraf (whichever is taken later). Patients should talk to their healthcare provider about the best way to feed their baby during this time.

Patients should tell their healthcare provider about all the medicines they take. Some types of medicines will affect the blood levels of COTELLIC.

Common side effects of COTELLIC in combination with Zelboraf include diarrhea, sunburn or sun sensitivity, nausea, fever and vomiting. COTELLIC and Zelboraf can also cause changes in blood test results.

Patients should tell their healthcare provider if they have any side effect that bothers them or that does not go away. These are not all the possible side effects of COTELLIC and Zelboraf.

Patients should call their doctor for medical advice about side effects. Patients may report side effects to FDA at (800) FDA-1088 or www.fda.gov/medwatch. Patients may also report side effects to Genentech at (888) 835-2555.

Please see both Full COTELLIC Prescribing Information and Patient Information and Full Zelboraf Prescribing Information and Medication Guide for additional Important Safety Information at www.cotellic.com and www.zelboraf.com.

On October 7, 2016 Clovis Oncology (NASDAQ:CLVS) reported the oral presentation of the primary efficacy and safety data from its NDA dataset for rucaparib at the 2016 ESMO (Free ESMO Whitepaper) Congress in Copenhagen (Press release, Clovis Oncology, OCT 7, 2016, View Source;p=RssLanding&cat=news&id=2210141 [SID:SID1234515646]). Rucaparib is currently under priority review with FDA for the monotherapy treatment of advanced ovarian cancer in patients with BRCA-mutated tumors inclusive of both germline and somatic BRCA mutations who have been treated with two or more chemotherapies, and the submission has a PDUFA date of February 23, 2017.

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Rucaparib is the Company’s oral, small molecule inhibitor of PARP1, PARP2 and PARP3 currently being developed for the treatment of ovarian cancer, specifically in patients with tumors with BRCA mutations and other DNA repair deficiencies beyond BRCA, including those with high genomic loss of heterozygosity (LOH) also known as "BRCA-like." The current NDA submission seeks approval in patients with tumor BRCA mutations, which includes both germline and somatic mutations.

"These results demonstrate that rucaparib may represent an important option for women with multiply relapsed BRCA-mutated ovarian cancer based on its encouraging efficacy and tolerability," said Rebecca S. Kristeleit, MD, PhD, The University College London, Cancer Institute, London, UK. "In my opinion, rucaparib has the hallmarks of an important new therapeutic option for ovarian cancer patients."

"We are pleased to present the primary efficacy and safety dataset that has been submitted to the FDA as the basis of our NDA for rucaparib in the treatment of advanced ovarian cancer. If approved, rucaparib would be the first PARP inhibitor in the U.S. indicated to treat ovarian cancer patients with germline or somatic BRCA mutations who have received two prior chemotherapies. Women with BRCA mutations represent about 25% of patients in the US living with ovarian cancer," said Patrick J. Mahaffy, CEO and President of Clovis Oncology. "Our NDA review is ongoing with FDA, and in addition we are actively preparing for a European submission during the fourth quarter of 2016."

Data from subgroups of two multicenter, single-arm open-label phase 2 studies, Study 10 (NCT01482715) and ARIEL2 (NCT01891344) were combined for an integrated efficacy and safety analysis which further characterized the clinical benefit of rucaparib at the recommended starting dose of 600 mg BID in women with advanced ovarian cancer. In the two studies, 377 patients met the criteria for inclusion in the safety population (diagnosis of ovarian cancer and having received one or more doses of the recommended dose of 600 mg of rucaparib), and 106 patients met the criteria for inclusion in the efficacy population (received 2 or more prior chemotherapies, including 2 or more platinum-based regimens, had a mutation of BRCA (germline or somatic), and received one or more doses of the recommended dose of 600 mg of rucaparib.

The major efficacy outcome measure for this analysis was objective response rate (ORR) and duration of response (DOR) as assessed by the investigator according to RECIST. All responses were confirmed.

For the efficacy population (n=106), the median number of prior chemotherapies was three, with 39% having received two prior therapies and 61% of patients having received three or more prior therapies. The median number of prior platinum-based therapies was two, with 57% having received two prior platinum-based therapies, and 43% having received three or more prior platinum-based therapies. Seventy-five percent of patients in the efficacy population were platinum-sensitive (as defined by recurrence after progression free interval (PFI) of ≥6 months), 19% were platinum resistant (recurrence after PFI <6 months) and 7% were platinum refractory (progression on platinum, PFI <2 months).

Summary of Efficacy Data

The RECIST ORR (objective response rate as assessed by the investigator, which includes complete and partial responses) in the efficacy population was 57/106, or 54% (95% CI: 43.8-63.5). This includes nine (9%) complete responders (CR) and 48 (45%) partial responders (PR). Thirty-six patients (34%) had stable disease (SD) as the best response, while nine patients (9%) had progressive disease (PD) as the best response and four (4%) were not evaluable (NE). Seventy-five of 106 patients, or 71% (95% CI: 61.1-79.2) had a RECIST or CA-125 response.

For the 42 patients from Study 10 included in the efficacy population, the RECIST ORR was 25/42, or 60% (95% CI: 43.3-74.4). This included four CRs (10%) and 21 PRs (50%). In addition, 12 patients (29%) had SD, two patients (5%) had PD and three (7%) were NE. For the 64 patients from ARIEL2 included in the efficacy population, the RECIST ORR was 32/64, or 50% (95% CI: 37.2-62.8). This included five CRs (8%) and 27 PRs (42%). In addition, 24 patients (38%) had SD, seven (11%) had PD and one (2%) was NE. Study 10 was limited to platinum sensitive patients; ARIEL2 included platinum sensitive, platinum resistant and platinum refractory patients.

In addition, ORR was assessed by subgroups including BRCA mutation type, number of prior chemotherapies and prior platinum regimens, PFI and platinum status. Patients with a BRCA1 (n=67) or BRCA2 (n=39) mutation both showed an ORR of 54% (95% CI: 41.1-66.0, 37.2-69.9, respectively) in line with the overall population. The ORR for patients with germline BRCA mutations (n=88) and somatic BRCA mutations (n=13) was 53% (95% CI: 42.5-64.1) and 46% (95% CI: 19.2-74.9), respectively; in addition, five patients with a BRCA mutation but unknown germline or somatic status had an ORR of 80% (95% CI: 28.4-99.5). Patients who received two prior chemotherapies (n=41) achieved an ORR of 68% (95% CI: 51.9-81.9). Patients who received two prior platinum regimens (n=60) demonstrated an ORR of 65% (95% CI: 51.6-76.9). Response by length of PFI differed for patients with PFI<6 months (n=27), 6-12 months (n=56) and greater than 12 months (n=23), reporting 19% (95% CI: 6.3-38.1), 63% (95% CI: 48.6-75.1) and 74% (95% CI: 51.6-89.8), respectively. Response by platinum status was reported as 0% (95% CI: 0.0-41.0) for platinum-refractory patients (n=7), 25% (95% CI: 8.7-49.1) for platinum-resistant patients (n=20), and 66% (95% CI: 54.3-76.1) for platinum-sensitive patients (n=79).

Duration of response by investigator assessment in the efficacy population was 9.2 months (95% CI: 6.6-11.7 months), and the censoring rate among responders was 47%. As of the cutoff dates, 20 patients with a RECIST response had an ongoing response.

Additionally, analyses not contained within the NDA submission showed median progression-free survival by investigator assessment in the efficacy population to be 10.0 months. Of 106 patients, 50 patients did not have an event of disease progression or death at the data cut-off dates. Of these 50 patients, 32 patients were still on treatment, and 18 patients discontinued treatment for reasons other than disease progression or death at the data cut-off dates. Of note, 79% of patients remained progression-free at six months, and 41% remained progression-free at 12 months.

For the efficacy dataset, the cut off dates were November 30, 2015 and February 29, 2016, for Study 10 and ARIEL2, respectively.

Summary of Safety Data

Of the 377 ovarian cancer patients treated with a starting dose of rucaparib 600 mg, 377 (100%) experienced a treatment-emergent adverse event (AE) of any grade, and 229 (61%) experienced a treatment-emergent AE grade 3 or higher. A total of 360 patients (96%) experienced a treatment-related AE of any grade, and 177 (47%) experienced a treatment-related AE that was grade 3 or higher. AEs leading to dose interruption occurred in 221 patients (59%). Treatment-related AEs leading to dose reduction occurred in 167 patients (44%), and treatment discontinuation in 30 patients (8%). The primary reasons for dose reduction were anemia/decreased hemoglobin (17%), asthenia/fatigue (14%) and nausea (11%). The primary reasons for treatment discontinuation were asthenia/fatigue (2%), small intestinal obstruction (2%) and nausea (1%). Nine patients (2%) had AEs that led to death; eight were due to disease progression, and one death was due to sepsis, which was assessed by the investigator to be unrelated to treatment.

The most common treatment-emergent AEs (all grades) reported in ≥20 percent of patients included nausea (77%), asthenia/fatigue (77%), vomiting (46%), anemia (44%), increased ALT/AST (41%) and constipation (40%). The most common Grade 3/4 treatment-emergent AEs reported in ≥10 percent of patients were anemia (25%), asthenia/fatigue (11%) and ALT/AST elevations (11%).

The increases in aspartate (AST) and alanine (ALT) aminotransferase levels that were observed were asymptomatic, reversible and were rarely associated with increases in bilirubin. The elevations normalized over time with continued rucaparib treatment.

Mild to moderate creatinine elevations were observed within the first few weeks of treatment for most patients, for whom 79 (21%) experienced an AE, of whom two (0.5%) experienced a grade 3/4 event. These elevations in creatinine likely result from inhibition of the renal transporters MATE1 and MATE2-K, which can lead to an increase in serum creatinine in the absence of renal injury.

Myelodysplastic syndrome/acute myeloid leukemia was reported in less than one percent of patients.

The cut-off dates for the safety dataset were March 31, 2016 for Study 10 and April 29, 2016 for ARIEL2.

Presentation Details

The oral presentation, titled "Clinical activity of the poly(ADP-ribose) polymerase (PARP) inhibitor rucaparib in patients (pts) with high grade ovarian carcinoma (HGOC) and a BRCA mutation (BRCAmut): Analysis of pooled data from Study 10 (parts 1, 2a, and 3) and ARIEL2 (parts 1 and 2)" was presented today by Rebecca S. Kristeleit, PhD, The University College London, Cancer Institute, London, United Kingdom during the Session titled "Gynecological Cancers", from 2:00pm-3:30pm CEST (Abstract 856O: 2:45pm-3:00pm CEST).

The Trials-in-Progress poster presentation, titled "Window study of the PARP inhibitor rucaparib in patients with primary triple negative or BRCA1/2 related breast cancer (RIO)" is being presented Monday by Christy Toms, PhD, The Institute of Cancer Research, Sutton, United Kingdom during the Poster Session titled "Breast Cancer, Early Stage" from 1:00pm-2:00pm CEST (Abstract 219TiP, Poster Board #219).

The presentations will be available online at View Source at the time of their scheduled presentation at the Congress.

About Rucaparib

Rucaparib is an oral, small molecule inhibitor of PARP-1, PARP-2 and PARP-3 being developed for advanced ovarian cancer.

Specifically, rucaparib is being developed as monotherapy treatment of advanced ovarian cancer in patients with deleterious BRCA-mutated tumors inclusive of both germline and somatic BRCA mutations (as detected by an FDA-approved test) who have been treated with two or more chemotherapies. Rucaparib was granted Breakthrough Therapy designation for this proposed indication by the U.S. FDA in April 2015; and in late June 2016, Clovis completed its New Drug Application (NDA) submission to the FDA. The filing for treatment was accepted and has an action date of February 23, 2017. Rucaparib’s Marketing Authorization Application (MAA) to the European Medicines Agency for the proposed treatment indication is planned for Q4 2016.

Foundation Medicine, Clovis’ companion diagnostic partner, has submitted a Premarket Approval (PMA) application for its FoundationFocus CDxBRCA to the FDA in June 2016. The test is designed to identify tumor BRCA mutations. The timing of the submission is expected to allow for regulatory approval of the companion diagnostic in a similar timeframe.

Additionally, rucaparib is being developed as maintenance therapy in the ARIEL3 trial (NCT01968213) for patients with tumors with BRCA mutations and other DNA repair deficiencies beyond BRCA (commonly referred to as homologous recombination deficiencies, or HRD). Data from ARIEL3 are expected in Q4 2017, which is expected to be followed by the submission of a supplemental NDA for second-line maintenance therapy.

Clovis is also exploring rucaparib in other solid tumor types with BRCA mutations or molecular evidence of the HRD signature, including prostate, breast and gastroesophageal cancers.

Clovis holds worldwide rights for rucaparib.

About Ovarian Cancer

According to the American Cancer Society, more than 22,000 women will be diagnosed with ovarian cancer in the U.S. during 2016. There are often no clearly identifiable initial symptoms, and in an estimated 80 to 85% of ovarian cancer cases, the cancer has spread to other parts of the body before a person is diagnosed and can be treated. Ovarian cancer ranks fifth in cancer deaths and causes more deaths than any other cancer of the female reproductive system. One in four women with ovarian cancer have a germline or somatic BRCA mutation, and new treatment options are needed to treat unique patient populations.