On June 5, 2016 AbbVie (NYSE: ABBV), a global biopharmaceutical company, reported safety and preliminary efficacy data from a Phase 1 study of ABT-414 – an investigational antibody drug conjugate (ADC) for epidermal growth factor receptor (EGFR) amplified, recurrent glioblastoma (GBM) – showed no dose-limiting toxicities and frequent, reversible ocular toxicities (Press release, AbbVie, JUN 5, 2016, View Source [SID:1234513029]). Additionally, an estimated 30 percent (n=44) of patients treated with ABT-414 as monotherapy were progression free at six months [95% CI=17, 44] (secondary endpoint). These results, from an expansion cohort of one arm (Arm C) of a three-arm open-label study, were presented today at the 52nd Annual Meeting of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) in Chicago.1 Amplified EGFR is the most common genetic mutation associated with malignant GBM, an aggressive brain cancer.2

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As of January 7, 2016, the most common serious adverse event (>1 patient) (n=48) was seizure (8%). Additionally, Best Response Assessment in Neuro-Oncology (RANO) Criteria, an assessment of tumor response used in GBM, identified two partial responses, 18 patients with stable disease, and 24 with progressive disease for a total of 44 patients with complete data.1

"With standard of care therapy,3 patients with GBM, the most common and most aggressive form of brain cancer,4 have a median survival of 15 months after diagnosis and two-year survival is 30%.5 There remains an urgent unmet need for new treatment options for this devastating brain cancer," said Martin van den Bent, M.D., Ph.D., head, Neuro-Oncology Unit, Erasmus MC Cancer Institute, the Netherlands, and lead investigator of the study. "These data are important as they demonstrate the potential of ABT-414 and underscore the need for further investigation in glioblastoma."

Additional Safety Findings
Grade 3/4 treatment emergent adverse events (TEAEs) (>1 patient) were keratitis (15%), corneal epithelial microcysts (8%), hemiparesis (6%), hyperglycemia (6%), muscular weakness (6%), seizure (6%), blurred vision (4%) and ulcerative keratitis (4%).The most common TEAEs (?25% patients) in this study arm were blurred vision (60%), headache (29%), photophobia (29%), dry eye (27%), eye pain (27%), and fatigue (27%). The most common serious adverse event (>1 patient) (n=48) was seizure (8%).1

"These results suggest that ABT-414 may have important activity for certain groups of patients with glioblastoma and support the continuation of the ongoing randomized studies," said Gary Gordon, M.D., vice president, oncology clinical development, AbbVie. "AbbVie is committed to continuing to invest in technologies and approaches, including antibody drug conjugates like ABT-414, with the goal of delivering a remarkable impact on cancer treatment."

Based on these results, together with previously presented data from this study, AbbVie advanced ABT-414 to a randomized Phase 2 clinical trial in patients with EGFR-amplified GBM.1

About this Study
The Phase 1, open-label trial was designed to evaluate the safety, pharmacokinetics and maximum tolerated dose of ABT-414. Three study arms evaluated ABT-414 with radiotherapy and temozolomide (TMZ) in patients with newly diagnosed glioblastoma (GBM) (Arm A), with TMZ in patients with newly diagnosed glioblastoma who have just completed radiation and TMZ or recurrent GBM (Arm B) or as monotherapy in patients with recurrent GBM (Arm C).1

Eligible patients in Arm C were adults with a Karnofsky Performance Status (KPS) score ?70, EGFR amplification (confirmed centrally), recurrent GBM, normal end-organ function and no prior treatment with bevacizumab. Forty-eight EGFR-amplified recurrent GBM patients were treated in this arm. The median age was 59 years (range, 35-80). Most patients had prior therapies: 40 percent had one, 48 percent had two, and 10 percent had three or more prior therapies.1

About ABT-414
ABT-414 is an investigational monoclonal antibody drug conjugate (ADC) targeting EGFR (epidermal growth factor receptor) developed by AbbVie researchers with components in-licensed from Life Science Pharmaceuticals, Inc. and Seattle Genetics.1 It is being evaluated for the treatment of patients with EGFR-amplified glioblastoma, an aggressive malignant primary brain tumor.1,4 In 2014, the FDA and the European Medicines Agency granted orphan drug designation for the treatment of glioblastoma and glioma, respectively.6,7 ABT-414 is an investigational compound and its efficacy and safety have not been established by the FDA or any other health authority.

About Glioblastoma
Glioblastoma is the most common and most aggressive type of malignant primary brain tumor.4 Mutations in EGFR are the most common genetic abnormality associated with glioblastoma, with a frequency of about 50 percent.2 Prior to diagnosis, patients may experience headache, vision problems, nausea/vomiting, personality changes and seizures.4 For adults with more aggressive glioblastoma, treated with standard therapy, median survival is about 15 months.5 Treatment for glioblastoma remains challenging.4 Standard treatment is surgical resection, radiotherapy and concomitant adjunctive chemotherapy.5

On June 5, 2016 Merck (NYSE:MRK), known as MSD outside the United States and Canada, reported findings from three separate studies evaluating the use of KEYTRUDA (pembrolizumab), the company’s anti-PD-1 therapy, in combination with other treatment regimens including talimogene laherparepvec, dabrafenib plus trametinib, or low-dose ipilimumab in patients with advanced melanoma (Press release, Merck & Co, JUN 5, 2016, View Source [SID:1234513009]). These data, from MASTERKEY-265, KEYNOTE-022, and KEYNOTE-029, respectively, are included in the 52nd Annual Meeting of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) in Chicago (Abstracts #9568, #3014, and #9506).

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"We continue to build on our leadership in advanced melanoma by evaluating KEYTRUDA with multiple combination partners utilizing diverse mechanisms of action with the goal of improving outcomes while maintaining tolerability," said Dr. Roger Dansey, senior vice president and therapeutic area head, oncology late-stage development, Merck Research Laboratories. "These encouraging early data point to the potential for KEYTRUDA to become an important component of combination therapy in melanoma."

Each of these studies was designed to answer specific questions around the use of KEYTRUDA in various combination treatment settings. In each of the three studies, the safety profile of the combination regimens was shown to be manageable.

"Anti-PD-1 drug therapies, like pembrolizumab, have shown benefit as a monotherapy in the treatment of advanced melanoma, and it is important to understand their potential in combination with other effective therapeutics, including immunotherapies and targeted therapies," said Dr. Georgina Long, professor of melanoma medical oncology and translational melanoma research, Melanoma Institute Australia and University of Sydney. "Physicians are focused on different treatment paths for different types of patients and, with the promising data presented at ASCO (Free ASCO Whitepaper) this year, we aim to better understand the role of monotherapy and develop combination treatment strategies for patients with advanced melanoma who may not benefit as much from monotherapy."

The KEYTRUDA (pembrolizumab) clinical development program includes patients with more than 30 tumor types in more than 270 ongoing or planned studies, including more than 100 trials that combine KEYTRUDA with other cancer treatments – these include other immuno-oncology therapies, standard therapies and targeted therapies.

Findings from MASTERYKEY-265: KEYTRUDA with talimogene laherparepvec (Abstract #9568)

MASTERKEY-265 is an ongoing phase 1b study evaluating the safety, efficacy, and tolerability of KEYTRUDA in combination with talimogene laherparepvec in patients with previously untreated, unresectable advanced melanoma. The trial is a collaboration between Merck and Amgen. Talimogene laherparepvec is a herpes simplex virus-1 (HSV-1)-based oncolytic immunotherapy used for the treatment of melanoma lesions in the skin and lymph nodes.

Updated data from 21 evaluable patients showed that a combination of KEYTRUDA (200 mg every two weeks) with talimogene laherparepvec (up to 4 mL of 106 PFU/mL, then 108 PFU/mL every two weeks) resulted in a confirmed overall response rate (ORR) of 57.1 percent (n=12/21) (95% CI, 34-78.2), per modified immune-related response criteria (irRC) – 23.8 percent were complete responses (n=5/21) and 33.3 percent were partial responses (n=7/21).

The safety profile of KEYTRUDA in combination with talimogene laherparepvec was consistent with that observed in previously reported studies of KEYTRUDA or talimogene laherparepvec monotherapy in patients with advanced melanoma. Seven patients (33%) experienced treatment-related Grade 3-4 adverse events, including: anemia, aseptic meningitis, autoimmune hepatitis, generalized rash, headache, hyperglycemia, hypoglycemia, hypophosphatemia, increased alanine aminotransferase, increased aspartate aminotransferase, increased gamma-glutamyltransferase, muscle spasms, macular rash, rash, and pneumonitis. Two patients (10%) experienced a treatment-related adverse event that led to permanent discontinuation of KEYTRUDA. No patients (0%) experienced a treatment-related adverse event that led to permanent discontinuation of talimogene laherparepvec. No dose-limiting toxicities were reported.

These data were presented by Dr. Long on June 4.

Findings from KEYNOTE-022: KEYTRUDA with dabrafenib plus trametinib (Abstract #3014)

KEYNOTE-022 is an ongoing phase 1/2 study designed to assess the safety and efficacy of KEYTRUDA in combination with dabrafenib plus trametinib in patients with advanced melanoma. Dabrafenib (a BRAF inhibitor) and trametinib (a MEK inhibitor) is a combination regimen used in the treatment of certain types of advanced melanoma.

Based on early data from the 15 patients treated in phase 1, treatment with KEYTRUDA (pembrolizumab) (2 mg/kg every three weeks) with dabrafenib (150 mg twice daily) plus trametinib (2 mg daily) resulted in nine partial responses, five of which were confirmed. Additionally, of the patients with lesion data available, 92.3 percent experienced a reduction in tumor size (n=12/13).

Grade 3-4 adverse events occurring in greater than or equal to 10 percent of patients included ALT increased (n=3), AST increased (n=3), pyrexia (n=3), GGT increased (n=2), and WBC count decreased (n=2). Four patients (26.7%) experienced a treatment-related adverse even that led to discontinuation. There were no treatment-related deaths. The phase 2 part of the study is ongoing and will further evaluate the safety and efficacy of the KEYTRUDA combination regimen compared to dabrafenib plus trametinib.

On June 5, these data will be presented by Dr. Antoni Ribas in a poster session from 8:00 – 11:30 a.m. CDT (Location: Hall A) and in a poster discussion from 4:45 – 6:00 p.m. CDT (Location: Hall B1).

Findings from KEYNOTE-029: KEYTRUDA with low-dose ipilimumab (Abstract #9506)

KEYNOTE-029 is an ongoing phase 1/2 study evaluating the safety, efficacy, and tolerability of KEYTRUDA in combination with low-dose ipilimumab in patients with advanced melanoma. Ipilimumab is a CTLA-4 inhibitor used in the treatment of melanoma.

Findings from 153 evaluable patients with advanced melanoma showed that KEYTRUDA (2 mg/kg every three weeks) in combination with low-dose ipilimumab (1 mg/kg every three weeks for four doses) demonstrated an ORR of 57 percent (95% CI, 49-65) by independent central review – 10 percent were complete responses (n=15/153) and 47 percent were partial responses (n=72/153). The six-month progression-free survival (PFS) rate was 70 percent and the six-month overall survival (OS) rate was 93 percent. At the time of analysis, median PFS (95% CI, 12.4 months-NR) and OS (95% CI, NR-NR) were not reached; 98 percent of responses were ongoing. Median follow-up duration was 10.0 months (range 0.8-14.1).

Sixty-four patients (42%) experienced treatment-related Grade 3-4 adverse events. Thirty-eight patients (25%) experienced immune-mediated Grade 3-4 adverse events, including: colitis, hepatitis, hyperthyroidism, hypophysitis, infusion reaction, pancreatitis, pneumonitis, nephritis, skin reactions, and type 1 diabetes mellitus. Sixteen patients (10%) experienced a treatment-related adverse event that led to ipilimumab discontinuation only, 11 patients (7%) experienced a treatment-related adverse event that led to KEYTRUDA (pembrolizumab) discontinuation after completion or discontinuation of ipilimumab, and 16 patients (10%) experienced a treatment-related adverse event that led to ipilimumab and KEYTRUDA discontinuation, including one patient who discontinued ipilimumab for colitis and later discontinued KEYTRUDA for increased lipase. There were no treatment-related deaths.

These data will be presented in an oral session by Dr. Long on June 6 at 2:51 p.m. CDT (Location: Arie Crown Theater).

About KEYTRUDA (pembrolizumab) Injection 100 mg

KEYTRUDA is a humanized monoclonal antibody that works by increasing the ability of the body’s immune system to help detect and fight tumor cells. KEYTRUDA blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, thereby activating T lymphocytes which may affect both tumor cells and healthy cells.

KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic melanoma.

KEYTRUDA is also indicated for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors express PD-L1 as determined by an FDA-approved test with disease progression on or after platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving KEYTRUDA. This indication is approved under accelerated approval based on tumor response rate and durability of response. An improvement in survival or disease-related symptoms has not yet been established. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

KEYTRUDA is administered at a dose of 2 mg/kg as an intravenous infusion over 30 minutes every three weeks for the approved indications.

Selected Important Safety Information for KEYTRUDA (pembrolizumab)

Immune-mediated pneumonitis, including fatal cases, occurred in patients receiving KEYTRUDA. Pneumonitis occurred in 32 (2.0%) of 1567 patients, including Grade 1 (0.8%), 2 (0.8%), and 3 (0.4%) pneumonitis. Monitor patients for signs and symptoms of pneumonitis. Evaluate suspected pneumonitis with radiographic imaging. Administer corticosteroids for Grade 2 or greater pneumonitis. Withhold KEYTRUDA for Grade 2; permanently discontinue KEYTRUDA for Grade 3 or 4 or recurrent Grade 2 pneumonitis.

Immune-mediated colitis occurred in 31 (2%) of 1567 patients, including Grade 2 (0.5%), 3 (1.1%), and 4 (0.1%) colitis. Monitor patients for signs and symptoms of colitis. Administer corticosteroids for Grade 2 or greater colitis. Withhold KEYTRUDA (pembrolizumab) for Grade 2 or 3; permanently discontinue KEYTRUDA for Grade 4 colitis.

Immune-mediated hepatitis occurred in 16 (1%) of 1567 patients, including Grade 2 (0.1%), 3 (0.7%), and 4 (0.1%) hepatitis. Monitor patients for changes in liver function. Administer corticosteroids for Grade 2 or greater hepatitis and, based on severity of liver enzyme elevations, withhold or discontinue KEYTRUDA.

Hypophysitis occurred in 13 (0.8%) of 1567 patients, including Grade 2 (0.3%), 3 (0.3%), and 4 (0.1%) hypophysitis. Monitor patients for signs and symptoms of hypophysitis (including hypopituitarism and adrenal insufficiency). Administer corticosteroids and hormone replacement as clinically indicated. Withhold KEYTRUDA for Grade 2; withhold or discontinue for Grade 3 or 4 hypophysitis.

Hyperthyroidism occurred in 51 (3.3%) of 1567 patients, including Grade 2 (0.6%) and 3 (0.1%) hyperthyroidism. Hypothyroidism occurred in 127 (8.1%) of 1567 patients, including Grade 3 (0.1%) hypothyroidism. Thyroid disorders can occur at any time during treatment. Monitor patients for changes in thyroid function (at the start of treatment, periodically during treatment, and as indicated based on clinical evaluation) and for clinical signs and symptoms of thyroid disorders. Administer replacement hormones for hypothyroidism and manage hyperthyroidism with thionamides and beta-blockers as appropriate. Withhold or discontinue KEYTRUDA for Grade 3 or 4 hyperthyroidism.

Type 1 diabetes mellitus, including diabetic ketoacidosis, occurred in 3 (0.1%) of 2117 patients. Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Administer insulin for type 1 diabetes, and withhold KEYTRUDA and administer anti-hyperglycemics in patients with severe hyperglycemia.

Immune-mediated nephritis occurred in 7 (0.4%) of 1567 patients, including Grade 2 (0.2%), 3 (0.2%), and 4 (0.1%) nephritis. Monitor patients for changes in renal function. Administer corticosteroids for Grade 2 or greater nephritis. Withhold KEYTRUDA for Grade 2; permanently discontinue KEYTRUDA for Grade 3 or 4 nephritis.

Other clinically important immune-mediated adverse reactions can occur. For suspected immune-mediated adverse reactions, ensure adequate evaluation to confirm etiology or exclude other causes. Based on the severity of the adverse reaction, withhold KEYTRUDA and administer corticosteroids. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Based on limited data from clinical studies in patients whose immune-related adverse reactions could not be controlled with corticosteroid use, administration of other systemic immunosuppressants can be considered. Resume KEYTRUDA when the adverse reaction remains at Grade 1 or less following corticosteroid taper. Permanently discontinue KEYTRUDA for any Grade 3 immune-mediated adverse reaction that recurs and for any life-threatening immune-mediated adverse reaction.

The following clinically significant, immune-mediated adverse reactions occurred in less than 1% (unless otherwise indicated) of 1567 patients: arthritis (1.6%), exfoliative dermatitis, bullous pemphigoid, uveitis, myositis, Guillain-Barré syndrome, myasthenia gravis, vasculitis, pancreatitis, hemolytic anemia, and partial seizures arising in a patient with inflammatory foci in brain parenchyma.

Severe and life-threatening infusion-related reactions have been reported in 3 (0.1%) of 2117 patients. Monitor patients for signs and symptoms of infusion-related reactions including rigors, chills, wheezing, pruritus, flushing, rash, hypotension, hypoxemia, and fever. For Grade 3 or 4 reactions, stop infusion and permanently discontinue KEYTRUDA (pembrolizumab).

Based on its mechanism of action, KEYTRUDA can cause fetal harm when administered to a pregnant woman. If used during pregnancy, or if the patient becomes pregnant during treatment, apprise the patient of the potential hazard to a fetus. Advise females of reproductive potential to use highly effective contraception during treatment and for 4 months after the last dose of KEYTRUDA.

In Trial 6, KEYTRUDA was discontinued due to adverse reactions in 9% of 555 patients; adverse reactions leading to discontinuation in more than one patient were colitis (1.4%), autoimmune hepatitis (0.7%), allergic reaction (0.4%), polyneuropathy (0.4%), and cardiac failure (0.4%). Adverse reactions leading to interruption of KEYTRUDA occurred in 21% of patients; the most common (≥1%) was diarrhea (2.5%). The most common adverse reactions with KEYTRUDA vs ipilimumab were fatigue (28% vs 28%), diarrhea (26% with KEYTRUDA), rash (24% vs 23%), and nausea (21% with KEYTRUDA). Corresponding incidence rates are listed for ipilimumab only for those adverse reactions that occurred at the same or lower rate than with KEYTRUDA.

In Trial 2, KEYTRUDA was discontinued due to adverse reactions in 12% of 357 patients; the most common (≥1%) were general physical health deterioration (1%), asthenia (1%), dyspnea (1%), pneumonitis (1%), and generalized edema (1%). Adverse reactions leading to interruption of KEYTRUDA occurred in 14% of patients; the most common (≥1%) were dyspnea (1%), diarrhea (1%), and maculo-papular rash (1%). The most common adverse reactions with KEYTRUDA vs chemotherapy were fatigue (43% with KEYTRUDA), pruritus (28% vs 8%), rash (24% vs 8%), constipation (22% vs 20%), nausea (22% with KEYTRUDA), diarrhea (20% vs 20%), and decreased appetite (20% with KEYTRUDA). Corresponding incidence rates are listed for chemotherapy only for those adverse reactions that occurred at the same or lower rate than with KEYTRUDA.

No formal pharmacokinetic drug interaction studies have been conducted with KEYTRUDA.

It is not known whether KEYTRUDA is excreted in human milk. Because many drugs are excreted in human milk, instruct women to discontinue nursing during treatment with KEYTRUDA and for 4 months after the final dose.

Safety and effectiveness of KEYTRUDA (pembrolizumab) have not been established in pediatric patients.

Our Focus on Cancer

Our goal is to translate breakthrough science into innovative oncology medicines to help people with cancer worldwide. At Merck Oncology, helping people fight cancer is our passion and supporting accessibility to our cancer medicines is our commitment. Our focus is on pursuing research in immuno-oncology and we are accelerating every step in the journey – from lab to clinic – to potentially bring new hope to people with cancer.

As part of our focus on cancer, Merck is committed to exploring the potential of immuno-oncology with one of the fastest-growing development programs in the industry. We are currently executing an expansive research program that includes more than 270 clinical trials evaluating our anti-PD-1 therapy across more than 30 tumor types. We also continue to strengthen our immuno-oncology portfolio through strategic acquisitions and are prioritizing the development of several promising immunotherapeutic candidates with the potential to improve the treatment of advanced cancers.

For more information about our oncology clinical trials, visit www.merck.com/clinicaltrials.

On June 5, 2016 AbbVie (NYSE: ABBV), a global biopharmaceutical company, reported that treatment with rovalpituzumab tesirine (Rova-T), a delta-like protein 3 (DLL3)-targeted antibody-drug conjugate (ADC), demonstrated a confirmed overall response rate (ORR) of 39 percent and clinical benefit rate (stable disease or better) of 89 percent in patients with recurrent or refractory small cell lung cancer (SCLC), identified with high expression of DLL3 (Press release, AbbVie, JUN 5, 2016, View Source [SID:1234513030]). Rova-T demonstrated a one-year overall survival (OS) rate of 32 percent in the recurrent/refractory second- and third-line patient population. These new data were presented at the 52nd Annual Meeting of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) in Chicago and featured in the "Best of ASCO (Free ASCO Whitepaper)" program, which presents scientific and educational highlights from the meeting. Less than one percent of all data abstracts are selected for this program.

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In the trial, the most common treatment-emergent adverse events were fatigue (35 percent), pleural effusion (31 percent), edema peripheral (27 percent), nausea (19 percent), hypoalbuminemia (18 percent), thrombocytopenia, rash maculo-papular and decreased appetite (16 percent each). Grade three and higher severe toxicities were thrombocytopenia (11 percent), pleural effusion (8 percent), fatigue (4 percent), edema peripheral, and rash maculo-papular (3 percent each).

"These data further contribute to our understanding of the potential impact that treatment with Rova-T, a predictive biomarker-based therapy, could have on pretreated small cell lung cancer patients identified as high expressers of DLL3," said Charles M. Rudin, M.D., Ph.D., Chief of the Thoracic Oncology Service at Memorial Sloan Kettering. "The results presented at ASCO (Free ASCO Whitepaper) support further clinical development of this compound."

Small cell lung cancer (SCLC) is an aggressive, difficult-to-treat form of cancer that accounts for roughly 13-15 percent of all lung cancers.1,2 The five year survival rate for extensive-stage SCLC remains at less than 5 percent3 and there are limited treatment options available for the more than 234,000 people diagnosed with SCLC annually.1,2,4 Treatment options for patients remain limited, with chemotherapy and radiation being the most common forms of first- and second-line treatment.5

"Due to the aggressive nature of small cell lung cancer, there are limited treatment options available, resulting in a typically poor prognosis for most patients," said Mike Severino, M.D., executive vice president of research and development and chief scientific officer, AbbVie. "Rova-T represents a potential new approach to treating this disease by targeting DLL3, a protein that is expressed in the majority of small cell lung cancer patients. We are committed to further developing this compound and look forward to the possibility of delivering it to patients in need of new treatment options."

About the Phase 1a/1b Trial
This Phase 1a/1b, multicenter, open label, dose escalation trial was designed to assess the safety, pharmacokinetics, and preliminary efficacy of rovalpituzumab tesirine (Rova-T) as monotherapy in patients with recurrent small cell lung cancer (SCLC). The trial enrolled 74 patients, all of whom had failed at least one prior standard therapy. The primary objectives were maximum tolerated dose and an overall response rate (ORR), assessed by Response Evaluation Criteria In Solid Tumors (RECIST). Secondary objectives included pharmacokinetics and RECIST-assessed progression-free survival (PFS) and overall survival (OS). As well, the clinical benefit rate (stable disease or better) was assessed by RECIST.

About Rovalpituzumab Tesirine (Rova-T)
Rova-T is an investigational antibody-drug conjugate targeting the cancer-stem cell-associated delta-like protein 3 (DLL3)6, which is expressed in more than 80 percent of small cell lung cancer (SCLC) patient tumors, where it is prevalent on tumor cells, including cancer stem cells, but not present in healthy tissue.7 Rova-T combines a targeted antibody that delivers a cytotoxic agent directly to the DLL3-expressing cancer cells while minimizing toxicity to healthy cells. Rova-T is under investigation as a third-line treatment in SCLC.7 Studies designed to select a Rova-T regimen for first-line registration will be starting soon.8 The expression of DLL3 suggests Rova-T may be useful across multiple tumor types, including metastatic melanoma, glioblastoma multiforme and some prostate, pancreatic and colorectal cancers.7

Rova-T is an investigational compound and its efficacy and safety have not been established by the FDA or any other health authority.

On June 05, 2016 Myriad Genetics, Inc. (NASDAQ:MYGN), a leader in molecular diagnostics and personalized medicine, reported that results from three studies with the Myriad myRisk Hereditary Cancer test will be featured in podium presentations at the 2016 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) annual meeting (Press release, Myriad Genetics, JUN 5, 2016, View Source [SID:1234513010]). These presentations demonstrate the expanding benefits of gene panel testing and underscore the need for gene panel testing to become the standard-of-care for hereditary cancer risk evaluation.

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"We’re very excited to have several podium presentations that feature the myRisk Hereditary Cancer test and advance the state-of-the-art of hereditary cancer testing and risk assessment," said Johnathan Lancaster, M.D., Ph.D., chief medical officer, Myriad Genetic Laboratories. "There are three important findings at this year’s meeting. First, the myRisk test identified a significant number of deleterious mutations that would otherwise have been missed by syndrome-directed testing. Second, among patients with suspected hereditary colon cancer, myRisk identified twice as many deleterious mutations in non-Lynch Syndrome genes as in Lynch genes. Third, the use of the myRisk test did not result in inappropriate patient care or increased distress among patients with an uncertain or negative test result."

The results of the studies to be presented are described below and abstracts are available at: abstracts.asco.org. Follow Myriad on Twitter via @MyriadGenetics to stay informed about news and updates from the Company.

myRisk Hereditary Cancer Podium Presentations
Title: Yield of multiplex panel testing exceeds expert opinion and validated prediction models.
Presenter: Gregory Idos, Stanford University Cancer Institute.
Date: Sunday, June 5, 2016, 9:45 – 9:57 a.m.
Location: S404, Abstract 1509.

This study evaluated the diagnostic yield and clinical utility of panel testing using the myRisk Hereditary Cancer test in 1,000 patients undergoing hereditary cancer-risk assessment. Before testing, differential diagnoses (DDx) were generated after clinical genetics assessment. After testing, the results showed that 11.6 percent of patients tested positive for a deleterious mutation. The most frequently identified mutations were in BRCA1 (18 percent) and BRCA2 (18 percent), MUTYH (17 percent), APC (7 percent), CHEK2 (6 percent) and ATM (5 percent). Importantly, 70 percent of the mutations were included in the DDx before testing. However, 26 percent of the deleterious mutations were not clinically suspected before testing, which demonstrates the value of gene panel testing in hereditary cancer risk assessment.

Title: Safety of multiplex gene testing for inherited cancer risk: interim analysis of a clinical trial.
Presenter: Allison Kurian, Stanford University Cancer Institute.
Date: Tuesday, June 7, 2016, 8:36 – 8:48 a.m.
Location: S102, Abstract: 1503.

This study evaluated the safety of gene panel testing among patients who were undergoing cancer-risk assessment. The interim analysis of the first 1,000 patients found that 11.6 percent had a deleterious mutation in a cancer susceptibility gene. Overall, self-reported surgery rates were low and there was no difference between patients who had a deleterious mutation and those with a variant of uncertain significance (VUS). Most patients never/rarely had thoughts of cancer affecting their daily activities, did not regret testing and wanted to know the results. Patients with a deleterious mutation reported higher distress and uncertainty scores than those with a VUS or negative result. There was no difference in distress or uncertainty among patients with a VUS or negative result. Based on these findings, gene panel testing did not result in inappropriate medical management or increased distress/uncertainty among VUS and negative patients.

Title: Prevalence of germline mutations in cancer risk genes among unselected colorectal cancer (CRC) patients (pts).
Presenter: Matthew Yurgelun, Dana-Farber Cancer Institute.
Date: Tuesday, June 7, 2016, 8:12 – 8:24 a.m.
Location: S102, Abstract: 1501.

This study evaluated the prevalence of deleterious mutations in 1,100 patients with colorectal cancer (CRC) who were treated at the Dana-Farber Cancer Institute. The results showed that 10 percent of patients had a deleterious mutation: 3.1 percent in Lynch Syndrome (LS) genes and 7.1 percent in non-LS genes. Importantly, only 35 percent of high-penetrance non-Lynch mutation carriers had clinical histories suggesting their syndrome. Patients with non-LS mutations were more likely to have more than one CRC, family history of ovarian cancer, and somatic KRAS G12C mutations relative to patients with no deleterious mutations.

About Myriad myRisk Hereditary Cancer Testing
The Myriad myRisk Hereditary Cancer test uses an extensive number of sophisticated technologies and proprietary algorithms in an 850 step laboratory process to evaluate 25 clinically significant genes associated with eight hereditary cancer sites including: breast, colon, ovarian, endometrial, pancreatic, prostate and gastric cancers and melanoma. For more information visit: View Source

On June 05, 2016 OncoMed Pharmaceuticals Inc. (NASDAQ:OMED) reported the presentation of safety, biomarker and efficacy data from four clinical-stage programs at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) 2016 Annual Meeting (Press release, OncoMed, JUN 5, 2016, View Source [SID:1234513011]). Presentations included the first Phase 1b combination data for OncoMed’s Wnt pathway inhibitors, ipafricept (FZD8-Fc, OMP-54F28) in recurrent platinum-sensitive ovarian cancer and vantictumab (anti-Fzd7, OMP-18R5) in Her2-negative breast cancer. Updated data were also presented for the company’s Phase 1b clinical trials of demcizumab in first-line non-small cell lung cancer (NSCLC) and tarextumab in extensive-stage small cell lung cancer (SCLC).

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"These first Phase 1b data from our ongoing studies of ipafricept and vantictumab in combination with standard of care are demonstrating initial safety, biomarker and efficacy trends that would warrant advancing into randomized Phase 2 trials, once we identify the optimal dosing schedules for each drug. Ipafricept and vantictumab have been well tolerated and we are learning more about the distinct pharmacological profiles of each agent," said Jakob Dupont, M.D., Chief Medical Officer. "Ipafricept, combined with standard of care, demonstrated a noteworthy overall response rate of 84 percent in the ovarian cancer setting, including 40 percent complete responses, in the uncontrolled Phase 1b trial. Vantictumab also produced promising anti-tumor activity in combination with standard of care, particularly in triple-negative and third-line breast cancer patients, and we see early evidence that our six-gene signature biomarker may be predictive for improved survival outcomes with vantictumab treatment. In addition, the updated survival data presented for demcizumab and tarextumab in lung cancer build upon earlier results from those Phase 1b studies and support the respective randomized Phase 2 clinical trials for each of these therapeutic candidates."

Initial Safety and Efficacy Data for Wnt Pathway Inhibitors

Ipafricept: Poster Discussion (Abstract #2515): Phase 1b of WNT inhibitor Ipafricept (IPA, decoy receptor for WNT ligands) with Carboplatin (C) and Paclitaxel (P) in Recurrent Platinum-Sensitive Ovarian Cancer (OC); Dr. Roisin E. O’Cearbhaill of Memorial Sloan Kettering Cancer Center

Trial Design
The Phase 1b study is designed as a dose-escalation study to assess the safety and tolerability of ipafricept in combination with paclitaxel and carboplatin in patients with recurrent platinum-sensitive epithelial ovarian cancer. Secondary objectives include a preliminary assessment of efficacy. As of the data cut-off date of April 14, 2016, there have been 24 patients enrolled and evaluable for safety and 19 evaluable for efficacy.

Safety
Interim safety results showed that the combination of ipafricept with chemotherapy was well tolerated. The most common toxicities reported were nausea and fatigue, and ipafricept-related adverse events included neutropenia and hypophosphatemia. Following the incidence of certain bone fractures in Phase 1a clinical studies of its Wnt inhibitors, OncoMed implemented an enhanced bone safety plan that includes monitoring of blood bone markers, bone density, and administration of zoledronic acid bone protection in certain patients and no fragility fractures have since been observed.

Efficacy
An interim efficacy assessment demonstrated encouraging evidence of anti-tumor effects. Of the 19 patients evaluable for response, the overall response rate was 84 percent with eight complete responses and eight partial responses. An exploratory biomarker analysis described patient tumors with high Wnt activation to be more likely to achieve a complete response to ipafricept with carboplatin/paclitaxel treatment.

A maximum-tolerated dose has not yet been established and the Phase 1b clinical trial with ipafricept continues to enroll patients in escalating dose cohorts. Study drug is administered two days prior to chemotherapy based on strong preclinical evidence that sequential dosing may sensitize tumors to the effects of taxane chemotherapy.

Vantictumab: Poster Discussion (Abstract #2516): Phase 1b Study of WNT Inhibitor Vantictumab (VAN, human monoclonal antibody) with Paclitaxel (P) in Patients (pts) with 1st- to 3rd-Line Metastatic HER2-Negative Breast Cancer (BC); Dr. Monica Mita of the Cedars-Sinai Samuel Oschin Comprehensive Cancer Institute

Trial Design
The Phase 1b study is designed as a dose escalation study to assess the safety and tolerability of vantictumab in combination with paclitaxel in patients with metastatic first-, second- or third-line HER2-negative breast cancer. Secondary objectives include a preliminary assessment of efficacy and exploratory objectives include the identification of predictive biomarkers. As of April 14, 2016, there have been 31 patients enrolled.

Safety
Of the 31 patients evaluable for safety, interim results showed that vantictumab did not appear to exacerbate paclitaxel side effects. The most common toxicities reported were fatigue, constipation, diarrhea and nausea. No fragility fractures have been observed in the vantictumab Phase 1b following the implementation of an enhanced bone safety plan of monitoring blood bone markers, bone density and administration of zoledronic acid bone protection in certain patients.

Efficacy
An interim efficacy assessment demonstrated evidence of anti-tumor effects. Of the 27 evaluable for response, the overall response rate was 33 percent. Some of the most encouraging anti-tumor responses were observed in patient subgroups with high unmet medical need, such as third-line patients where four of 11 (36%) achieved partial responses and patients with triple-negative breast cancer in which six of 15 (40%) patients achieved partial responses. Historically these subgroups would be expected to be among the least responsive to treatment.

Biomarker Data
OncoMed’s six-gene signature biomarker appeared to successfully identify patients with better progression-free and overall survival outcomes with vantictumab and paclitaxel treatment. The six gene Wnt pathway signature does not appear prognostic in the HER2-negative breast cancer setting. Patients whose tumors were high in gene expression for the previously identified markers demonstrated improved progression-free survival (PFS) and overall survival (OS) following treatment compared to those whose tumors were low. Enrollment in the final planned cohort for the vantictumab plus paclitaxel Phase 1b is ongoing.

Ipafricept and vantictumab are part of OncoMed’s collaboration with Bayer Pharma AG. Bayer can elect to exercise its options on ipafricept and vantictumab at any point through completion of Phase 1b trials.

Updated Phase 1b Data for Demcizumab and Tarextumab

Demcizumab: Poster Discussion (Abstract #9023): A Phase 1b Study of the Anti-Cancer Stem Cell Agent Demcizumab, Pemetrexed and Carboplatin in Patients with 1st Line Non-Squamous Non-Small Cell Lung Cancer; Dr. Mark McKeage of University of Auckland

Trial Design
The Phase 1b study was designed as a dose-escalation study to assess safety, biomarkers, and efficacy of demcizumab in combination with pemetrexed and carboplatin in patients with first-line Stage IIIb/IV NSCLC. As of April 8, 2016, there have been 46 patients enrolled and evaluable for safety and survival endpoints and 40 evaluable for tumor response as measured by RECIST. Demcizumab was administered with chemotherapy to 23 patients on a continuous basis (up to disease progression) and 23 received demcizumab on a truncated schedule for up to approximately 63 days. The truncated dose schedule is the regimen being used in DENALI, a Phase 2 clinical trial of demcizumab in combination with chemotherapy currently enrolling with expected data in late 2017 or early 2018.

Results
Final results for the 23 patients who received truncated dosing of demcizumab plus chemotherapy continued to show a tail on the survival Kaplan-Meier curve with 8 patients (35%) alive between 18 to 37 months since initiating treatment. Median PFS and OS for the overall population of truncated demcizumab dosed patients were 5.8 months and 11.5 months, respectively. The combination of demcizumab plus chemotherapy was generally well-tolerated with the most common related adverse events being fatigue, nausea and manageable hypertension.

Demcizumab is part of OncoMed’s collaboration with Celgene. Celgene can elect to exercise its options to co-develop and co-commercialize demcizumab with OncoMed through completion of certain randomized Phase 2 clinical trials.

Tarextumab: Poster Session (Abstract #8564): Updated results of Phase 1b study of tarextumab (TRXT, anti-Notch2/3) in combination with etoposide and platinum (EP) in patients (pts) with untreated extensive-stage small-cell lung cancer (ED-SCLC); Dr. Anne Chiang of the Yale School of Medicine

Trial Design
The Phase 1b study was designed as a dose-escalation study to assess safety, biomarkers and efficacy of tarextumab in combination with etoposide and platinum therapy in patients with untreated extensive-stage SCLC. As of April 21, 2016, all 27 patients enrolled in the Phase 1b trial were evaluable for safety, biomarkers, and survival, with 26 patients evaluable for tumor response.

Results
Updated data continued to demonstrate evidence of dose response as higher doses of tarextumab (≥12mg/kg) resulted in a median PFS of 5.3 months and median OS of 16 months. In contrast, median PFS and OS for low-dose tarextumab were 4.3 and 7.6 months, respectively.

Biomarker Data
New data were presented indicating that patients whose tumors were high in Hes1, Hes6, Hey2 and Hey1 gene expression showed improved survival compared to those whose tumors were low in these markers. These results were particularly pronounced among patients who received high-dose tarextumab. Taken together, these results further support the selected 15 mg/kg dose of tarextumab in combination with etoposide and platinum therapy in OncoMed’s Phase 2 PINNACLE trial of patients with extensive-stage SCLC. Given the correlation observed with improved survival, the Hes/Hey genes may be useful as predictive biomarkers. The PINNACLE Phase 2 protocol was recently amended to assess the efficacy outcome of patients with the newly identified Hes/Hey predictive gene signature as a secondary endpoint. These are key genes in the Notch pathway. The primary endpoint of the study will evaluate the PFS outcome for patients who receive tarextumab with platinum and etoposide chemotherapy versus the platinum and etoposide alone, and an examination of PFS among tumors high in Notch 3 gene expression as a primary endpoint has been removed. Data from the Phase 2 trial are expected late 2016/early 2017.

Tarextumab is part of OncoMed’s collaboration with GlaxoSmithKline (GSK). GSK has an exclusive license to tarextumab during certain time periods through completion of proof-of-concept Phase 2 trials.