On September 26, 2015 Merck (NYSE: MRK), known as MSD outside the United States and Canada, reported the first-time presentation of findings investigating the use of KEYTRUDA (pembrolizumab), the company’s anti-PD-1 therapy, as a monotherapy in patients with advanced unresectable nasopharyngeal carcinoma (NPC) – a type of head and neck cancer – whose tumors express PD-L1 (≥1% of cells in tumor nests or PD-L1+ bands in stroma) (Press release, Merck & Co, SEP 26, 2015, View Source [SID:1234507575]). Data were from a Phase 1b study (KEYNOTE-028) and showed an overall response rate (ORR) (confirmed and unconfirmed) of 22.2 percent (95% CI, 8.6-42.3) in evaluable patients (n=27) who were treated with KEYTRUDA. Results were presented in an oral session by Dr. Chiun Hsu, National Taiwan University Hospital, at the European Cancer Congress (ECC) in Vienna (Abstract #2801).

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"Advanced nasopharyngeal carcinoma is a severe form of head and neck cancer often associated with a poor prognosis," said Dr. Hsu. "These data presented at ECC represent the potential for new approaches to treat this type of cancer, for which there are currently limited treatment options, and further support the need for additional research into how KEYTRUDA may work for certain types of head and neck cancer."

Merck has initiated a comprehensive clinical development program evaluating KEYTRUDA in head and neck cancer across multiple lines of therapy as monotherapy and in combination with chemotherapy as well as other agents. In KEYNOTE-028, KEYTRUDA is being evaluated in patients with advanced unresectable NPC that is not responding to current therapy or for which current therapy is not appropriate. This is the second study to show early activity of KEYTRUDA in patients with head and neck cancer and the first study of an anti-PD-1 therapy to demonstrate clinical activity in patients with recurrent or metastatic NPC. For more information about our oncology clinical trials, visit www.keynoteclinicaltrials.com.

"The findings emerging from this trial again demonstrate that KEYTRUDA is active across a broad range of cancers, including those that are difficult to treat with standard treatments," said Dr. Roger Dansey, senior vice president and therapeutic area head, oncology late-stage development, Merck Research Laboratories. "Based on these and other results to date, we are continuing to advance a comprehensive head and neck clinical program for KEYTRUDA, and we remain focused on realizing its full potential to address the unmet treatment needs for patients with difficult-to-treat cancers such as nasopharyngeal carcinoma."

Additional Nasopharyngeal Carcinoma Results from KEYNOTE-028

KEYNOTE-028 is an ongoing multi-cohort, non-randomized Phase 1b basket trial (a trial design that allows for the study of multiple sub-populations of different tumor or histological types within one study) evaluating the safety, tolerability, and anti-tumor activity of KEYTRUDA monotherapy (10 mg/kg dosed every two weeks) in more than 450 patients across 20 different types of cancer. The study was designed to evaluate patients with advanced solid tumors that express PD-L1 and which have not responded to current therapy or for which current therapy is not appropriate.

These early findings from 27 heavily pre-treated patients with advanced NPC demonstrated an ORR of 22.2 percent (n=6/27) (per RECIST v1.1), including six partial responses (95% CI, 8.6-42.3). Additionally, 55.6 percent of patients had stable disease (n=15/27) (95% CI, 35.3-74.5), the disease control rate (DCR) was 77.8 percent (n=21/27) (95% CI, 57.7-91.4), and tumor shrinkage was achieved in 67 percent of patients. The 6-month progression-free survival (PFS) rate was 49.7 percent and the 12-month PFS rate was 28.9 percent. The median follow-up duration for evaluable patients was 12.9 months (range, 2.2−15.0) and the median response duration was 10.8 months (range, 4.8- 10.8).

Adverse events were generally consistent with previously reported safety data for KEYTRUDA. Grade 3-5 investigator-assessed, treatment-related adverse events were hepatitis (n=2), pneumonitis (n=2), anemia (n=1), facial pain (n=1), increased blood creatine phosphokinase (n=1), proteinuria (n=1), and sepsis (n=1). Immune-mediated adverse events were hypothyroidism (n=5), hepatitis (n=4), and pneumonitis (n=3). There was one treatment-related death due to bacterial sepsis.

About PD-L1 and PD-L1 Expression

PD-L1, also called programmed death-ligand 1, is a protein expressed on many types of cells, including some cancer cells. Under normal conditions, the interaction of PD-L1 with another protein, called programmed death receptor-1 (PD-1), serves as an important immune system checkpoint, keeping the immune system in balance and preventing the body from attacking its own cells when inflammation or an infection is present. When cancerous tumors express PD-L1, however, they are able to escape detection and destruction by cytotoxic T-cells – a type of cancer-killing immune cell – allowing the tumor to survive and grow. Tumor PD-L1 expression has been observed at varying levels across many tumor types, including breast, lung, bladder cancer, and nasopharyngeal carcinoma. High levels of PD-L1 expression, called overexpression, are under investigation for potential use as a way to help identify patients with an enhanced likelihood to respond to certain immune-based treatment approaches.

About Nasopharyngeal Cancer

Nasopharyngeal cancer (NPC) is a type of head and neck cancer that starts in the epithelial cells that line the surface of the nasopharynx, the upper part of the throat behind the nose and near the base of skull.1 There are three types of NPC, based on how the cancer cells look under the microscope: keratinizing squamous cell carcinoma, non-keratinizing differentiated carcinoma, and undifferentiated carcinoma.1 Leading risk factors for NPC include Chinese or Asian ancestry, being exposed to the Epstein-Barr virus, and drinking large amounts of alcohol.2 In most parts of the world (including the United States), there is less than one case of NPC for every 100,000 people each year.3 In 2015, about 3,200 cases of NPC are expected to occur in the United States.3

About KEYTRUDA (pembrolizumab)

KEYTRUDA is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2. By binding to the PD-1 receptor and blocking the interaction with the receptor ligands, KEYTRUDA releases the PD-1 pathway-mediated inhibition of the immune response, including the anti-tumor immune response. KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. 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.

The KEYTRUDA clinical development program has rapidly expanded to encompass more than 30 tumor types in more than 130 clinical trials, of which more than 70 trials combine KEYTRUDA with other cancer treatments. Registration-enabling trials of KEYTRUDA monotherapy are currently enrolling patients in melanoma, NSCLC, head and neck cancer, bladder cancer, gastric cancer, colorectal cancer, and Hodgkin Lymphoma, with further trials in planning for other cancers.

Selected Important Safety Information for KEYTRUDA

Pneumonitis occurred in 12 (2.9%) of 411 patients, including Grade 2 or 3 cases in 8 (1.9%) and 1 (0.2%) patients, respectively, receiving KEYTRUDA. 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 pneumonitis.

Colitis (including microscopic colitis) occurred in 4 (1%) of 411 patients, including Grade 2 or 3 cases in 1 (0.2%) and 2 (0.5%) patients, respectively, receiving KEYTRUDA. Monitor patients for signs and symptoms of colitis. Administer corticosteroids for Grade 2 or greater colitis. Withhold KEYTRUDA for Grade 2 or 3; permanently discontinue KEYTRUDA for Grade 4 colitis.

Hepatitis (including autoimmune hepatitis) occurred in 2 (0.5%) of 411 patients, including a Grade 4 case in 1 (0.2%) patient, receiving KEYTRUDA. 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 2 (0.5%) of 411 patients, including a Grade 2 case in 1 and a Grade 4 case in 1 (0.2% each) patient, receiving KEYTRUDA. Monitor patients for signs and symptoms of hypophysitis (including hypopituitarism and adrenal insufficiency). Administer corticosteroids for Grade 2 or greater hypophysitis. Withhold KEYTRUDA for Grade 2; withhold or discontinue for Grade 3; and permanently discontinue KEYTRUDA for Grade 4 hypophysitis.

Hyperthyroidism occurred in 5 (1.2%) of 411 patients, including Grade 2 or 3 cases in 2 (0.5%) and 1 (0.2%) patients, respectively, receiving KEYTRUDA. Hypothyroidism occurred in 34 (8.3%) of 411 patients, including a Grade 3 case in 1 (0.2%) patient, receiving KEYTRUDA. 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 corticosteroids for Grade 3 or greater hyperthyroidism. Withhold KEYTRUDA for Grade 3; permanently discontinue KEYTRUDA for Grade 4 hyperthyroidism. Isolated hypothyroidism may be managed with replacement therapy without treatment interruption and without corticosteroids.

Type 1 diabetes mellitus, including diabetic ketoacidosis, has occurred in patients receiving KEYTRUDA. Monitor patients for hyperglycemia and other signs and symptoms of diabetes. Administer insulin for type 1 diabetes, and withhold KEYTRUDA in cases of severe hyperglycemia until metabolic control is achieved.

Nephritis occurred in 3 (0.7%) patients, consisting of one case of Grade 2 autoimmune nephritis (0.2%) and two cases of interstitial nephritis with renal failure (0.5%), one Grade 3 and one Grade 4. 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. The following clinically significant immune-mediated adverse reactions occurred in patients treated with KEYTRUDA: exfoliative dermatitis, uveitis, arthritis, myositis, pancreatitis, hemolytic anemia, partial seizures arising in a patient with inflammatory foci in brain parenchyma, severe dermatitis including bullous pemphigoid, myasthenic syndrome, optic neuritis, and rhabdomyolysis.

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 of the adverse reaction to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Restart KEYTRUDA if the adverse reaction remains at Grade 1 or less. Permanently discontinue KEYTRUDA for any severe or Grade 3 immune-mediated adverse reaction that recurs and for any life-threatening immune-mediated adverse reaction.

Infusion-related reactions, including severe and life-threatening reactions, have occurred in patients receiving KEYTRUDA. Monitor patients for signs and symptoms of infusion-related reactions including rigors, chills, wheezing, pruritus, flushing, rash, hypotension, hypoxemia, and fever. For severe or life-threatening reactions, stop infusion and permanently discontinue KEYTRUDA.

Based on its mechanism of action, KEYTRUDA may 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.

KEYTRUDA was discontinued for adverse reactions in 9% of 411 patients. Adverse reactions, reported in at least two patients, that led to discontinuation of KEYTRUDA were: pneumonitis, renal failure, and pain. Serious adverse reactions occurred in 36% of patients. The most frequent serious adverse reactions, reported in 2% or more of patients, were renal failure, dyspnea, pneumonia, and cellulitis.

The most common adverse reactions (reported in at least 20% of patients) were fatigue (47%), cough (30%), nausea (30%), pruritus (30%), rash (29%), decreased appetite (26%), constipation (21%), arthralgia (20%), and diarrhea (20%).

The recommended dose of KEYTRUDA is 2 mg/kg administered as an intravenous infusion over 30 minutes every three weeks until disease progression or unacceptable toxicity. 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. Safety and effectiveness of KEYTRUDA have not been established in pediatric patients.

On September 26, 2015 Medivation, Inc. (NASDAQ: MDVN) reported updated data from a Phase 2 trial evaluating the investigational use of enzalutamide as a single agent for the treatment of advanced triple-negative breast cancer (TNBC) (Press release, Medivation, SEP 26, 2015, View Source [SID:1234507573]). Results from an exploratory overall survival analysis of study data were presented during an oral plenary session at the 2015 European Cancer Congress in Vienna, Austria. The presentation was selected to be featured in the upcoming "Highlights Session" of the 2015 European Cancer Congress.

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"We are excited by these updated data as we continue to monitor patients in the trial. Findings from the provisional analysis demonstrate the potential for a diagnostic test to help select women with this particularly aggressive type of breast cancer who may benefit from enzalutamide treatment," said Javier Cortés, M.D., director of the breast cancer program at Vall D’Hebron Institute of Oncology and head of the breast cancer program at Ramon y Cajal University Hospital in Madrid. "This finding is promising and potentially important for patients with TNBC."

A novel gene expression profiling assay was developed using data derived from the Phase 2 trial in patients with advanced TNBC, with a goal of developing a diagnostic test that could select patients who may respond to enzalutamide treatment. Nearly half of the enrolled patients (47%) tested positive for the novel gene expression profiling assay. An exploratory analysis of updated overall survival data demonstrated that those TNBC patients on enzalutamide whose tumors tested positive for the gene expression profile ("diagnostic positive") have to date experienced a 10.5-month longer median survival duration compared to those patients on enzalutamide whose tumor tested negative for the gene expression profile ("diagnostic negative"). The exploratory analysis demonstrated that median overall survival to date for diagnostic positive advanced TNBC patients treated with enzalutamide was 18.0 months (95% CI: 12.0-21.3) compared with 7.5 months for diagnostic negative advanced TNBC patients treated with enzalutamide (95% CI: 4.8 – 11.2).

Medivation released its initial exploratory analysis of then current overall survival data at the 2015 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in June 2015. At that time, the median overall survival in patients whose TNBC was diagnostic positive was not yet reached (95% CI: 12.9 months – not yet reached) and for those with diagnostic negative TNBC the median overall survival was 7.5 months (95% CI: 4.8 – 11.2). Medivation provided full details of the trial design in its Form 10-Q filed with the Securities and Exchange Commission on August 6, 2015.

The most common (reported in ≥ 10% of patients) adverse events reported as related to enzalutamide treatment in the intent-to-treat population were fatigue (35%), nausea (26%), decreased appetite (13%), diarrhea (10%), and hot flush (10%).

"The data presented today highlight the potential advantages of using a novel genomic profiling assay to identify patients who might respond to treatments," said Amy Peterson, M.D., vice president of clinical development at Medivation. "This approach could have implications for future development of targeted therapies in triple negative breast cancer."

About the Phase 2 Study
The Phase 2 open label single arm, multicenter trial enrolled 118 women with advanced TNBC that expressed any amount of androgen receptor by immunohistochemistry. The objective of the study was to evaluate the benefit of enzalutamide, 160 mg/day orally, as single agent therapy for advanced TNBC and to identify an appropriate biomarker to help select those women more likely to respond to therapy. The primary endpoint of the trial was the clinical benefit rate at 16 weeks (CBR16), defined as the proportion of women with a complete response (CR), partial response (PR), or stable disease for at least 16 weeks. Secondary endpoints of the trial included clinical benefit rate at 24 weeks (CBR24), and progression-free survival (PFS), defined as time from the date of first dose of study drug until documented disease progression or death due to any cause.

XTANDI is not approved for the treatment of advanced AR positive, TNBC. The diagnostic referred to in this press release is neither approved nor commercially available.

About XTANDI (enzalutamide) capsules
XTANDI is approved by the U.S. Food and Drug Administration for the treatment of patients with metastatic castration-resistant prostate cancer (CRPC).

Enzalutamide Mechanism of Action
Enzalutamide is an androgen receptor inhibitor that acts on three different steps in the androgen receptor signaling pathway.

XTANDI (enzalutamide) capsules HCP Important Safety Information
Important Safety Information
Contraindications XTANDI is not indicated for women and is contraindicated in women who are or may become pregnant. XTANDI can cause fetal harm when administered to a pregnant woman.

Warnings and Precautions
Seizure In Study 1, conducted in patients with metastatic castration-resistant prostate cancer (CRPC) who previously received docetaxel, seizure occurred in 0.9% of XTANDI patients and 0% of placebo patients. In Study 2, conducted in patients with chemotherapy-naive metastatic CRPC, seizure occurred in 0.1% of XTANDI patients and 0.1% of placebo patients. There is no clinical trial experience readministering XTANDI to patients who experienced a seizure, and limited safety data are available in patients with predisposing factors for seizure. Study 1 excluded the use of concomitant medications that may lower threshold; Study 2 permitted the use of these medications. Because of the risk of seizure associated with XTANDI use, patients should be advised of the risk of engaging in any activity during which sudden loss of consciousness could cause serious harm to themselves or others. Permanently discontinue XTANDI in patients who develop a seizure during treatment.

Posterior Reversible Encephalopathy Syndrome (PRES) In post approval use, there have been reports of PRES in patients receiving XTANDI. PRES is a neurological disorder which can present with rapidly evolving symptoms including seizure, headache, lethargy, confusion, blindness, and other visual and neurological disturbances, with or without associated hypertension. A diagnosis of PRES requires confirmation by brain imaging, preferably MRI. Discontinue XTANDI in patients who develop PRES.

Adverse Reactions
The most common adverse reactions ( ≥ 10%) reported from two combined clinical studies that occurred more commonly ( ≥ 2% over placebo) in XTANDI patients were asthenia/fatigue, back pain, decreased appetite, constipation, arthralgia, diarrhea, hot flush, upper respiratory tract infection, peripheral edema, dyspnea, musculoskeletal pain, weight decreased, headache, hypertension, and dizziness/vertigo.

In Study 1, Grade 3 and higher adverse reactions were reported among 47% of XTANDI patients and 53% of placebo patients. Discontinuations due to adverse events were reported for 16% of XTANDI patients and 18% of placebo patients. In Study 2, Grade 3-4 adverse reactions were reported in 44% of XTANDI patients and 37% of placebo patients. Discontinuations due to adverse events were reported for 6% of both study groups.

Lab Abnormalities: Grade 1-4 neutropenia occurred in 15% of XTANDI patients (1% Grade 3-4) and 6% of placebo patients (0.5% Grade 3-4). Grade 1-4 thrombocytopenia occurred in 6% of XTANDI patients (0.3% Grade 3-4) and 5% of placebo patients (0.5% Grade 3-4). Grade 1-4 elevations in ALT occurred in 10% of XTANDI patients (0.2% Grade 3-4) and 16% of placebo patients (0.2% Grade 3-4). Grade 1-4 elevations in bilirubin occurred in 3% of XTANDI patients (0.1% Grade 3-4) and 2% of placebo patients (no Grade 3-4).

Infections: In Study 1, 1% of XTANDI patients compared to 0.3% of placebo patients died from infections or sepsis. In Study 2, 1 patient in each treatment group (0.1%) had an infection resulting in death.

Falls (including fall-related injuries), occurred in 9% of XTANDI patients and 4% of placebo patients. Falls were not associated with loss of consciousness or seizure. Fall-related injuries were more severe in XTANDI patients, and included non-pathologic fractures, joint injuries, and hematomas.

Hypertension occurred in 11% of XTANDI patients and 4% of placebo patients. No patients experienced hypertensive crisis. Medical history of hypertension was balanced between arms. Hypertension led to study discontinuation in < 1% of all patients.

Drug Interactions
Effect of Other Drugs on XTANDI Avoid strong CYP2C8 inhibitors, as they can increase the plasma exposure to XTANDI. If co-administration cannot be avoided, reduce the dose of XTANDI.

Avoid strong or moderate CYP3A4 or CYP2C8 inducers as they can alter the plasma exposure to XTANDI.

Effect of XTANDI on Other Drugs Avoid CYP3A4, CYP2C9, and CYP2C19 substrates with a narrow therapeutic index, as XTANDI may decrease the plasma exposures of these drugs. If XTANDI is co-administered with warfarin (CYP2C9 substrate), conduct additional INR monitoring.

On September 28, 2015 Innate Pharma SA (the "Company" – Euronext Paris: FR0010331421 – IPH) reported that the first patient was treated in the Phase I/II trial testing IPH2201, a first-in-class NKG2A checkpoint inhibitor, as a single agent in platinum resistant or sensitive patients with high grade ovarian cancer (Press release, Innate Pharma, SEP 26, 2015, View Source [SID:1234507571]). The trial is sponsored by NCIC Clinical Trials Group and conducted in Canada. Thirty-eight (38) patients are planned to be enrolled.

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Pierre Dodion, Chief Medical Officer of Innate Pharma, said: "There is evidence to suggest that the immune system plays a key role in ovarian cancer. Furthermore, there is a body of data indicating that ovarian cancers may at least partly escape immune surveillance via expression of HLA-E, the ligand of NKG2A. Once a patient relapses after first line treatment, the disease is ultimately fatal in virtually all cases. In addition, the development of new active agents in ovarian cancer has been slow. We are therefore very enthusiastic to test IPH2201 in patients with such a high medical need".

This is the second out of four trials announced by Innate Pharma, included in the frame of the global co-development and commercialization agreement signed with AstraZeneca for IPH2201 in April 2015. The first trial (IPH2201-201) is an open label Phase II trial testing IPH2201 as a single agent in a pre-operative setting of squamous cell carcinoma of the oral cavity (OCSCC). The first patient was treated at the Charité Comprehensive Cancer Center (CCCC), Berlin, Germany, in December 2014.

As part of Innate’s program, two further trials, testing IPH2201 in combination with ibrutinib in patients with Chronic Lymphocytic Leukemia, and with cetuximab in patients with Head and Neck cancer, will start in 2015. The initial development plan also includes Phase II combination clinical trials with IPH2201 and durvalumab (MEDI4736), an anti-PD-L1 immune checkpoint inhibitor, in solid tumors, which will be performed by AstraZeneca.

On September 28, 2015 Epizyme, Inc. (NASDAQ: EPZM) reported results from the ongoing phase 1 trial of tazemetostat, its first-in-class EZH2 inhibitor (Press release, Epizyme, SEP 26, 2015, View Source [SID:1234507562]). The data showed that tazemetostat demonstrated clinical activity in a broader group of patients with INI1-negative and SMARCA4-negative tumors than previously reported, achieved inhibition of EZH2 in tumor tissue, and had an acceptable safety profile when administered as oral monotherapy in adult patients with relapsed or refractory INI1-negative and SMARCA4-negative tumors. The data were presented at the European Cancer Congress 2015 (ECC) in Vienna, Austria by Antoine Italiano, M.D., Ph.D., of the Institut Bergonié in Bordeaux, France. Based on tazemetostat’s clinical activity observed to date and other supportive research, Epizyme will initiate a global phase 2 study in adults and a global phase 1 study in children with INI1-negative tumors and synovial sarcoma in the fourth quarter of 2015.

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INI1-negative and SMARCA4-negative tumors, such as rhabdoid tumors and epithelioid sarcoma are serious and debilitating cancers. Approximately 1,400 patients each year in the major global markets develop these tumors1, which have no established standard of care. INI1 and SMARCA4 are critical proteins of the SWI/SNF complex, which oppose the activity of EZH2. Genetic alterations or loss of function of either can result in EZH2-dependent oncogenesis in certain cancer backgrounds, thus rendering these tumors sensitive to EZH2 inhibition.

"INI1-negative tumors represent a group of devastating diseases with a very poor prognosis even for patients who can undergo a complete surgical resection. Tazemetostat has induced objective responses that are durable for some patients and has an excellent safety profile," said Dr. Italiano. "Our data provide evidence that potentially changes the landscape of clinical research in this group of tumors and could improve the treatment paradigm for these traditionally refractory diseases."

"We are excited by these data, which show clinical activity in patients with INI1-negative and SMARCA4-negative tumors. These results are consistent with preclinical data that demonstrate the important role of EZH2 in INI1- and SMARCA4-negative tumors such as malignant rhabdoid tumors where median survival after relapse is approximately nine months," said Peter Ho, M.D., Ph.D., Chief Medical Officer, Epizyme. "We are now turning our attention to initiating global registration-supporting clinical trials in adults and children with these aggressive tumors, for which new treatments are needed."

In total, 30 patients with solid tumors were enrolled into this ongoing phase 1 study, including eight patients in a food effect sub-study. Of these 30 patients, eight had INI1-negative tumors, comprised of five with malignant rhabdoid tumors and three with epithelioid sarcomas (ES). Additionally, three patients had SMARCA4-negative tumors including two patients with malignant rhabdoid tumor of the ovary, also referred to as small cell carcinoma of the ovary hypercalcemic type (SCCOHT), and one patient with thoracic sarcoma. Nineteen patients had other solid tumors that were not characterized by INI1 or SMARCA4 loss, including three patients with synovial sarcomas.

Synovial sarcomas occur in approximately 1,800 patients each year in the major markets. Synovial sarcomas are INI1-deficient rather than INI1-negative. A fusion protein that is characteristic for synovial sarcoma displaces INI1 from the SWI/SNF complex. Displacement of INI1 confers dependence of these tumors on EZH2, and hence sensitivity to an EZH2 inhibitor in preclinical models.

In addition to the 30 patients with solid tumors, 21 patients with advanced Non-Hodgkin Lymphoma (NHL) were also enrolled into this ongoing phase 1 study, and the safety data from the ECC update presentation includes these patients. The data cutoff for this presentation was August 31, 2015.

Summary of Results

A total of 11 patients with INI1-negative or SMARCA4-negative tumors have been treated. The tumor histology of these patients includes MRT, MRTO, ES and thoracic sarcoma. Nine of these 11 patients have been treated at or above the recommended phase 2 dose of 800 mg twice daily.

Six of the 11 patients experienced a reduction in tumor size as best response, with four patients experiencing tumor reduction of over 30%.

Of five patients with an INI1-negative malignant rhabdoid tumor, one patient achieved a complete response (CR) at week eight and remains on study and in CR through week 65.

Of three patients with SMARCA4-negative tumors, two patients have malignant rhabdoid tumor of the ovary. One MRTO patient achieved a PR at week 8 and remains on study through week 25. A second MRTO patient remains on study with stable disease (SD) through week 26.

Of three patients with an INI1-negative epithelioid sarcoma, one patient achieved a PR of short duration and remains on study with SD through week 25. The second patient remains on study with SD through week 24.
Clinical activity was not observed in the 19 patients with other tumors, including the three patients with synovial sarcomas.
Inhibition of EZH2, as measured by post-treatment H3K27 trimethylation compared to baseline, was observed in tumor tissue of INI1-negative patients as assessed by immunohistochemistry.

The majority of adverse events observed in the study were grade 1 or grade 2 within the entire population of 51 patients with NHL and solid tumors. The most frequent adverse events regardless of attribution were asthenia, decreased appetite, thrombocytopenia, nausea, dyspnea, anemia and constipation. Five grade 3 or greater treatment-related adverse events have been observed including one each of: thrombocytopenia, neutropenia, hypertension, liver function test elevation and decreased appetite.

Solid tumor patients enrolled in this study had been heavily pre-treated, with over half of patients having received three or more prior anti-cancer therapies.

Study Design
The data presented at ECC are from the ongoing first-in-human phase 1 trial of tazemetostat in adults with relapsed or refractory B-cell lymphomas or advanced solid tumors. The primary objective of the study was to determine the recommended phase 2 dose. Secondary endpoints included safety, pharmacokinetics, pharmacodynamics and tumor response evaluated every eight weeks.
Tazemetostat is administered orally twice daily. Five cohorts were studied in the dose escalation phase: 100 mg, 200 mg, 400 mg, 800 mg and 1600 mg; and two cohorts, 800 mg and 1600 mg, were evaluated in the dose expansion phase. Patients enrolled into the food effects sub-study received tazemetostat at 400 mg.

Expanded Tazemetostat Phase 1 and Phase 2 Plans
A planned phase 2 trial studying tazemetostat in adult patients with INI1-negative solid tumors or synovial sarcoma is expected to begin in the fourth quarter of 2015. A phase 1 dose escalation study in pediatric patients with INI1-deficient solid tumors is also expected to start in the fourth quarter of 2015. The INI1-deficient tumor studies will enroll subjects in the U.S., EU and Australia.

Epizyme is already enrolling patients into an international five-arm, multi-center, phase 2 study that will assess the safety and efficacy of tazemetostat in patients with relapsed or refractory NHL, stratified by cell of origin and EZH2 mutation status.

The company plans to initiate additional trials of tazemetostat, including:

A combination study of tazemetostat with R-CHOP in patients with diffuse large B-cell lymphoma (DLBCL), including higher risk front-line patients. R-CHOP, which represents the current first-line regimen for patients with DLBCL, is comprised of rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone.
A combination study of tazemetostat with a B-cell signaling agent or other emerging targeted therapy for B-cell lymphomas.
About EZH2 in Cancer
EZH2 is a histone methyltransferase (HMT) that is increasingly understood to play a potentially oncogenic role in a number of cancers. These include non-Hodgkin lymphomas, rhabdoid tumors and other INI1-deficient cancers such as epithelioid sarcomas and synovial sarcoma as well as a range of other solid tumors.

About Tazemetostat
Epizyme is developing tazemetostat for the treatment of non-Hodgkin lymphoma patients and patients with INI1-deficient solid tumors. Tazemetostat is a first-in-class small molecule inhibitor of EZH2 created by Epizyme using its proprietary product platform. In many human cancers, aberrant EZH2 enzyme activity results in misregulation of genes that control cell proliferation resulting in the rapid and unconstrained growth of tumor cells. Tazemetostat is the WHO International Non-Proprietary Name (INN) for EPZ-6438.

Additional information about this program, including clinical trial information, may be found here: View Source

On September 28, 2015 Boehringer Ingelheim reported at the European Cancer Congress (ECC) in Vienna, Austria, further data to support the efficacy of VARGATEF (nintedanib*) in combination with docetaxel for the treatment of advanced non-small cell lung cancer (NSCLC) with adenocarcinoma histology (Press release, Boehringer Ingelheim, SEP 26, 2015, View Source [SID:1234507557]). Further analysis of the data from the pivotal LUME-Lung 1 trial showed that after first-line chemotherapy adenocarcinoma patients receiving VARGATEF plus docetaxel had a significantly reduced rate of tumour growth over time, compared to patients receiving docetaxel alone.1 At the time of treatment initiation, the average tumour size of the 658 adenocarcinoma patients who took part in the trial was 82.5mm (diameter). After six months of treatment, the adenocarcinoma patients receiving VARGATEF plus docetaxel experienced about 10% less tumour growth over time (9.7mm), compared to those receiving placebo plus docetaxel (tumour size at 6 months: 98.4mm placebo plus docetaxel vs 88.7mm nintedanib plus docetaxel).1

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Advanced adenocarcinoma patients with the poorest prognosis received an even more pronounced benefit from VARGATEF plus docetaxel, compared to docetaxel alone, after first-line chemotherapy:

Adenocarcinoma patients whose disease progressed within nine months of starting first-line chemotherapy (T<9) received a 16.8mm reduction in tumour size over time after six months (tumour size at baseline 88.3mm; tumour size at 6 months: 114.6mm placebo plus docetaxel vs 97.8mm nintedanib plus docetaxel; difference in growth over time of 13%)
Adenocarcinoma patients who had continuously progressed during first-line therapy (PD-FLT) experienced a 19.7mm reduction in tumour size over time after six months (tumour size at baseline 98.1mm; tumour size at 6 months: 124.7mm placebo plus docetaxel vs 105mm nintedanib plus docetaxel; a difference in growth over time of 15%)

Professor Martin Reck, lead investigator of the LUME-Lung 1 trial said, "The reduction in tumour burden seen in adenocarcinoma patients receiving nintedanib plus docetaxel is very encouraging and it is particularly positive to see the additional benefit for those patients who progress quickly when receiving first-line therapy as they often have the poorest prognosis. Tumour burden is commonly associated with clinical outcomes and as such is a relevant and valuable measurement. These latest data add to our wealth of knowledge and reiterate the efficacy of nintedanib which has previously been shown to extend overall survival to over one year for this difficult to treat cancer."

The Phase III LUME-Lung 1 trial randomised 1,314 patients with stage IIIB/IV recurrent NSCLC to receive either VARGATEF plus docetaxel or placebo plus docetaxel (1:1).2 Tumour growth was evaluated in a planned post-hoc analysis using all available tumour measurements. Mixed-effects models were employed to measure the relationship between time from treatment initiation and tumour size (measured as the sum of longest diameter of target lesions [SLD]).1

Dr Mehdi Shahidi, Medical Head, Solid Tumour Oncology, Boehringer Ingelheim commented, "The announcement of the latest data from the LUME-Lung 1 trial further illustrates how VARGATEF in combination with docetaxel can potentially improve the lives of lung cancer sufferers following its EU approval in 2014. We have a long-term commitment to discovering novel and innovative treatments to better the lives of patients with different types of cancer and look forward to bringing further advances in the future."

VARGATEF in combination with docetaxel was approved in the EU in 2014 for use by adult patients with locally advanced, metastatic or locally recurrent NSCLC of adenocarcinoma tumour histology after first-line chemotherapy. The LUME-Lung 1 study demonstrated the efficacy and safety of the treatment:2

VARGATEF plus docetaxel significantly prolonged progression-free survival compared to docetaxel alone for patients with adenocarcinoma (PFS: primary endpoint; 4.0 vs 2.8 months)
VARGATEF plus docetaxel significantly extended overall survival to beyond one year for patients with adenocarcinoma, compared to docetaxel alone (OS: key secondary endpoint; 12.6 vs 10.3 months)
VARGATEF plus docetaxel enabled one in four patients with adenocarcinoma to live for at least two years after first-line chemotherapy

VARGATEF in combination with docetaxel demonstrated a familiar and generally manageable side-effect profile without further compromising patients’ overall, health-related, quality of life compared to docetaxel alone. The most common adverse events for patients taking docetaxel vs VARGATEF plus docetaxel included: nausea 18% vs 24%; vomiting 9% vs 17%; diarrhoea 22% vs 42% and elevated liver enzymes 8% vs 29%.

Adenocarcinoma is the most common type of lung cancer and the majority of patients are diagnosed in an advanced stage.3 Most patients will experience disease progression during or after first-line chemotherapy and there is a significant need for new, effective second-line treatments.2,3