On December 19, 2016 Loxo Oncology, Inc. (Nasdaq:LOXO), a biopharmaceutical company innovating the development of highly selective medicines for patients with genetically defined cancers, reported a comprehensive program update for larotrectinib (LOXO-101), a selective inhibitor of tropomyosin receptor kinase (TRK), and its pipeline drug candidates, LOXO-292 and LOXO-195 (Press release, Loxo Oncology, DEC 19, 2016, View Source [SID1234517119]).

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"Since initiating our NAVIGATE Phase 2 trial in October 2015, we have been hard at work identifying TRK fusion patients and engaging with regulators to pursue a rapid path to market for larotrectinib," said Josh Bilenker, M.D., chief executive officer of Loxo Oncology. "Based on current enrollment and written regulatory correspondence, we are able to provide this exciting update for larotrectinib, and begin planning for a potential commercial launch. We look forward to sharing top-line data for the NDA dataset in concert with worldwide regulatory filings. We are also excited to bring LOXO-292 and LOXO-195 forward into potential proof-of-concept studies in 2017."

The larotrectinib, LOXO-292, and LOXO-195 updates are summarized as follows:

Larotrectinib (LOXO-101): TRK Inhibitor

Loxo Oncology’s larotrectinib program is currently approximately 85% enrolled to goal, and the company plans to complete enrollment for the primary efficacy analysis in early 2017.
The efficacy and safety database sizes for larotrectinib will be within precedents set by prior targeted therapy drug approvals in oncology.
The larotrectinib clinical trials will remain open to continue long-term follow-up of enrolled patients and provide a mechanism for continued drug access to newly identified patients through trial enrollment during regulatory interactions.
The company expects to be in a position to report top-line data for the NDA dataset in the second half of 2017 and expects to submit a New Drug Application (NDA) in late 2017 or early 2018 and a European Marketing Authorisation Application (MAA) in 2018.
Loxo Oncology intends to submit for approval "for the treatment of unresectable or metastatic solid tumors with NTRK-fusion proteins in adult and pediatric patients who require systemic therapy and who have either progressed following prior treatment or who have no acceptable alternative treatments."
The Company plans to present clinical data from the SCOUT Phase 1/2 trial in pediatric patients in mid-2017.
U.S. Food and Drug Administration (FDA) has granted rare pediatric disease designation to larotrectinib for the treatment of infantile fibrosarcoma, a rare pediatric cancer. The designation provides the opportunity for Loxo Oncology to apply for participation in the FDA’s Rare Pediatric Disease Priority Review Voucher Program.
LOXO-292: Highly Selective RET Inhibitor

Initiate Phase 1 study: Early 2017
Initial Phase 1 clinical data: Potentially by year end 2017
LOXO-195: Next-Generation TRK Inhibitor for Potential Acquired Resistance

Initiate Phase 1 study: Mid-2017
Initial Phase 1 clinical data: Potentially by year end 2017

About Larotrectinib (LOXO-101)
Larotrectinib (LOXO-101) is a potent, oral and selective investigational new drug in clinical development for the treatment of patients with cancers that harbor abnormalities involving the tropomyosin receptor kinases (TRKs). Growing research suggests that the NTRK genes, which encode for TRKs, can become abnormally fused to other genes, resulting in growth signals that can lead to cancer in many sites of the body. In an ongoing Phase 1 clinical trial, larotrectinib has demonstrated encouraging preliminary efficacy. Larotrectinib is also being evaluated in the NAVIGATE global Phase 2 multi-center basket trial in patients with solid tumors that harbor TRK gene fusions, and the SCOUT Phase 1/2 trial in pediatric patients, including patients with advanced cancer, TRK gene fusions and infantile fibrosarcoma. Larotrectinib has been granted Breakthrough Therapy Designation and Rare Pediatric Disease Designation by the U.S. FDA. For additional information about the larotrectinib clinical trials, please refer to www.clinicaltrials.gov. Interested patients and physicians can contact the Loxo Oncology Physician and Patient Clinical Trial Hotline at 1-855-NTRK-123 or visit www.loxooncologytrials.com.

On December 19, 2016 Merck (NYSE:MRK), known as MSD outside the United States and Canada, reported that KEYTRUDA (pembrolizumab), the company’s anti-PD-1 therapy, has been approved in Japan for the treatment of certain patients with PD-L1-positive unresectable advanced/recurrent non-small cell lung cancer (NSCLC) in the first- and second-line treatment settings at a fixed dose of 200 mg every three weeks (Press release, Merck & Co, DEC 19, 2016, View Source [SID1234517108]). MSD will manufacture and market KEYTRUDA in Japan and will promote it with Taiho Pharmaceutical Co., Ltd.

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"This approval in both the first- and second-line settings for advanced non-small cell lung cancer in patients whose tumors express PD-L1 marks an important milestone in Japan," said Dr. Roger M. Perlmutter, president, Merck Research Laboratories. "Through advanced research, Merck is demonstrating its commitment to bringing meaningful therapeutic advances to people with cancer throughout the world."

The Japanese Ministry of Health, Labour, and Welfare (MHLW) approval is supported by findings from both the KEYNOTE-024 and KEYNOTE-010 studies. KEYNOTE-024 is a randomized, open-label, phase 3 study evaluating KEYTRUDA monotherapy at a fixed dose of 200 mg compared to standard of care platinum-containing chemotherapy for the treatment of patients with both squamous and non-squamous metastatic NSCLC. The study enrolled patients who had not received prior systemic chemotherapy treatment for their metastatic disease and whose tumors had high PD-L1 expression (as defined by a tumor proportion score [TPS] of 50 percent or more) with no EGFR or ALK aberrations. KEYNOTE-010 is an open-label, randomized, phase 2/3 trial assessing two doses of KEYTRUDA (pembrolizumab) (2 mg/kg or 10 mg/kg every three weeks) compared to docetaxel (75 mg/m2 every three weeks), a standard of care chemotherapy. This study enrolled patients with any level of PD-L1 expression (as defined by a TPS of one percent or more) who had progressed following platinum-containing chemotherapy and, if appropriate, targeted therapy for EGFR or ALK genomic tumor aberrations.

The PD-L1 IHC 22C3 PharmDx kit made by Dako North America, Inc., an Agilent Technologies Company, was approved in Japan on Nov. 25 for use in detecting PD-L1, an immune-related biomarker expressed on some tumor cells. The diagnostic is intended to aid in identifying appropriate patients for treatment with KEYTRUDA, including previously treated patients whose tumors have any level of PD-L1 expression and previously untreated patients whose tumors have high levels of PD-L1 expression. Tumors with a TPS of less than one percent are considered to have no PD-L1 expression.

About KEYTRUDA (pembrolizumab)

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 administered as an intravenous infusion over 30 minutes every three weeks for the approved indications. KEYTRUDA for injection is supplied in a 100 mg single use vial.

KEYTRUDA Indications and Dosing in the U.S.

Melanoma

KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic melanoma at a dose of 2 mg/kg every three weeks until disease progression or unacceptable toxicity.

Lung Cancer

KEYTRUDA is indicated for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have high PD-L1 expression [tumor proportion score (TPS) ≥50%] as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations.

KEYTRUDA (pembrolizumab) is also indicated for the treatment of patients with metastatic NSCLC whose tumors express PD-L1 (TPS ≥1%) 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.

In metastatic NSCLC, KEYTRUDA is administered at a fixed dose of 200 mg every three weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.

Head and Neck Cancer

KEYTRUDA is indicated for the treatment of patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) with disease progression on or after platinum-containing chemotherapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. In HNSCC, KEYTRUDA is administered at a fixed dose of 200 mg every three weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.

Selected Important Safety Information for KEYTRUDA (pembrolizumab)

KEYTRUDA can cause immune-mediated pneumonitis, including fatal cases. Pneumonitis occurred in 94 (3.4%) of 2799 patients receiving KEYTRUDA, including Grade 1 (0.8%), 2 (1.3%), 3 (0.9%), 4 (0.3%), and 5 (0.1%) pneumonitis, and occurred more frequently in patients with a history of prior thoracic radiation (6.9%) compared to those without (2.9%). 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.

KEYTRUDA can cause immune-mediated colitis. Colitis occurred in 48 (1.7%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.4%), 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 for Grade 2 or 3; permanently discontinue KEYTRUDA for Grade 4 colitis.

KEYTRUDA (pembrolizumab) can cause immune-mediated hepatitis. Hepatitis occurred in 19 (0.7%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.1%), 3 (0.4%), 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.

KEYTRUDA can cause hypophysitis. Hypophysitis occurred in 17 (0.6%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.2%), 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.

KEYTRUDA can cause thyroid disorders, including hyperthyroidism, hypothyroidism, and thyroiditis. Hyperthyroidism occurred in 96 (3.4%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.8%) and 3 (0.1%) hyperthyroidism. Hypothyroidism occurred in 237 (8.5%) of 2799 patients receiving KEYTRUDA, including Grade 2 (6.2%) and 3 (0.1%) hypothyroidism. Thyroiditis occurred in 16 (0.6%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.3%) thyroiditis. 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.

KEYTRUDA can cause type 1 diabetes mellitus, including diabetic ketoacidosis, which have been reported in 6 (0.2%) of 2799 patients. Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Administer insulin for type 1 diabetes, and withhold KEYTRUDA and administer antihyperglycemics in patients with severe hyperglycemia.

KEYTRUDA can cause immune-mediated nephritis. Nephritis occurred in 9 (0.3%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.1%), 3 (0.1%), 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

KEYTRUDA can cause other clinically important immune-mediated adverse reactions. 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 (pembrolizumab) 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 2799 patients: arthritis (1.5%), exfoliative dermatitis, bullous pemphigoid, rash (1.4%), uveitis, myositis, Guillain-Barré syndrome, myasthenia gravis, vasculitis, pancreatitis, hemolytic anemia, and partial seizures arising in a patient with inflammatory foci in brain parenchyma.

KEYTRUDA can cause severe or life-threatening infusion-related reactions, which have been reported in 6 (0.2%) of 2799 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.

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.

KEYTRUDA was discontinued due to adverse reactions in 8% of 682 patients with metastatic NSCLC. The most common adverse event resulting in permanent discontinuation of KEYTRUDA was pneumonitis (1.8%). Adverse reactions leading to interruption of KEYTRUDA occurred in 23% of patients; the most common (≥1%) were diarrhea (1%), fatigue (1.3%), pneumonia (1%), liver enzyme elevation (1.2%), decreased appetite (1.3%), and pneumonitis (1%). The most common adverse reactions (occurring in at least 20% of patients and at a higher incidence than with docetaxel) were decreased appetite (25% vs 23%), dyspnea (23% vs 20%), and nausea (20% vs 18%).

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 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, 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 nearly 400 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 December 19, 2016 Eisai Co., Ltd. (Headquarters: Tokyo, CEO: Haruo Naito, "Eisai") reported that the anticancer agent TREAKISYM (generic name: bendamustine hydrochloride) has been approved in Japan for an additional indication as first-line treatment for low-grade B-cell non-Hodgkin’s lymphoma and mantle cell lymphoma (MCL) (Press release, Eisai, DEC 19, 2016, View Source [SID1234517101]). TREAKISYM is the subject of a licensing agreement concluded between Eisai and SymBio Pharmaceuticals Limited (Headquarters: Tokyo, Representative Director, President & CEO: Fuminori Yoshida, "SymBio"). Through the approval of this additional indication, TREAKISYM will now be available for adjunctive use with rituximab for untreated low-grade B-cell non-Hodgkin’s lymphoma and MCL.

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TREAKISYM was initially approved in Japan in October 2010 as monotherapy for relapsed or refractory low-grade B-cell non-Hodgkin’s lymphoma and MCL. Under the licensing agreement concluded between the two companies, Eisai has been marketing the product since December 2010. In August 2016, TREAKISYM was approved in Japan for an additional indication of chronic lymphocytic leukemia. For this approval of the indication for first-line low-grade B-cell non-Hodgkin’s lymphoma and MCL, this indication met the development requests set by the Japanese Ministry of Health, Labour and Welfare’s Council on Unapproved Drugs/Off-label Use, and SymBio submitted a supplemental New Drug Application in December 2015.

Non-Hodgkin’s lymphoma is a general term that refers to lymphocytes within white blood cells that have mutated into lymphomas, except for Hodgkin’s lymphoma, and represent the majority of lymphomas diagnosed in Japan. Non-Hodgkin’s lymphoma is categorized by progression speed, which means lymphoma progressing annually is low-grade, monthly is mid-grade and weekly is high-grade. In addition, non-Hodgkin’s lymphoma can be further categorized by which cells have become cancerous (such as B-cells) and how mature the cells are. As low-grade B-cell non-Hodgkin’s lymphoma and MCL are difficult to cure completely, they are both diseases with high unmet medical needs.

Eisai positions oncology as a key therapeutic area and is aiming to discover revolutionary new medicines with the potential to cure cancer. Eisai remains committed to maximizing the value of TREAKISYM as well as its in-house developed anticancer agents including Halaven and Lenvima , seeking to contribute further to addressing the diverse needs of patients with cancer and their families.

1. About bendamustine hydrochloride (generic name, product name: TREAKISYM for injection 25 mg, 100 mg) Bendamustine hydrochloride is an anticancer agent originally synthesized by German (formerly ‘East German’) pharmaceutical company Jenapharm and is marketed in Europe as a treatment for diseases such as non-Hodgkin’s lymphoma, multiple myeloma and chronic lymphocytic leukemia. In the United States the product is currently marketed for the treatment of chronic lymphocytic leukemia and relapsed B-cell non-Hodgkin’s lymphoma. Eisai concluded an exclusive licensing agreement with SymBio in August 2008 concerning the joint development and marketing of TREAKISYM in Japan, which was followed by a subsequent agreement between the two companies in May 2009 concerning the development and marketing of the agent in Singapore and South Korea.

2. About TREAKISYM (changed parts have been underlined)
Product Name: TREAKISYM for Injection, for intravenous infusion 25 mg, 100 mg
Generic Name: bendamustine hydrochloride
Indications and Usage: 1. Low-grade B-cell non-Hodgkin’s lymphoma Mantle cell lymphoma 2. Chronic lymphocytic leukemia
Dosage and Administration:
1. For low-grade B-cell non-Hodgkin’s lymphoma and mantle cell lymphoma
(1) As first-line treatment When used adjunctively with rituximab (recombinant DNA), the usual adult dose of bendamustine hydrochloride is 90 mg/m2 body surface area infused intravenously over 60 minutes on Days 1 and 2 of repeated 28-day cycles. The dose may be reduced appropriately according to the patient’s condition.
(2) For relapsed or refractory disease The usual adult dose of bendamustine hydrochloride is 120 mg/m2 body surface area infused intravenously over 60 minutes on Days 1 and 2 of repeated 21-day cycles. The dose may be reduced appropriately according to the patient’s condition.
2. For chronic lymphocytic leukemia The usual adult dose of bendamustine hydrochloride is 100 mg/m2 body surface area infused intravenously over 60 minutes on Days 1 and 2 of repeated 28-day cycles. The dose may be reduced appropriately according to the patient’s condition.