On December 19, 2016 Juno Therapeutics, Inc. (NASDAQ: JUNO), a biopharmaceutical company developing innovative cellular immunotherapies for the treatment of cancer, reported that it has defeated an attempt to invalidate a patent exclusively licensed by Juno that covers, among other things, a chimeric antigen receptor (CAR) T cell used for the treatment of B-cell malignancies, and that it is suing Kite Pharma, Inc., seeking a declaratory judgment that Kite’s lead product candidate, KTE-C19, will infringe the patent when commercially produced(Press release, Juno, DEC 19, 2016, View Source [SID1234517122]).

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In August 2015, Kite Pharma, Inc. filed an inter partes review in the U.S. Patent & Trademark Office in an attempt to invalidate U.S. Patent No. 7,446,190 by challenging all of its claims. Juno exclusively licenses the ’190 patent, titled "Nucleic Acids Encoding Chimeric T Cell Receptors," from Sloan Kettering Institute for Cancer Research, an affiliate of Memorial Sloan Kettering Cancer Center. The patent covers, among other things, a construct for a CD-19 targeted CAR T cell treatment that employs a CD28 costimulatory domain.

The U.S. Patent & Trademark Office instituted a review of the patent and on December 16, 2016 issued a final written decision upholding all the claims of the patent.

"We are obviously pleased by the USPTO’s decision to uphold the patent," said Bernard J. "Barney" Cassidy, General Counsel of Juno Therapeutics. "Our efforts to amicably and reasonably resolve the dispute Kite initiated have been thwarted and today we are taking the next step towards fully resolving matters. Importantly, our filing will not prevent continued patient access while the legal dispute continues."

The lawsuit is being filed in the U.S. District Court for the District of Delaware. Juno and the Sloan Kettering Institute are represented by Irell & Manella LLP in both the IPR and the litigation.

On December 19, 2016 RedHill Biopharma Ltd. (NASDAQ:RDHL) (TASE:RDHL) ("RedHill" or the "Company"), a biopharmaceutical company primarily focused on development and commercialization of late clinical-stage, proprietary, orally-administered, small molecule drugs for gastrointestinal and inflammatory diseases and cancer, reported that the first patients have been screened and a first patient has been dosed in the Phase Ib/II clinical study evaluating YELIVA (ABC294640) in patients with refractory or relapsed multiple myeloma (Press release, RedHill Biopharma, DEC 19, 2016, View Source [SID1234517121]).

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The open-label, dose escalation Phase Ib/II study is being conducted at Duke University Medical Center and is expected to enroll up to 77 patients with refractory or relapsed multiple myeloma who have previously been treated with proteasome inhibitors and immunomodulatory drugs.

Dr. Yubin Kang, MD, Associate Professor in the Division of Hematologic Malignancies and Cellular Therapy in the Department of Medicine at Duke University School of Medicine, is the lead investigator for the study.

The study is supported by a $2 million grant from the National Cancer Institute (NCI) Small Business Innovation Research Program (SBIR) awarded to Apogee Biotechnology Corp. (Apogee), in conjunction with Duke University, with additional support from RedHill.

YELIVA is a proprietary, first-in-class, orally-administered sphingosine kinase-2 (SK2) selective inhibitor, with anti-cancer and anti-inflammatory activities. By inhibiting the SK2 enzyme, YELIVA blocks the synthesis of sphingosine 1-phosphate (S1P), a lipid signaling molecule that promotes cancer growth and pathological inflammation.

RedHill is pursuing and evaluating multiple clinical programs in oncology, inflammatory and gastrointestinal indications with YELIVA, as well as potential collaboration opportunities with larger pharmaceutical companies to evaluate YELIVA as an add-on therapy to existing oncology treatments.

Results from a Phase I study with YELIVA in patients with advanced solid tumors confirmed that the study, conducted at the Medical University of South Carolina Hollings Cancer Center (MUSC), successfully met its primary and secondary endpoints, demonstrating that the drug is well-tolerated and can be safely administered to cancer patients at doses that provide circulating drug levels that are predicted to have therapeutic activity.

A Phase II study with YELIVA for the treatment of advanced hepatocellular carcinoma (HCC) was initiated at MUSC Hollings Cancer Center, following ethics approval and successful submission to the U.S. FDA. The study is supported by a $1.8 million grant from the NCI, awarded to MUSC, which is intended to fund a broad range of studies on the feasibility of targeting sphingolipid metabolism for the treatment of a variety of solid tumor cancers, with additional support from RedHill.

A Phase I/II clinical study evaluating YELIVA in patients with refractory/relapsed diffuse large B-cell lymphoma was initiated at the Louisiana State University Health Sciences Center in New Orleans in June 2015 and was recently amended to address overall recruitment prospects. The study will now also include Kaposi sarcoma patients. The study is supported by a grant from the NCI awarded to Apogee, with additional support from RedHill.

A Phase Ib study to evaluate YELIVA as a radioprotectant for prevention of mucositis in head and neck cancer patients undergoing therapeutic radiotherapy is planned to be initiated in the first half of 2017.

Additional Phase I/II studies with YELIVA for other indications are in various stages of preparation.

The ongoing studies with YELIVA (ABC294640) are registered on www.ClinicalTrials.gov, a web-based service by the U.S. National Institute of Health, which provides public access to information on publicly and privately supported clinical studies.

About Multiple Myeloma:
Multiple myeloma is a malignant plasma cell disorder which is usually not curable 1. Symptomatic multiple myeloma is characterized by a clonal proliferation of plasma cells preceding clinical findings that include bone lesions, fractures, anemia, renal failure and hypercalcemia2. Approximately 30,000 new cases of multiple myeloma are expected to be diagnosed in the U.S. in 2016, accounting for 1.8% of all cancers. The 5-year survival rate of myeloma is estimated at 48.5% and approximately 95,000 people are living with myeloma in the United States3. The risk of multiple myeloma increases as people age. Most patients diagnosed with this cancer are at least 65 years old4, making treatment with the most effective therapies problematic. The worldwide sales of multiple myeloma therapies are estimated to exceed $12 billion in 20165.

About YELIVA (ABC294640):
YELIVA (ABC294640) is a Phase II-stage, proprietary, first-in-class, orally-administered, sphingosine kinase-2 (SK2) selective inhibitor with anti-cancer and anti-inflammatory activities. RedHill is pursuing with YELIVA multiple clinical programs in oncology, inflammatory and gastrointestinal indications. By inhibiting the SK2 enzyme, YELIVA blocks the synthesis of sphingosine 1-phosphate (S1P), a lipid signaling molecule that promotes cancer growth and pathological inflammation. SK2 is an innovative molecular target for anticancer therapy because of its critical role in catalyzing the formation of S1P, which is known to regulate cell proliferation and activation of inflammatory pathways. YELIVA was originally developed by U.S.-based Apogee Biotechnology Corp. and completed multiple successful pre-clinical studies in oncology, inflammation, GI and radioprotection models, as well as the ABC-101 Phase I clinical study in cancer patients with advanced solid tumors. The Phase I study included the first-ever longitudinal analysis of plasma S1P levels as a potential pharmacodynamic (PD) biomarker for activity of a sphingolipid-targeted drug. The administration of YELIVA resulted in a rapid and pronounced decrease in S1P levels, with several patients having prolonged stabilization of disease. The development of YELIVA was funded to date primarily by grants and contracts from U.S. federal and state government agencies awarded to Apogee Biotechnology Corp., including the U.S. National Cancer Institute, the U.S. Department of Health and Human Services’ Biomedical Advanced Research and Development Authority (BARDA), the U.S. Department of Defense and the FDA Office of Orphan Products Development.

On December 19, 2016 Pfizer Inc. reported results from a sub-analysis studying Asian patients from the Phase 3 PALOMA-2 trial of IBRANCE (palbociclib), in combination with letrozole, as first-line therapy for postmenopausal women with estrogen receptor-positive, human epidermal growth factor receptor 2-negative (ER+, HER2-) metastatic breast cancer (Press release, Pfizer, DEC 19, 2016, View Source [SID1234517120]). Results showed the combination of IBRANCE and letrozole significantly extended progression-free survival (PFS) by more than 11 months compared with letrozole plus placebo, and demonstrated that the median PFS exceeded two years in these patients. Data from this sub-analysis was shared on December 17 as an oral presentation at the 2nd ESMO (Free ESMO Whitepaper) Asia Congress in Singapore.

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"It is exciting to see that the significant efficacy shown in the PALOMA-2 trial extends to Asian patients, further supporting the potential for IBRANCE to be a standard of care treatment in Asia Pacific, a region where more than 600,000 women are affected by breast cancer each year. " said Dr. Mahmood Alam, Regional Medical Lead, Pfizer Oncology for the Asia Pacific region.

In this sub-analysis of the PALOMA-2 trial, investigator-assessed median PFS for Asian women treated with IBRANCE plus letrozole was 25.7 months (95% CI, 19.2-not estimable) compared with 13.9 months (95% CI, 7.4-22.0) for women treated with letrozole plus placebo (HR=0.48 [95% CI, 0.27-0.87], 1-sided P=0.007).

"Across the Asia Pacific region, breast cancer has grown into a major health concern, with significant increases in breast cancer incidence in recent years in several Asian countries," said Dr. Seock-Ah Im of Seoul National University Hospital, "Patients with metastatic breast cancer, in particular those in Asia, eagerly await new and innovative treatment options."

The Phase 3 PALOMA-2 trial evaluated the use of IBRANCE in combination with letrozole in the first-line setting, which was first studied in the randomized Phase 2 PALOMA-1 trial, and the results reinforce the clinical benefit of IBRANCE in this treatment setting. The findings of this PALOMA-2 sub-analysis evaluating the efficacy and safety in Asian women are consistent with the overall findings of PALOMA-2. The most common adverse events of all grades with IBRANCE plus letrozole versus placebo plus letrozole were neutropenia (95% vs 13%), infections (66% vs 50%) and stomatitis (49% vs 20%). For more information, please see Important Safety Information for IBRANCE below.

Breast cancer is the most common cancer in women worldwide, with an estimated 1.7 million new cases each year and more than 600,000 in the Asia Pacific region.1 While one-third of women with breast cancer globally were estimated to be under 50 when they were diagnosed, 42 percent of women diagnosed with breast cancer throughout Asia-Pacific were under 50.2 Globally, up to 30 percent of women diagnosed with and treated for early breast cancer will go on to develop metastatic breast cancer,3,4 which currently remains incurable.5 Patients diagnosed with metastatic breast cancer today face a median survival of 18 to 24 months,6 and are in great need of more meaningful advances and options in the treatment to address the high unmet need.

IBRANCE/palbociclib is currently approved by regulatory authorities in in Asia in Macau, Singapore, Malaysia, Hong Kong, South Korea and India in combination with letrozole for the treatment of postmenopausal women with ER+, HER2- advanced breast cancer as initial endocrine-based therapy for their metastatic disease.

About PALOMA-2
PALOMA-2 is a randomized (2:1), multicenter, multinational, double-blind Phase 3 study designed to assess the PFS of IBRANCE (125 mg orally once daily for three out of four weeks in repeated cycles) in combination with letrozole (2.5 mg once daily continuously) versus letrozole plus placebo as a first-line treatment for postmenopausal women with ER+, HER2- metastatic breast cancer. PALOMA-2 evaluated a total of 666 women from 186 global sites in 17 countries.7

The full prescribing information for IBRANCE can be found at www.pfizer.com.

About IBRANCE (palbociclib)
IBRANCE is the first and only U.S. Food and Drug Administration FDA approved oral inhibitor of CDKs 4 and 6,7 which are key regulators of the cell cycle that trigger cellular progression.8,9 In the U.S., IBRANCE is indicated for the treatment of HR+, HER2- advanced or metastatic breast cancer in combination with letrozole as initial endocrine based therapy in postmenopausal women, or fulvestrant in women with disease progression following endocrine therapy.2 The indication in combination with letrozole is approved under accelerated approval based on PFS. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial, PALOMA-2.7

Important IBRANCE (palbociclib) Safety Information from the U.S. Prescribing Information
Neutropenia was the most frequently reported adverse reaction in PALOMA-1 (75%) and PALOMA-3 (83%). In PALOMA-1, Grade 3 (57%) or 4 (5%) decreased neutrophil counts were reported in patients receiving IBRANCE plus letrozole. In PALOMA-3, Grade 3 (56%) or Grade 4 (11%) decreased neutrophil counts were reported in patients receiving IBRANCE plus fulvestrant. Febrile neutropenia has been reported in about 1% of patients exposed to IBRANCE. One death due to neutropenic sepsis was observed in PALOMA-3. Inform patients to promptly report any fever.

Monitor complete blood count prior to starting IBRANCE, at the beginning of each cycle, on Day 14 of first 2 cycles, and as clinically indicated. Dose interruption, dose reduction, or delay in starting treatment cycles is recommended for patients who develop Grade 3 or 4 neutropenia.

Pulmonary embolism (PE) has been reported at a higher rate in patients treated with IBRANCE plus letrozole in PALOMA-1 (5%) and in patients treated with IBRANCE plus fulvestrant in PALOMA-3 (1%) compared with no cases in patients treated either with letrozole alone or fulvestrant plus placebo. Monitor for signs and symptoms of PE and treat as medically appropriate.

Based on the mechanism of action, IBRANCE can cause fetal harm. Advise females of reproductive potential to use effective contraception during IBRANCE treatment and for at least 3 weeks after the last dose. IBRANCE may impair fertility in males and has the potential to cause genotoxicity. Advise male patients with female partners of reproductive potential to use effective contraception during IBRANCE treatment and for 3 months after the last dose. Advise females to inform their healthcare provider of a known or suspected pregnancy. Advise women not to breastfeed during IBRANCE treatment and for 3 weeks after the last dose because of the potential for serious adverse reactions in nursing infants.

The most common adverse reactions (≥10%) of any grade reported in PALOMA-1 of IBRANCE plus letrozole vs letrozole alone included neutropenia (75% vs 5%), leukopenia (43% vs 3%), fatigue (41% vs 23%), anemia (35% vs 7%), upper respiratory infection (31% vs 18%), nausea (25% vs 13%), stomatitis (25% vs 7%), alopecia (22% vs 3%), diarrhea (21% vs 10%), thrombocytopenia (17% vs 1%), decreased appetite (16% vs 7%), vomiting (15% vs 4%), asthenia (13% vs 4%), peripheral neuropathy (13% vs 5%), and epistaxis (11% vs 1%).

Grade 3/4 adverse reactions (≥10%) in PALOMA-1 reported at a higher incidence in the IBRANCE plus letrozole group vs the letrozole alone group included neutropenia (54% vs 1%) and leukopenia (19% vs 0%). The most frequently reported serious adverse events in patients receiving IBRANCE plus letrozole were pulmonary embolism (4%) and diarrhea (2%).

Lab abnormalities occurring in PALOMA-1 (all grades, IBRANCE plus letrozole vs letrozole alone) were decreased WBC (95% vs 26%), decreased neutrophils (94% vs 17%), decreased lymphocytes (81% vs 35%), decreased hemoglobin (83% vs 40%), and decreased platelets (61% vs 16%).

The most common adverse reactions (≥10%) of any grade reported in PALOMA-3 of IBRANCE plus fulvestrant vs fulvestrant plus placebo included neutropenia (83% vs 4%), leukopenia (53% vs 5%), infections (47% vs 31%), fatigue (41% vs 29%), nausea (34% vs 28%), anemia (30% vs 13%), stomatitis (28% vs 13%), headache (26% vs 20%), diarrhea (24% vs 19%), thrombocytopenia (23% vs 0%), constipation (20% vs 16%), vomiting (19% vs 15%), alopecia (18% vs 6%), rash (17% vs 6%), decreased appetite (16% vs 8%), and pyrexia (13% vs 5%).

Grade 3/4 adverse reactions (≥10%) in PALOMA-3 reported at a higher incidence in the IBRANCE plus fulvestrant group vs the fulvestrant plus placebo group included neutropenia (66% vs 1%) and leukopenia (31% vs 2%). The most frequently reported serious adverse reactions in patients receiving IBRANCE plus fulvestrant were infections (3%), pyrexia (1%), neutropenia (1%), and pulmonary embolism (1%).

Lab abnormalities occurring in PALOMA-3 (all grades, IBRANCE plus fulvestrant vs fulvestrant plus placebo) were decreased WBC (99% vs 26%), decreased neutrophils (96% vs 14%), anemia (78% vs 40%), and decreased platelets (62% vs 10%).

Avoid concurrent use of strong CYP3A inhibitors. If patients must be administered a strong CYP3A inhibitor, reduce the IBRANCE dose to 75 mg/day. If the strong inhibitor is discontinued, increase the IBRANCE dose (after 3-5 half-lives of the inhibitor) to the dose used prior to the initiation of the strong CYP3A inhibitor. Grapefruit or grapefruit juice may increase plasma concentrations of IBRANCE and should be avoided. Avoid concomitant use of strong CYP3A inducers. The dose of sensitive CYP3A substrates with a narrow therapeutic index may need to be reduced as IBRANCE may increase their exposure.

IBRANCE has not been studied in patients with moderate to severe hepatic impairment or in patients with severe renal impairment (CrCl <30 mL/min).

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.