On December 22, 2015 Celgene Corporation (NASDAQ: CELG) reported the settlement of litigation with Natco Pharma Ltd. of India, Natco’s U.S. partner, Arrow International Limited, and Arrow’s parent company, Watson Laboratories, Inc. (a wholly-owned subsidiary of Allergan plc) relating to patents for REVLIMID (lenalidomide) (Press release, Celgene, DEC 22, 2015, View Source [SID:1234508630]).

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As part of the settlement, the parties will file Consent Judgments with the United States District Court for the District of New Jersey that enjoin Natco from marketing generic lenalidomide before the expiration of the patents-in-suit, except as provided for in the settlement, as described below.

In settlement of all outstanding claims in the litigation, Celgene will permit entry of generic lenalidomide before the April 2027 expiration of Celgene’s last-to-expire patent listed in the Orange Book for REVLIMID. Celgene has agreed to provide Natco with a license to Celgene’s patents required to manufacture and sell an unlimited quantity of generic lenalidomide in the United States beginning on January 31, 2026. In addition, Natco will receive a volume-limited license to sell generic lenalidomide in the United States commencing in March 2022. The volume limit is expected to be a mid-single-digit percentage of the total lenalidomide capsules dispensed in the United States during the first full year of entry. The volume limitation is expected to increase gradually each 12 months until March of 2025, and is not expected to exceed one-third of the total lenalidomide capsules dispensed in the U.S. in the final year of the volume-limited license under this agreement. Natco’s ability to market lenalidomide in the U.S. will be contingent on its obtaining approval of an Abbreviated New Drug Application.

"We believe strongly in our patent estate for REVLIMID, and that this settlement appropriately recognizes the strength of our patents. This settlement provides clarity around the future of REVLIMID, and we will continue to focus on developing our many important pipeline assets, which provide great potential promise to patients with unmet medical needs," said Bob Hugin, Chairman and CEO of Celgene Corporation. "We remain confident in the strength of our patents, and will continue to vigorously defend them."

On December 21, 2015 Array BioPharma Inc. (NASDAQ: ARRY) reported the closing of its definitive agreement with Pierre Fabre following approval of the agreement by the European Commission on Competition (ECC) (Filing, 8-K, Array BioPharma, DEC 21, 2015, View Source [SID:1234508616]). The definitive agreement, announced on November 16, 2015, relates to globally developing and commercializing Array’s late-stage novel oncology products, binimetinib and encorafenib. Binimetinib, a MEK inhibitor, and encorafenib, a BRAF inhibitor, are currently advancing in three, global Phase 3 trials for melanoma and ovarian cancer.

About the Array / Pierre Fabre Agreement
Under the terms of the agreement, Array will receive an upfront payment of $30 million and retains exclusive commercialization rights for binimetinib and encorafenib in the United States, Canada, Japan, Korea and Israel. Pierre Fabre will have exclusive rights to commercialize both products in all other countries, including Europe, Asia and Latin America. Array is entitled to receive up to $425 million if certain development and commercialization milestones are achieved, and is eligible for robust, tiered double-digit royalties. Array and Pierre Fabre have agreed to split future development costs on a 60:40 basis (Array:Pierre Fabre) with initial funding committed for new clinical trials in colorectal cancer and melanoma. All ongoing binimetinib and encorafenib clinical trials remain substantially funded through completion by Novartis.

About Binimetinib and Encorafenib
RAF and MEK are key protein kinases in the RAS/RAF/MEK/ERK pathway. Research has shown this pathway regulates several key cellular activities including proliferation, differentiation, migration, survival and angiogenesis. Inappropriate activation of proteins in this pathway has been shown to occur in many cancers, such as non-small cell lung cancer, melanoma, colorectal, ovarian and thyroid cancers. Binimetinib is a small molecule MEK inhibitor and encorafenib is a small molecule BRAF inhibitor, both of which target key enzymes in this pathway. Three Phase 3 trials in advanced cancer patients continue to advance: NRAS-mutant melanoma (NEMO, with binimetinib), low-grade serous ovarian cancer (MILO, with binimetinib) and BRAF-mutant melanoma (COLUMBUS, with binimetinib and encorafenib). Array announced on December 16, 2015 that NEMO met its primary endpoint of improving progression-free survival compared with dacarbazine treatment. Array plans to submit binimetinib to regulatory authorities for marketing approval in NRAS-mutant melanoma during the first half of 2016. Array also projects a regulatory filing of binimetinib in combination with encorafenib in BRAF melanoma in 2016.

About Pierre Fabre and Pierre Fabre Oncology
Pierre Fabre is a French privately-owned health and beauty care company created in 1961 by Mr. Pierre Fabre. In 2014, global sales reached €2.1 billion across 130 countries. The company is structured around two divisions: Pharmaceuticals (Prescription drugs, Consumer Health Care) and Dermo-cosmetics (including the European and Asian market-leader Eau Thermale Avene brand). Pierre Fabre employs some 10,000 people worldwide and owns subsidiary in 43 countries. In 2014, the company allocated 17 percent of its pharmaceuticals sales to R&D with a focus on 4 therapeutic areas: oncology, dermatology, CNS and consumer health care.
Pierre Fabre Oncology, a business unit of the Pierre Fabre company, is supported by over 1,000 employees with a strong focus on European markets. In 2014, worldwide annual sales of Pierre Fabre Oncology products surpassed $200 million on the strength of the Oral Navelbine, Javlor and Busilvex brands. In addition, Pierre Fabre has a significant commitment and track record in pharmaceutical R&D, developing products for patients afflicted with lung, breast and other solid tumors and hematological cancers.

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On December 21, 2015 Foundation Medicine, Inc. (NASDAQ:FMI) reported that it has signed a national agreement for FoundationOne, a comprehensive genomic profiling assay for solid tumors, with UnitedHealthcare, one of the nation’s largest private payers (Press release, Foundation Medicine, DEC 21, 2015, View Source [SID:1234508618]). The Agreement, which became effective December 15, 2015, covers FoundationOne for patients with metastatic stage IV non-small cell lung cancer (NSCLC). In the United States, approximately 50 percent of patients with NSCLC have metastatic disease at the time of diagnosis.1

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FoundationOne is a comprehensive genomic profile that enables physicians to make treatment decisions for patients with cancer by identifying the molecular growth drivers of their cancers and by helping oncologists match the identified drivers with relevant targeted therapeutic options. Requiring only a small amount of tumor tissue, FoundationOne interrogates the entire coding sequence of 315 cancer-related genes plus select introns from 28 genes that are known to be altered in solid tumors.

"UnitedHealthcare’s coverage decision is a critical first step towards ensuring that comprehensive genomic profiling becomes standard-of-care treatment for patients with metastatic disease," said Bonnie J. Addario, lung cancer survivor, and founder of the Bonnie J. Addario Lung Cancer Foundation and the Addario Lung Cancer Medical Institute. "Lack of reimbursement for comprehensive genomic profiling tests, like FoundationOne, continues to be one of the major barriers impeding patient access to potentially life-extending therapies for which the patient is a molecular match."

"This national coverage agreement with UnitedHealthcare is an important step towards broader reimbursement for Foundation Medicine, and importantly, it’s a significant advance for patients with metastatic NSCLC," said Michael Pellini, M.D., chief executive officer for Foundation Medicine. "Studies demonstrate that improved clinical outcomes are achieved by matching patients to targeted therapies based on the unique genomic alterations contributing to the disease. We look forward to building upon our relationship with UnitedHealthcare and other national insurers as we continue to demonstrate clinical and economic evidence supporting coverage and payment for FoundationOne in additional cancer types."

On December 21, 2015 OPKO Health, Inc. (NYSE: OPK) through its subsidiary GeneDx, reported results from the largest published study to date of patients who received hereditary genetic testing with Next Generation Sequencing (NGS) cancer panels (Press release, Opko Health, DEC 21, 2015, View Source [SID:1234508623]). The study, "Pathogenic and Likely Pathogenic Variant Prevalence among the First 10,000 Patients Referred for Next Generation Cancer Panel Testing," was published in the December 2015 issue of Genetics in Medicine. GeneDx’s analysis of the data generated from the first 10,030 patients highlights the clinical utility of testing for multiple cancer genes to identify variants that would not have been identified through previously used testing methods. The patients, who were referred for testing between August, 2013 and October, 2014, underwent genetic testing for panels of genes associated with hereditary cancer.

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While many patients were found to carry pathogenic or likely pathogenic variants in well-established, high-risk cancer genes, approximately half of the pathogenic variants identified were in genes with moderate risk and in recently identified cancer genes. Notably, among women with breast cancer, 50% of positive findings were in genes other than BRCA1 or BRCA2. Additionally, several individuals had pathogenic variants in high-risk genes that were somewhat unexpected, so clinical presentation alone might not have prompted testing for these genes.

"We believe that molecular diagnostic testing for panels containing multiple genes are significantly more accurate in determine the heritable factors which increase the risk of cancer, and may permit more tailored treatment for cancer patients and screening for their family members," said Sherri Bale, PhD, FACMG, Co-Founder and Managing Director of GeneDx. "Our experience, based on a large database of patients, demonstrates that multi-gene panels have the potential to identify pathogenic variants in genes that would not typically have been tested and most likely would have been missed. This study provides important empirical data for clinical decision-making when choosing between single genes and NGS cancer panel testing for a variety of cancers."

On December 19, 2015 Merck (NYSE:MRK), known as MSD outside the United States and Canada, reported results from the pivotal KEYNOTE-010 study, the first study of its kind to evaluate the potential of an immunotherapy compared to chemotherapy based on prospective measurement of PD-L1 expression in patients with advanced non-small cell lung cancer (NSCLC) (Press release, Merck & Co, DEC 19, 2015, View Source [SID:1234508607]). In the Phase 2/3 study, KEYTRUDA (pembrolizumab), Merck’s anti-PD-1 (programmed death receptor-1) therapy, significantly improved overall survival (OS) compared to chemotherapy in patients with any level of PD-L1 expression, as defined by a tumor proportion score (TPS) of 1 percent or more. The results were published in The Lancet and will be presented at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Asia 2015 Congress.

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"Because lung cancer remains one of the most common and most challenging cancers to treat, understanding the role that KEYTRUDA can play in helping patients was essential to our development program. In this study in patients with PD-L1 expression of one percent or greater, KEYTRUDA demonstrably improved overall survival compared to chemotherapy in previously-treated patients with non-small cell lung cancer, including both squamous and non-squamous histologies," said Dr. Roger M. Perlmutter, president, Merck Research Laboratories.

Merck plans to submit a supplemental Biologics License Application (sBLA) to the U.S. Food and Drug Administration for KEYTRUDA based on findings from KEYNOTE-010 by the end of 2015. The Company plans to submit a Marketing Authorization Application to the European Medicines Agency in early 2016.

Overall Survival Findings from KEYNOTE-010

The Phase 2/3 KEYNOTE-010 study included 1,034 patients with advanced NSCLC with PD-L1 expression (TPS of 1% or more). Similar findings were shown in patients who received the FDA-approved dose of KEYTRUDA (pembrolizumab) (2 mg/kg every three weeks) (n=345) and an investigational dose of KEYTRUDA (10 mg/kg every three weeks) (n=346). Both groups of patients who received KEYTRUDA were compared to patients who received docetaxel (n=343). PD-L1 expression was assessed by the immunohistochemistry companion diagnostic test PD-L1 IHC 22C3 PharmDx, made by Dako North America, Inc., an Agilent Technologies Company. The findings from KEYNOTE-010 are based on the final study analysis. The median follow-up was 13.1 months (IQR, 8.6-17.7).

In the total study population (all levels of PD-L1 expression), both doses of KEYTRUDA studied significantly improved OS compared with docetaxel. Specifically, KEYTRUDA resulted in a 29 percent improvement in OS for the 2 mg/kg dose (HR 0.71, P=0.0008; 95% CI, 0.58-0.88) and a 39 percent improvement in OS for the 10 mg/kg dose (HR 0.61, P<0.0001; 95% CI, 0.49-0.75), compared to docetaxel. The estimated 1-year OS rates for KEYTRUDA were 43.2 percent and 52.3 percent, respectively, compared to 34.6 percent for docetaxel. Median OS for KEYTRUDA were 10.4 months (95% CI, 9.4-11.9) and 12.7 months (95% CI, 10.0-17.3), respectively, compared to 8.5 months for docetaxel (95% CI, 7.5-9.8).

Among patients with higher levels of PD-L1 expression (a TPS score of 50 percent or greater), OS was superior for both KEYTRUDA doses compared with docetaxel. Specifically, KEYTRUDA improved OS by 46 percent for the 2 mg/kg dose (HR 0.54, P=0.0002; 95% CI, 0.38-0.77) and by 50 percent for the 10 mg/kg dose (HR 0.50, P<0.0001; 95% CI, 0.36-0.70), compared to docetaxel. Median OS for KEYTRUDA (2 mg/kg and 10 mg/kg, respectively) was 14.9 months (95% CI, 10.4 to not reached) and 17.3 months (95% CI, 11.8 to not reached), compared to 8.2 months for docetaxel (95% CI, 6.4-10.7).

"This is an exciting time, and studies such as KEYNOTE-010 with KEYTRUDA are paving the way to a better understanding of how to identify the right medicine for each patient," said Dr. Roy Herbst, Chief of Medical Oncology, Yale Cancer Center and Smilow Cancer Hospital at Yale-New Haven. "These study findings show KEYTRUDA provided superior overall survival in patients with advanced lung cancer who had positive PD-L1 expression, and support its potential in the treatment of this disease."

Additional Findings from KEYNOTE-010

In the total study population, KEYTRUDA (pembrolizumab) prolonged progression-free survival (PFS) at both doses, though statistical significance was not met (HR 0.88 [95% CI, 0.74-1.05], P=0.07 for 2 mg/kg; HR 0.79 [95% CI, 0.66-0.94], P=0.004 for 10 mg/kg). Among patients treated with KEYTRUDA (2 mg/kg and 10 mg/kg, respectively), median PFS was 3.9 months (95% CI, 3.1-4.1) and 4.0 months (95% CI, 2.7-4.3), compared to 4.0 months for docetaxel (95% CI, 3.1-4.2).

Patients with higher levels of PD-L1 expression (a TPS score of 50 percent or greater) who were treated with KEYTRUDA had significantly prolonged PFS compared to docetaxel (HR 0.59 [95% CI, 0.44-0.78, P=0.0001] for 2 mg/kg; HR 0.59 [95% CI, 0.45-0.78, P<0.0001] for 10 mg/kg). Among patients treated with KEYTRUDA (2 mg/kg and 10 mg/kg, respectively), median PFS was 5.0 months (95% CI, 4.0-6.5) and 5.2 months (95% CI, 4.1-8.1), compared to 4.1 months for docetaxel (95% CI, 3.6-4.3).

Additionally, the safety of KEYTRUDA was consistent with what has been seen in previous trials among advanced lung cancer patients. Grade 3-5 treatment-related adverse events for KEYTRUDA (2 mg/kg and 10 mg/kg, respectively) included: decreased appetite (n=3, n=1), fatigue (n=4, n=6), nausea (n=1, n=2), rash (n=1, n=1), diarrhea (n=2, n=0), asthenia (n=1, n=2), stomatitis (n=0, n=1), and anemia (n=3, n=1). The most common immune-mediated adverse events for KEYTRUDA (2 mg/kg and 10 mg/kg, respectively) included: hypothyroidism (8% [n=28], 8% [n=28]), hyperthyroidism (4% [n=12], 6% [n=20]), and pneumonitis (5% [n=16], 4% [n=15]). There were three treatment-related deaths among patients receiving KEYTRUDA at the 2 mg/kg dose (pneumonitis [n=2], pneumonia [n=1]) and three treatment-related deaths among patients receiving KEYTRUDA at the 10 mg/kg dose (myocardial infarction [n=1], pneumonia [n=1], and pneumonitis [n=1]).

About KEYNOTE-010 and the KEYTRUDA Development Program

KEYNOTE-010 is a global, open-label, randomized, pivotal Phase 2/3 study (ClinicalTrials.gov, NCT01905657) evaluating two doses of KEYTRUDA (2 mg/kg or 10 mg/kg every three weeks) compared to docetaxel (75 mg/m^2 every three weeks) in 1,034 patients with squamous and non-squamous NSCLC who experienced disease progression after platinum-containing systemic therapy and whose tumors expressed PD-L1. The primary endpoints were OS and PFS. Tumor response was assessed at week 9, then every 9 weeks thereafter per RECIST 1.1 criteria by independent, central, blinded, radiographic review and investigator-assessed, immune-related response criteria.

The KEYTRUDA program currently addresses more than 30 tumor types in more than 160 clinical trials, including more than 80 combinations of KEYTRUDA with other cancer treatments. In lung cancer, KEYTRUDA is being studied across lines of therapy, both as a monotherapy and in combination with chemotherapy. Registration-enabling trials of KEYTRUDA (pembrolizumab) are currently enrolling patients in melanoma, NSCLC, head and neck cancer, bladder cancer, gastric cancer, colorectal cancer, esophageal cancer, breast cancer, Hodgkin lymphoma, multiple myeloma and other tumors, with further trials in planning for other cancers.