On January 16, 2018 Constellation Pharmaceuticals, Inc., a clinical-stage biopharmaceutical company developing tumor-targeted and immuno-oncology therapies based on its pioneering research and development in cancer epigenetics, reported it has initiated a Phase 1b/2 clinical trial to evaluate CPI-1205, a small-molecule inhibitor of Enhancer of Zeste Homolog 2 (EZH2), combined with checkpoint inhibitor ipilimumab (marketed as YERVOY by Bristol-Myers Squibb) and potentially other cancer immunotherapies (Press release, Constellation Pharmaceuticals, JAN 16, 2018, View Source [SID1234523138]). The study, named ORIOn-E, is based on translational insights which identified combination approaches using epigenetics-mediated mechanisms aimed at Overcoming Resistance to Immune Oncology therapies by inhibiting EZH2.

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"This is the second combination study we’ve initiated evaluating the potential for CPI-1205 to overcome resistance mechanisms to existing cancer therapies," said Jigar Raythatha, president and chief executive officer of Constellation Pharmaceuticals. "Our preclinical results with CPI-1205 demonstrate that epigenetic targets can be utilized by cancers to suppress the immune system and render immunotherapy treatment options less effective. We aim to build on this insight with CPI-1205 in clinical trials and with other epigenetic therapies that we discover and develop in this important area of research."

CPI-1205 is a potent, highly selective, first-generation small-molecule inhibitor of an enzyme called EZH2. In pre-clinical studies, CPI-1205 has shown potential to re-wire T regulatory and T effector cells within tumors to enhance tumor rejection alone and synergistically in combination with immune checkpoint inhibition.

"Since they were first made available in the U.S., checkpoint inhibitor therapies like ipilimumab have provided considerable benefit for patients with many different cancers. However, many patients do not respond to therapy or relapse after initial response," said Adrian Senderowicz, M.D., senior vice president and chief medical officer of Constellation Pharmaceuticals. "CPI-1205 plays a critical role in inhibiting the suppressive function of regulatory T cells and consequently may address resistance mechanisms that limit the benefit of immune checkpoint inhibitors in patients."

The Phase 1b portion is a dose escalation study designed to evaluate the safety, pharmacokinetics, pharmacodynamics and the assessment of potential predictive biomarkers in patients across solid tumors when treated with CPI-1205 in combination with ipilimumab. The Phase 2 portion will be conducted in melanoma patients, among other cancers.

About CPI-1205
CPI-1205 is a therapeutic candidate from Constellation Pharmaceuticals’ EZH2 portfolio and is an inhibitor of Enhancer of Zeste Homolog 2 (EZH2). The function of EZH2 is to selectively suppress gene expression of several pro-cancer pathways that contribute to drug resistance.

On January 16, 2018 Array BioPharma Inc. (Nasdaq: ARRY) reported the upcoming presentation of updated safety results and clinical activity from the safety lead-in of the Phase 3 BEACON CRC trial evaluating the triplet combination of encorafenib, a BRAF inhibitor, binimetinib, a MEK inhibitor and cetuximab, an anti-EGFR antibody, in patients with BRAF-mutant colorectal cancer (CRC) (Press release, Array BioPharma, JAN 16, 2018, View Source;p=RssLanding&cat=news&id=2326690 [SID1234523136]). These data will be presented at the 2018 Gastrointestinal Cancers Symposium (ASCO GI) in San Francisco, California.

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BEACON CRC SAFETY LEAD-IN

Title:

Abstract #627: BEACON CRC Study Safety Lead-in (SLI) in Patients With BRAFV600E Metastatic Colorectal Cancer (mCRC): Efficacy and Tumor Markers

Presenter:

Eric Van Cutsem, M.D., University Hospitals Gasthuisberg Leuven and KU Leuven, Leuven, Belgium

Date:

Saturday, January 20

Times:

7:00 am – 7:55 am PT and 12:30 pm – 2:00 pm PT

Updated data on the safety and tolerability profile of the triplet combination and measures of efficacy, including mPFS, ORR, duration of response, as well as tumor marker data, will be available as part of the presentation on January 20. The presentation will be available as a PDF from the Publications section of the Array website starting January 20.

Array’s BEACON CRC Phase 3 trial safety lead-in abstract published on January 16 contains previously presented safety and clinical activity data, as well as new data on changes in tumor markers.

About Encorafenib and Binimetinib
BRAF and MEK are key protein kinases in the MAPK signaling pathway (RAS-RAF-MEK-ERK). Research has shown this pathway regulates several key cellular activities including proliferation, differentiation, survival and angiogenesis. Inappropriate activation of proteins in this pathway has been shown to occur in many cancers, including melanoma and colorectal cancer. Encorafenib is a late-stage small molecule BRAF inhibitor and binimetinib is a late-stage small molecule MEK inhibitor, both of which target key enzymes in this pathway. Encorafenib and binimetinib are being studied in clinical trials in advanced cancer patients, including the Phase 3 BEACON CRC trial and the Phase 3 COLUMBUS trial.

The U.S. Food and Drug Administration (FDA) is currently reviewing the New Drug Applications (NDAs) to support use of the combination of encorafenib and binimetinib for the treatment of patients with BRAF-mutant advanced, unresectable or metastatic melanoma. The FDA set a target action date under the Prescription Drug User Fee Act (PDUFA) of June 30, 2018 for both applications. In addition, the European Medicines Agency (EMA) is reviewing the Marketing Authorization Applications for encorafenib and binimetininb.

Encorafenib and binimetinib are investigational medicines and are not currently approved in any country.

Array BioPharma has exclusive rights to encorafenib and binimetinib in the U.S. and Canada. Array has granted Ono Pharmaceutical exclusive rights to commercialize both products in Japan and South Korea and Pierre Fabre exclusive rights to commercialize both products in all other countries, including Europe, Asia and Latin America. The BEACON CRC trial is being conducted with support from Pierre Fabre and Merck KGaA, Darmstadt, Germany (support is for sites outside of North America).

On January 16, 2018 Linnaeus Therapeutics, Inc. ("Linnaeus"), a privately held biopharmaceutical company focused on the development and commercialization of novel, small molecule oncology therapeutics, reported that preclinical data from studies conducted at the University of Pennsylvania by its scientific founders was published in the journal eLife (Press release, Linnaeus Therapeutics, JAN 16, 2018, View Source [SID1234539506]).

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The paper, entitled "Activation of G protein-coupled estrogen receptor signaling inhibits melanoma and improves response to immune checkpoint blockade" was authored by Natale, et al.

For decades, research has associated female sex and a history of previous pregnancy with better outcomes after a melanoma diagnosis, but the mechanism for this protective effect has remained a mystery. This publication provides a potential explanation for this melanoma-protective effect. The mechanism is related to a cellular protein called the G protein-coupled estrogen receptor (GPER). When GPER was activated and combined with anti–PD-1 inhibitor drugs in mouse cancer models, the therapy dramatically extended survival in all animals and completely eliminated the tumor in up to 50 percent of the mice.

"The validation of our science by the acceptance of this paper in eLife underscores the importance of the G protein estrogen receptor ("GPER") as a therapeutic target," said Patrick Mooney, M.D., Chief Executive Officer of Linnaeus. "This data clearly demonstrates that using LNS8801 to target GPER should have therapeutic effects in various cancers, and we are excited to move this toward human studies in the future."

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On January 16, 2018 Foundation Medicine, Inc. (NASDAQ:FMI) reported that the company has entered into a broad partnership with Pfizer Inc. (NYSE: PFE)(Press release, Foundation Medicine, JAN 16, 2018, View Source [SID1234523141]) . The partnership focuses on development, regulatory support and commercialization of companion diagnostics (CDx) that will be included in updates to FoundationOne CDx. FoundationOne CDx is Foundation Medicine’s FDA-approved comprehensive genomic profiling (CGP) assay for all solid tumors that incorporates multiple companion diagnostics. Pfizer will also benefit from access to FoundationInsights, Foundation Medicine’s data analytics platform, to facilitate novel biomarker discovery and to optimize clinical trial design. The unique combination of FoundationInsights and FoundationOne CDx will potentially enable Pfizer to leverage Foundation Medicine’s platform technology to accelerate discovery and development of precision oncology therapeutics.

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Pfizer currently has 10 FDA-approved oncology medicines that treat a diverse array of solid tumors and hematologic malignancies. In addition, its oncology pipeline includes 17 assets in clinical development and 19 phase 3 studies.

"Our mission to transform cancer care includes partnering with biopharma companies to expedite development of personalized treatment options for patients. We are proud to partner with Pfizer who shares our commitment to precision oncology and biomarker-driven drug development," said Melanie Nallicheri, chief business officer and head of biopharma at Foundation Medicine. "The combination of our FDA-approved comprehensive genomic profiling platform and molecular information solutions, coupled with Pfizer’s robust oncology portfolio, enables us to enhance the impact of precision oncology to advance patient care."

FoundationOne CDx assesses all classes of genomic alterations in 324 genes known to drive cancer growth, providing potentially actionable information to help guide treatment decisions. It also reports genomic biomarkers, such as microsatellite instability (MSI) and tumor mutational burden (TMB), that can help inform the use of immunotherapies; genomic alterations in other genes relevant to patient management; and relevant clinical trial information. As such, it is designed to help streamline companion diagnostic development, mitigate risk and advance targeted therapy development. Currently FoundationOne CDx is FDA-approved as a CGP assay for all solid tumors and a broad companion diagnostic for patients with certain types of non-small cell lung cancer, melanoma, colorectal cancer, ovarian cancer or breast cancer to identify those patients who may benefit from treatment with one of 17 on-label targeted therapies.

Concurrent with FDA approval, the Centers for Medicare & Medicaid Services (CMS) issued a preliminary National Coverage Determination (NCD) for FoundationOne CDx. The draft NCD would provide coverage for FDA-approved companion diagnostic claims, as well as a pathway for additional coverage with evidence development in other solid tumor types. The final policy is expected to issue during the first quarter of 2018 following public comment on the preliminary NCD and an administrative period.