On March 4, 2015 Eisai Co., and Merck reported on a clinical trial collaboration to evaluate the safety, tolerability and efficacy of Merck’s anti-PD-1 therapy, pembrolizumab (marketed in the U.S. under the brand name KEYTRUDA), in combination with Eisai oncology compounds
lenvatinib mesylate (a multi-targeting RTK inhibitor marketed in the U.S. under the brand name LENVIMA, “lenvatinib”) and eribulin mesylate (a microtubule dynamics inhibitor marketed in
nearly 60 countries including Japan, the U.S., and Europe under the brand name HALAVEN, “eribulin”) in multiple clinical trials (Press release, Eisai, MAR 4, 2015, View Source [SID:1234502182]).

The planned studies include a multicenter, open-label Phase 1b/2 study of lenvatinib plus pembrolizumab in select solid tumors and an open-label, single-arm, multicenter Phase1b/2 study to evaluate the efficacy and safety of eribulin in combination with pembrolizumab in metastatic triple-negative breast cancer. Eisai and Merck will establish a Joint Development Committee to oversee clinical development activities. The studies are expected to begin in
the second half of 2015. Financial terms of the agreement were not disclosed.

“This collaboration could be a major step in the direction of developing combination regimens in different types of cancer, potentially maximizing the value of eribulin and lenvatinib,” said
Kenichi Nomoto, PhD, president, oncology product creation unit, Eisai Product Creation Systems. “Together, Eisai and Merck seek to explore combination regimens that have the potential to create synergistic effects between lenvatinib and pembrolizumab as well as between eribulin and pembrolizumab. Our hope is that we will bring treatments to market that make a difference in the lives of people battling cancer.”

“Cancer is a complex disease that often requires different approaches to help patients achieve the best possible outcome,” said Dr. Eric Rubin, therapeutic area head, oncology early-stage development, Merck Research Laboratories. “The collaboration with Eisai exemplifies Merck’s focus on advancing breakthrough science in immuno-oncology. We look forward to evaluating pembrolizumab in combination with eribulin and also with lenvatinib in different tumor types.”

The combinations of lenvatinib and pembrolizumab, and eribulin and pembrolizumab, are investigational. The efficacy and safety of these combinations have not been established.

On March 4, 2015 Bristol-Myers Squibb reported that the U.S. Food and Drug Administration (FDA) has approved Opdivo (nivolumab) injection, for intravenous use, for the treatment of patients with metastatic squamous non-small cell lung cancer (NSCLC) with progression on or after platinum-based chemotherapy (Press release, Bristol-Myers Squibb, MAR 4, 2015, View Source [SID:1234502174]). Opdivo is the first and only PD-1 (programmed death receptor-1) therapy to demonstrate overall survival in previously treated metastatic squamous NSCLC. Opdivo demonstrated significantly superior overall survival (OS) vs. docetaxel, with a 41% reduction in the risk of death (hazard ratio: 0.59 [95% CI: 0.44, 0.79; p=0.00025]), in a prespecified interim analysis of a Phase III clinical trial. The median OS was 9.2 months in the Opdivo arm (95% CI: 7.3, 13.3) and 6 months in the docetaxel arm (95% CI: 5.1, 7.3).

“Bristol-Myers Squibb is committed to patients with lung cancer, and we are pleased to offer Opdivo as the first immuno-oncology therapy for patients who have previously treated metastatic squamous NSCLC,” said Lamberto Andreotti, chief executive officer, Bristol-Myers Squibb. “Because lung cancer is one of the most commonly diagnosed cancers in the United States, with high mortality, there is a significant need for treatments that extend survival. We’re thankful to the many patients and healthcare providers that partnered with us to develop a new treatment that has the potential to address that unmet need.”

This approval is the second for Opdivo in the United States within three months, and is based on the results of CheckMate -017 and CheckMate -063.

Opdivo is associated with immune-mediated: pneumonitis, colitis, hepatitis, nephritis and renal dysfunction, hypothyroidism and hyperthyroidism, other adverse reactions; and embryofetal toxicity. Please see the Important Safety Information section below.

Proven Superior Survival vs. Standard of Care in a Phase III Clinical Trial

CheckMate -017 was a landmark Phase III, open-label, randomized, multinational, multicenter clinical trial that evaluated Opdivo (3 mg/kg intravenously over 60 minutes every two weeks) (n=135) vs. standard of care, docetaxel (75 mg/m2 intravenously administered every 3 weeks) (n=137), in patients with metastatic squamous NSCLC who had progressed during or after prior platinum doublet-based chemotherapy regimen. This trial included patients regardless of their PD-L1 (programmed death ligand-1) status. The primary endpoint of this trial was overall survival (OS).

In January, the trial was stopped based on an assessment conducted by the independent Data Monitoring Committee (DMC), which concluded that the study met its endpoint, demonstrating superior OS in patients receiving Opdivo compared to docetaxel. The prespecified interim analysis was conducted when 199 events (86% of the planned number of events for final analysis) were observed (86 in the Opdivo arm and 113 in the docetaxel arm).

Opdivo is the only FDA-approved monotherapy to demonstrate proven superior OS compared to standard of care in more than 15 years in previously treated metastatic squamous NSCLC. The median OS was 9.2 months in the Opdivo arm (95% CI: 7.3, 13.3) and 6 months in the docetaxel arm (95% CI: 5.1, 7.3). The hazard ratio was 0.59 (95% CI: 0.44, 0.79; p=0.00025). This hazard ratio translates to a 41% reduction in the risk of death with Opdivo compared to docetaxel.

“The FDA approval of Opdivo introduces an entirely new treatment modality that has demonstrated unprecedented results for the treatment of previously treated metastatic squamous NSCLC, with the potential to replace chemotherapy for these patients,” said Dr. Suresh Ramalingam, MD, Professor and Director of Medical Oncology, Winship Cancer Institute of Emory University. “This milestone brings to fruition the long-held hope that immuno-oncology medicines can be significantly effective in this difficult-to-treat population.”

About the CheckMate -063 Trial and the Safety Profile of Opdivo

The safety profile of Opdivo in squamous NSCLC was established in CheckMate -063, a Phase II single-arm, open-label, multinational, multicenter trial of Opdivo, administered as a single agent in patients with metastatic squamous NSCLC who have progressed after receiving a platinum-based therapy and at least one additional systemic treatment regimen (n=117). Patients received 3 mg/kg of Opdivo administered intravenously over 60 minutes every 2 weeks. This trial included patients regardless of their PD-L1 status. The most common adverse reactions (reported in ≥20% of patients) were fatigue (50%), dyspnea (38%), musculoskeletal pain (36%), decreased appetite (35%), cough (32%), nausea (29%), and constipation (24%). Serious adverse reactions occurred in 59% of patients receiving Opdivo. The most frequent serious adverse reactions reported in ≥2% of patients were dyspnea, pneumonia, chronic obstructive pulmonary disease exacerbation, pneumonitis, hypercalcemia, pleural effusion, hemoptysis, and pain. Opdivo was discontinued due to adverse reactions in 27% of patients. Twenty-nine percent of patients receiving Opdivo had a drug delay for an adverse reaction.

With at least 10 months of minimum follow up for all patients, the confirmed objective response rate (ORR), the study’s primary endpoint, was 15% (17/117) (95% CI = 9, 22) of which all were partial responses. The median time to onset of response was 3.3 months (range: 1.7 to 8.8 months) after the start of Opdivo treatment. Seventy-six percent of Opdivo responders (13/17 patients) had ongoing responses with durability of response ranging from 1.9+ to 11.5+ months; 10 of these 17 (59%) patients had durable responses of 6 months or longer.

“The approval of Opdivo for the treatment of previously treated metastatic squamous non-small cell lung cancer is a major advancement in delivering extended survival for patients fighting this deadly disease,” said Andrea Ferris, President and Chairman, Lungevity Foundation. “We are very excited for an immuno-oncology therapy to enter the market and offer options and hope for many of our patients. I applaud the FDA and Bristol-Myers Squibb for their work in making this important and first of its kind treatment available to patients so quickly.”

On March 4, 2015 Spectrum Pharmaceuticals reported it has entered into a licensing agreement with Hanmi Pharmaceuticals for poziotinib, a drug being investigated for the treatment of cancer (Press release, Spectrum Pharmaceuticals, MAR 4, 2015, View Source [SID:1234502172]).

Poziotinib (HM781-36B) is a novel, oral, quinazoline-based pan-HER inhibitor that irreversibly blocks signaling through the HER family of tyrosine-kinase receptors including HER1 (erbB1; EGFR), HER2 (erbB2), and HER4 (erbB4), as well as HER receptor mutations; this, in turn, leads to inhibition of the proliferation of tumor cells that overexpress these receptors. Mutations or overexpression/amplification of HER family receptors have been associated with a number of different cancers, including non-small cell lung cancer (NSCLC), breast cancer, gastric cancer, etc. Currently, poziotinib is being investigated by Hanmi in EGFR-mutant NSCLC (Phase 2, sponsored by National OncoVenture), gastric cancer (Phase 2), head & neck cancer (Phase 2) and HER2 positive breast cancer (Phase 2, sponsored by National OncoVenture). National OncoVenture is a funding initiative by the Korean government’s National Cancer Center.

“We continue to make progress on achieving our goal of becoming leaders in Oncology, and we believe that this late clinical stage drug acquisition continues to build and further strengthen our oncology portfolio,” said Rajesh C. Shrotriya, MD, Chairman and Chief Executive Officer of Spectrum Pharmaceuticals. “Poziotinib has shown promising early clinical activity with 60% (6/10) of patients with breast cancer having responses in Phase 1 clinical trials. These patients were heavily pre-treated, had previously received and failed multiple lines of treatment, and had been previously treated with the HER2-directed therapies, trastuzumab and lapatinib. In addition, tumor responses were also seen in patients with gastric cancer, colorectal cancer, and lung cancer. We are pleased to continue to work closely with Hanmi Pharmaceuticals and further our ongoing collaboration as we work together to bring more treatment options to cancer patients.”

“Despite the availability of a number of HER2-directed therapies, most patients with metastatic breast cancer relapse and die because of progressive disease,” said Dr. Francisco Esteva, Professor of Medicine, Director, Breast Medical Oncology Associate, Director of Clinical Investigation, Laura and Isaac Perlmutter Cancer Center New York University Langone Medical Center. “Therefore, there is a critical need for new treatments to improve the outcome for these patients. The fact that breast cancer patients previously treated with trastuzumab and lapatinib have shown responses to poziotinib is very exciting. If these early data are confirmed in additional clinical trials, poziotinib could become a very important treatment option for patients with breast cancer.”

Under the terms of the agreement, Spectrum received exclusive license to develop, manufacture and commercialize worldwide excluding Korea and China. Hanmi shall remain responsible for the cost of the ongoing Phase 2 studies through completion.

On March 4, 2015 TG Therapeutics reported an agreement with Checkpoint Therapeutics, Inc., a newly formed subsidiary of Coronado Biosciences to develop and commercialize Checkpoint’s fully human anti-PD-L1 and anti-GITR antibody research programs in the field of hematological malignancies (Press release, TG Therapeutics, MAR 4, 2015, View Source [SID:1234502171]). Checkpoint will develop and commercialize these antibodies in solid tumors. The antibodies were generated in the laboratory of Dr. Wayne Marasco, MD, PhD, a Professor in the Department of Cancer Immunology and AIDs at Dana-Farber Cancer Institute (Dana-Farber). Both programs are currently in pre-clinical development and are anticipated to enter the clinic in 2016. Under the terms of the agreement, TG Therapeutics will make an up-front payment as well as make development and sales-based milestone payments and will pay a tiered single digit royalty on net sales.

Mr. Michael S. Weiss, Executive Chairman, Interim CEO and President stated, “We are very excited to add Dr. Marasco’s anti-PD-L1 and anti-GITR programs to our growing portfolio of agents targeting hematological malignancies. Dr. Marasco is a recognized world expert in human antibody engineering and one of the pioneers of immunotherapy and we look forward to his continued involvement and guidance as Chair of the Scientific Advisory Board of our new partner, Checkpoint Therapeutics, Inc.” Mr. Weiss continued, “Checkpoint inhibitors and other immuno-oncology targeted agents have already demonstrated the ability to transform the way we treat cancer by unlocking the immune system, offering the promise of deep and durable remissions. While the recent introduction of novel targeted agents has already revolutionized the way we treat hematological malignancies, we at TG believe that incorporation of immuno-therapy will prove to be a second paradigm-shift in the treatment of these diseases, and it is our goal to be at the forefront leading this charge. As we’ve said previously, we will continue to build our portfolio to optimize our combination approach to provide the best possible outcomes to patients with B-cell malignancies without the need to use harsh chemotherapy, ideally pushing toward a cure. It is believed that these two antibodies can work synergistically together and we believe that adding them to the already marked activity we are seeing with our proprietary combination of TG-1101 and TGR-1202 across CLL and NHL could greatly enhance the therapeutic benefit to patients with hematological malignancies. Our goal is to advance both of these antibodies into the clinic in the second half of next year.”

ABOUT ANTI-PD-L1 & ANTI-GITR

Anti-PD-L1 antibodies target programmed cell death ligand 1 (PD-L1). Signals from PD-L1 on tumor cells and in tumor microenvironment help those tumors avoid immune attack and elimination by preventing activation of tumor specific effector T-cells. Anti-PD-L1 antibodies are designed to block that signal permitting effector T-cells to attack the cancer. Anti-GITR antibodies target glucocorticoid-induced tumor necrosis factor receptor related protein (GITR), which is regularly expressed on the surface of regulatory T-cells (Tregs) and is expressed on the surface of effector T-cells after their activation. Modulation of GITR with agonistic antibodies has been shown to amplify the antitumor immune responses in animal models via multiple mechanisms. Anti-GITR antibodies are designed to activate the GITR receptor thereby increasing the proliferation and function of effector T cells. At the same time, ligation of GITR on surface of Tregs could abrogate suppressive function of these cells on tumor specific effector T-cells thus further augmenting T-cell immune response. While targeting PD-1/PD-L1 axes alone has already demonstrated impressive anticancer efficacy and durable responses in humans, its efficacy appears to be limited to certain patients. It is believed the effects of anti-PD-L1 intervention can be enhanced by utilizing a co-stimulatory antibody, like one targeting GITR, that can turn on tumor specific effector T-cells. Combining immunotherapies like anti-PD-L1 that counters the tumor’s immune-evading defense system with an anti-GITR that activates effector T-cells, represents a rational approach to use the body’s own immune system to help fight cancer. Pre-clinical research on the combination of the two approaches has yielded very encouraging results to support synergistic potential of this combination.

ABOUT TG THERAPEUTICS, INC.

TG Therapeutics is a biopharmaceutical company focused on the acquisition, development and commercialization of novel treatments for B-cell malignancies and autoimmune diseases. Currently, the company is developing two therapies targeting hematological malignancies. TG-1101 (ublituximab) is a novel, glycoengineered monoclonal antibody that targets a specific and unique epitope on the CD20 antigen found on mature B-lymphocytes. TG Therapeutics is also developing TGR-1202, an orally available PI3K delta inhibitor. The delta isoform of PI3K is strongly expressed in cells of hematopoietic origin and is believed to be important in the proliferation and survival of B‐lymphocytes. Both TG-1101 and TGR-1202 are in clinical development for patients with hematologic malignancies. The Company also has a pre-clinical program to develop IRAK4 inhibitors, also for B-cell malignancies and autoimmune diseases. TG Therapeutics is headquartered in New York City.

ABOUT CHECKPOINT THERAPEUTICS, INC.

Checkpoint Therapeutics is an innovative, immuno-oncology company spun out of the labs of Dr. Wayne Marasco of Dana-Farber Cancer Institute, a teaching hospital affiliated with Harvard Medical School, as a newly formed subsidiary of Coronado Biosciences, Inc. (Nasdaq:CNDO). Checkpoint is developing novel checkpoint inhibitors and other immuno-oncology drug candidates that may be active on their own but are designed to also work synergistically together and with other immuno-oncology agents and targeted drugs. Checkpoint plans to build a portfolio of complimentary drug candidates to treat a wide variety of solid tumors and, through its partnership with TG Therapeutics, hematological cancers. Currently, the company is developing three antibodies targeting anti-PD-L1, anti-GITR and anti-CAIX. Checkpoint Therapeutics is headquartered in New York City.