On April 3, 2017 Bristol-Myers Squibb Company (NYSE:BMY) reported the first overall survival (OS) data from the Phase 3 CheckMate -067 clinical trial (Press release, Bristol-Myers Squibb, APR 3, 2017, View Source [SID1234518438]). With a minimum follow-up of 28 months, the median OS had not yet been reached in either of the two Opdivo treatment groups and was 20 months for the Yervoy monotherapy group (95% CI: 17.1-24.6). Opdivo in combination with Yervoy and as a monotherapy reduced the risk of death 45% [hazard ratio (HR) 0.55; 95% CI: 0.42-0.72; P<0.0001] and 37% (HR 0.63; 95% CI: 0.48-0.81; P<0.0001), respectively, compared with Yervoy alone. The two-year OS rates were 64% for the Opdivo plus Yervoy combination, 59% for Opdivo alone and 45% for Yervoy alone. Results will be presented today in the press program and an oral presentation during the Update, Novel Indication, and New Immuno-oncology Clinical Trials session from 3:35 to 3:50 p.m. ET (Late-Breaking Abstract CT075) at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Meeting 2017 in Washington, D.C.

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The updated safety data reported in this new analysis were consistent with previously reported experience, with no cumulative toxicity noted or new safety signals identified. Grade 3/4 treatment-related adverse events occurred in 58%, 21%, and 28% of the combination, Opdivo alone and Yervoy alone groups, respectively.

"It is encouraging to see such positive data from this trial, which further supports the scientific rationale to combine Immuno-Oncology agents as a potential treatment option for this aggressive form of melanoma. These CheckMate -067 survival data bolster our understanding of potential ways to combat untreated advanced melanoma and ultimately advance cancer care for patients," said James Larkin, Ph.D., FRCP, Consultant Medical Oncologist, Department of Medical Oncology, The Royal Marsden.

The proportion of patients experiencing complete responses (CR) compared to a previous 18 month follow-up analysis increased in the combination group to 17.2% from 12.1%, in the Opdivo alone group to 14.9% from 9.8%, and in the Yervoy alone group to 4.4% from 2.2%. Progression-free survival (PFS) and objective response rates (ORR) from updated analyses were both consistent with previous reports. The risk of disease progression was significantly reduced for both the combination and Opdivo monotherapy groups, 58% (HR 0.42; 95% CI: 0.34-0.51) and 46% (HR 0.54; 95% CI: 0.45-0.66), respectively, compared to Yervoy alone. The ORR for the two Opdivo groups, in combination and alone, and the Yervoy alone group was, respectively, 58.9% (95% CI: 53.3-64.4), 44.65% (95% CI: 39.1-50.3) and 19.0% (95% CI: 14.9-23.8).

"This first disclosure of overall survival data from CheckMate -067 helps to advance our understanding of the potential longer term benefits of Opdivo in combination with Yervoy in advanced melanoma, a cancer that historically has been difficult-to-treat," said Vicki Goodman, M.D., development lead, Melanoma and Genitourinary Cancers, Bristol-Myers Squibb.

About CheckMate -067

CheckMate -067 is a Phase 3, double-blind, randomized trial that evaluated the combination of Opdivo plus Yervoy or Opdivo monotherapy versus Yervoy monotherapy in 945 patients with previously untreated advanced melanoma. Patients in the combination group (n=314) received Opdivo 1 mg/kg plus Yervoy 3 mg/kg (Q3W) for four doses followed by Opdivo 3 mg/kg every two weeks (Q2W). Patients in the Opdivo monotherapy group (n=316) received Opdivo 3 mg/kg Q2W plus placebo. Patients in the Yervoy monotherapy group (n=315) received Yervoy 3 mg/kg every three weeks for four doses plus placebo. Patients were treated until progression or unacceptable toxic effects. OS and PFS were co-primary endpoints for the trial. Secondary endpoints included ORR, efficacy by tumor PD-L1 expression level and safety.

The Opdivo plus Yervoy combination and Opdivo monotherapy provided OS benefits across clinically relevant subgroups of patients versus Yervoy alone. Specifically, in patients with BRAF mutations, the combination reduced the risk of death 57% (HR 0.43; 95% CI: 0.28-0.66) and Opdivo monotherapy reduced the risk of death 40% (HR 0.60; 95% CI: 0.40-0.89) compared to Yervoy alone. In patients without BRAF mutations (Wild-type patients), the combination reduced the risk of death 38% (HR 0.62; 95% CI: 0.48-0.80) and Opdivo monotherapy reduced the risk of death 36% (HR 0.64; 95% CI: 0.49-0.83) compared to Yervoy alone. In patients with PD-L1 expression ≥5%, Opdivo in combination with Yervoy and Opdivo monotherapy resulted in a 40% (HR 0.60; 95% CI: 0.36-1.00) and 44% (HR 0.56; 95% CI: 0.34-0.90) reduction in risk of death, respectively, compared to Yervoy alone. In patients with PD-L1 expression <5%, the combination and Opdivo monotherapy resulted in a 45% (HR 0.55; 95% CI: 0.42-0.72) and a 35% (HR 0.65; 95% CI: 0.50-0.84) reduction in risk of death, respectively, compared to Yervoy alone.

The trial was not designed to statistically compare the two Opdivo groups. However, descriptive analyses found the combination treatment provided a relative reduction in the risk of death of 12% (HR 0.88; 95% CI: 0.69-1.12) when compared with Opdivo alone and reduced the risk of death for patients expressing PD-L1 <1% by 26% (HR 0.74; 95% CI: 0.52-1.06) and PD-L1 <5% by 16% (HR 0.84; 95% CI: 0.63-1.12) when compared to Opdivo alone. Survival between the two Opdivo containing groups was similar in patients expressing PD-L1 ≥1% (HR 1.03; 95% CI: 0.72-1.48) and PD-L1 ≥5% (HR 1.05; 95% CI: 0.61-1.83).

About Metastatic Melanoma

Melanoma is a form of skin cancer characterized by the uncontrolled growth of pigment-producing cells (melanocytes) located in the skin. Metastatic melanoma is the deadliest form of the disease and occurs when cancer spreads beyond the surface of the skin to other organs. The incidence of melanoma has been increasing steadily for the last 30 years. In the United States, 87,000 new diagnoses of melanoma and more than 9,700 related deaths are estimated for 2017. Globally, the World Health Organization estimates that by 2035, melanoma incidence will reach 388,262, with 98,288 related deaths. Melanoma is mostly curable when treated in its early stages. However, patients in the United States diagnosed with advanced melanoma classified as Stage IV historically have a five-year survival rate of 15% to 20% and 10-year survival of about 10% to 15%.

On April 3, 2017 Bicycle Therapeutics, a biotechnology company pioneering a new class of therapeutics based on its proprietary bicyclic peptide (Bicycle) product platform, reported that the company will present preclinical data supporting the ongoing development of its lead molecule, BT1718 (Press release, Bicycle Therapeutics, APR 3, 2017, View Source [SID1234518437]). This program is the first example of its Bicycle Drug Conjugate technology, which allows toxic payloads to be targeted to tumour types of high unmet medical need. BT1718 targets Type 1 Matrix Metalloproteinase (MT1-MTP), which is highly expressed in many solid tumours, including triple negative breast cancer and non-small cell lung cancer. The data will be presented in three poster presentations at the Annual Meeting of the American Association for Cancer Research (AACR) (Free AACR Whitepaper), being held in Washington, DC from April 1 through April 5, 2017.

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Details for the poster presentations at the 2017 AACR (Free AACR Whitepaper) Annual Meeting are as follows:
Title: Development of BT1718, a novel Bicycle Drug Conjugate for the treatment of lung cancer
Session Title: Novel Molecular Targets 1
Abstract #: 1167/12
Date & Time: April 3, 2017, 8:00 a.m. – 12:00 p.m. EST

Title: Bicyclic peptides for PET imaging of MT1-MMP expressing tumors
Session Title: Clinical Laboratory and Imagine Correlates
Abstract #: 3719/4
Date & Time: April 4, 2017, 8:00 a.m. – 12:00 p.m. EST

Title: BT1718, a novel bicyclic peptide-maytansinoid conjugate targeting MT1-MMP for the treatment of solid tumors: Design of bicyclic peptide and linker selection
Session Title: Novel Drug Delivery Technology
Abstract #: 5144 / 16
Date & Time: April 5, 2017, 8:00 a.m. – 12:00 p.m. EST

On April 3, 2017 Unum Therapeutics, a clinical stage biopharmaceutical company developing a universal cellular immunotherapy to treat multiple cancers, reported that the Company has been selected for two poster presentations on its Antibody-Coupled T cell Receptor (ACTR) platform at the AACR (Free AACR Whitepaper) 2017 Annual Meeting, which is being held in Washington DC, April 1-5, 2017 (Press release, Unum Therapeutics, APR 3, 2017, View Source [SID1234518436]). The first poster presentation will highlight data from non-clinical studies on targeting BCMA-positive multiplemyeloma cells with ACTR in combination with a humanized non-fucosylated anti-BCMA antibody, SEA-BCMA, developed using Seattle Genetics’ novel sugar-engineered antibody (SEA) technology. This is the first named program under Unum’s global collaboration with Seattle Genetics. The second poster will provide data from exploratory work on targeting Glypican-3 (GPC3) with ACTR in combination with an anti-GPC3 antibody, one of the targets that the companies are also investigating under their collaboration.

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The accepted abstracts are listed below and are available online on the AACR (Free AACR Whitepaper) 2017 conference website: www.aacr.org.
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Presentation Details:
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Abstract Number: 4605
Title: Efficient targeting of BCMA-positive multiple myeloma cells by Antibody-Coupled T cell Receptor (ACTR) engineered autologous T cells in combination with an anti-BCMA antibody
Authors: Tooba Cheema, Taylor Hickman, Katie O’Callaghan, *Lori Westendorf, *Luke Manlove, *Shyra Gardai, Allison Nelson, Ryan Boomer, Kathleen McGinness, Birgit Schultes, Seth Ettenberg, *Django Sussman and Heather Huet.
Authors’ Affiliation: Unum Therapeutics, *Seattle Genetics
Presenter: Tooba Cheema, Senior Scientist, Unum Therapeutics
Session: Immunoconjugates and Antibodies
Session Date and Time: April 4, 2017, 1:00 – 5:00 PM
Location: Convention Center, Halls A-C, Poster Section 26
Poster Board Number: 20
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Abstract Number: 3762
Title: Superior T cell activity of a membrane-proximal binding antibody when targeting Glypican-3 with an Antibody-Coupled T cell Receptor (ACTR) armed T cell
Authors: Greg Motz, John Shin, Kathy Whiteman, Birgit Schultes, Tapasya Pai, Lori Westendorf*, Seth Ettenberg, Travis Biechele*, Django Sussman* and Heather Huet
Authors’ Affiliation: Unum Therapeutics, *Seattle Genetics
Presenter: Greg Motz, Senior Scientist, Unum Therapeutics
Session: Innate Effectors in Immunity to Cancer
Session Date and Time: April 4, 2017, 8:00 – 12:00 PM
Location: Convention Center, Halls A-C, Poster Section 30
Poster Board Number: 18
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The posters will be posted on Unum’s website following the presentations.
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About Antibody-Coupled T cell Receptor (ACTR) Technology
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Unum’s proprietary ACTR is a chimeric protein that combines components from receptors normally found on two different human immune cell types – natural killer (NK) cells and T cells – to create a novel approach to cancer cell killing. T cells bearing the ACTR receptor protein can be directed to attack a tumor by combining with a monoclonal antibody that binds antigens on the cancer cell surface.
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In contrast to other T cell therapy approaches for cancer that are limited to a single cancer cell surface target and, therefore, treat a narrow set of tumors, Unum’s approach is not restricted by a specific tumor cell antigen and, thus, may have applications for treating many different types of cancers when combined with the right antibody.
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Unum is developing ACTR in combination with a range of tumor-targeting antibodies for use in both hematologic and solid tumor indications. ACTR087, Unum’s most advanced product candidate, combines Unum’s proprietary ACTR with rituximab, an anti-CD20 antibody. The ACTR087 study is the first clinical trial using a viral vector to permanently insert the ACTR gene into the genome of patients’ T cells.

On April 3, 2017 Syros Pharmaceuticals (NASDAQ:SYRS), a biopharmaceutical company pioneering the discovery and development of medicines to control the expression of disease-driving genes, reported that SY-1365, its first-in-class selective cyclin-dependent kinase 7 (CDK7) inhibitor, shows significant anti-proliferative activity in multiple in vitro and in vivo models of difficult-to-treat solid tumors, including triple negative breast, small cell lung and ovarian cancers (Press release, Syros Pharmaceuticals, APR 3, 2017, View Source [SID1234518435]). Leveraging its expertise in transcriptional biology and chemistry, Syros also showcased its work to further elucidate the biology of cyclin-dependent kinase 12 (CDK12) and cyclin-dependent kinase 13 (CDK13), advancing its aim of designing the first highly selective CDK12 and CDK13 inhibitors suitable for clinical development. These data were presented at the American Association of Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting in Washington, D.C.

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"SY-1365, our first-in-class selective CDK7 inhibitor, as well as our CDK12 and CDK13 inhibitor program highlight the power of our gene control platform to selectively target transcription and potentially treat diseases that have been underserved by other genomic-based approaches," said Nancy Simonian, M.D., Chief Executive Officer of Syros. "These new data show SY-1365 reduces proliferation and induces apoptosis in cancer cells in several difficult-to-treat tumors. The results build on earlier data demonstrating that SY-1365 preferentially kills cancer cells over non-cancerous cells and lowers the expression of disease-driving transcription factors. Our CDK12 and CDK13 inhibitor program further highlights the potential of our platform to produce drug candidates that target the transcription of unique sets of genes linked to specific tumors."

SY-1365 in Aggressive Transcriptionally Driven Solid Tumors
Data generated and presented by Syros scientists show SY-1365 induces anti-proliferative and pro-apoptotic effects in multiple solid tumor cell lines and preclinical models of aggressive, transcriptionally driven solid tumors. Results from these studies show SY-1365:

Induces potent anti-proliferative activity in a range of solid tumor cell lines, including triple negative breast, small cell lung and ovarian cancer cells, when profiled across a broad panel of more than 130 cancer cell lines.
Demonstrates substantial anti-tumor activity in both cell line-derived xenograft (CDX) and patient-derived xenograft (PDX) models of triple negative breast cancer, including regressions at a twice weekly dosing regimen consistent with the initial regimen planned for the Company’s upcoming Phase 1 clinical trial.
Demonstrates synergistic anti-tumor activity with a BCL-2 inhibitor in cancer cells, providing a mechanistic rationale for further investigating SY-1365 in combination with inhibitors targeting apoptotic pathways.
SY-1365 has been previously shown to induce apoptosis and preferentially kill cancer cells over non-cancerous cells in preclinical models of a range of aggressive cancers, including certain solid tumors and acute leukemias. Preclinical studies have also shown that SY-1365 lowers the expression of oncogenic transcription factors, such as MYC, in these transcriptionally driven cancers.

Syros is on track to begin a Phase 1 clinical trial of SY-1365 in the second quarter, initially in patients with advanced solid tumor malignancies including the transcriptionally driven solid tumors, triple negative breast, small cell lung and ovarian cancers. Syros plans to expand future clinical development of SY-1365 into acute leukemias based on data generated in this trial.

CDK12 and CDK13 Inhibition as Promising New Approach for Treating Cancer
Syros scientists presented data on the selective inhibition of CDK12 and CDK13 in ovarian and breast cancers. Using its gene control platform, Syros is optimizing potent and selective CDK12 and CDK13 inhibitors that may be suitable for clinical development. Syros scientists presented data on a suite of proprietary assays capable of assessing selectivity and cellular target engagement of CDK12. Using breast and ovarian cancer cell lines sensitive to CDK12 inhibition, Syros scientists further showed important differences between non-selective and selective inhibition of transcriptional kinases to guide development of these inhibitors.

Selectively inhibiting CDK12 and CDK13 has previously been shown to decrease the expression of DNA damage response genes and super-enhancer associated transcription factors implicated in cancer, including breast and ovarian cancers. These findings suggest that a selective CDK12 and CDK13 inhibitor could be effective as a monotherapy in certain cancers and as a combination therapy in other cancers by increasing their susceptibility to targeted therapies involved in DNA damage repair, such as PARP1 inhibitors.