Five Prime Therapeutics to Present New Pre-Clinical Data on FPA144 at the 2016 AACR Annual Meeting

On March 16, 2016 Five Prime Therapeutics, Inc. (Nasdaq:FPRX), a clinical-stage biotechnology company focused on discovering and developing innovative immuno-oncology protein therapeutics, reported that it will feature new preclinical data on FPA144 in a poster presentation during the 2016 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting, being held April 16-20 in New Orleans (Press release, Five Prime Therapeutics, MAR 16, 2016, View Source [SID:1234509614]).

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Abstract #1407 titled, "FPA144, a Therapeutic Monoclonal Antibody Targeting the FGFR2b Receptor, Promotes Antibody Dependent Cell-Mediated Cytotoxicity and Stimulates Sensitivity to PD-1 the 4T1 Breast Tumor Model in Mice," is now accessible on the meeting website. The poster presentation will take place from Monday, April 18, 2016, from 8:00 AM – 12:00 PM in Section 22. The poster will be made available on the publications page of the Five Prime website following the presentation.

FPA144 is an FGFR2b-specific humanized monoclonal antibody designed to treat patients with cancers that overexpress the FGFR2b receptor. FPA144 is a targeted immunotherapy that has been engineered to recruit NK cells into the tumor microenvironment and kill cancer cells by antibody-dependent cell-mediated cytotoxicity (ADCC). At the 2014 AACR (Free AACR Whitepaper) Annual Meeting, Five Prime presented data showing that FPA144 can produce complete and durable tumor growth inhibition in FGFR2b-overexpressing and FGFR2 gene-amplified gastric cancer xenografts in immune-compromised mice. The ongoing Phase 1 monotherapy trial is enrolling patients with gastric cancer, a disease in which FGFR2b protein overexpression and FGFR2 gene amplification have been associated with poor prognosis.

In recent months, Five Prime evaluated the anti-tumor effects and immune cell recruitment of FPA144 in the 4T1 model of breast cancer in immune-competent mice. Although the tumor cells in this model express FGFR2b, the FGFR2 gene is not amplified. Therapeutic treatment with FPA144 alone in the orthotopic 4T1 model resulted in a reduction in tumor burden (33%, P<0.001) and within 24 hours, the recruitment of NK cells to the site of tumor implantation, while a modified antibody lacking Fc effector function neither inhibited tumor growth nor led to the recruitment of NK cells. Together these data indicate that enhanced ADCC activity of FPA144 may have the potential to play an important mechanistic role in anti-tumor efficacy in cancers that have modest expression of FGFR2b.

In addition, four days after treatment with FPA144, there was an influx of T cells into the tumor as well as increased expression of PD-L1, providing a strong rationale that FPA144 may combine effectively with PD-1 blockade. Although PD-1 blockade by the RPM1-14 antibody did not inhibit tumor growth as a single agent in the 4T1 model, treatment with RPM1-14 in combination with FPA144, inhibited tumor growth by 49% (P<0.001), demonstrating an additive benefit of combination therapy. These results suggest that FPA144 alters the immune cell composition of the tumor microenvironment in a way that primes the tumor for additional anti-tumor activity when combined with PD-1 blockade.

About FPA144

FPA144 is an anti-FGF receptor 2b (FGFR2b) humanized monoclonal antibody in clinical development as a targeted immune therapy for tumors that over-express FGFR2b, as determined by a proprietary immunohistochemistry (IHC) diagnostic assay. FPA144 is designed to block tumor growth through two distinct mechanisms. First, it binds specifically to FGFR2b and prevents the binding of certain fibroblast growth factors that promote tumor growth. Second, it has been engineered to drive immune-based killing of tumor cells by antibody-dependent cell-mediated cytotoxicity (ADCC) and the recruitment of natural killer (NK) cells. FGFR2 gene amplification (as identified by FISH) is found in a number of tumors, including in approximately 5% of gastric cancer patients, and is associated with poor prognosis.

Kite Pharma Announces Clinical and Manufacturing Updates on KTE-C19 and MAGE-A3 Product Candidates at the Annual Meeting of the American Association for Cancer Research (AACR)

On March 16, 2016 Kite Pharma, Inc., (Nasdaq:KITE) ("Kite") a clinical-stage biopharmaceutical company focused on developing engineered autologous T cell therapy (eACT) products for the treatment of cancer, reported that two oral presentations and two poster presentations to be delivered at the upcoming American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting in New Orleans, Louisiana (Press release, Kite Pharma, MAR 16, 2016, View Source [SID:1234509601]). The oral presentations will address KTE-C19, Kite’s lead chimeric antigen receptor (CAR) product candidate, and, separately, an engineered T cell receptor (TCR) product candidate targeting the cancer testis antigen MAGE-A3. The TCR product candidate is currently being studied as part of a Cooperative Research and Development Agreement (CRADA) between Kite and the National Cancer Institute.

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Oral Presentations:

Title: Updated Phase 1 Results from ZUMA-1: A Phase 1-2 Multi-Center Study Evaluating the Safety and Efficacy of KTE-C19 (Anti-CD19 CAR T Cells) in Subjects with Refractory Aggressive Non-Hodgkin Lymphoma (NHL)

Date: Tuesday, April 19, 2016 3:00-5:00PM Central Time
Session: Early Clinical Trials Evaluating Cell-based, Checkpoint Inhibitors, and Novel Immunotherapeutics
Abstract Number: CT135
Location: Room 343, Morial Convention Center
Presenter: Armin Ghobadi, M.D., Washington University, St. Louis, MO

Title: A Phase 1 Study of an HLA-DPB1*0401-restricted T Cell Receptor Targeting MAGE-A3 for Patients with Metastatic Cancer

Date: Sunday, April 17, 2016 2:15-4:00PM Central Time
Session: Immuno-Oncology Clinical Trials I
Abstract Number: CT003
Location: La Nouvelle Ballroom, Morial Convention Center
Presenter: Yong-Chen W. Lu, Ph.D., Surgery Branch, National Cancer Institute

Poster Presentations:

Title: Manufacturing and Characterization of KTE-C19 in a Multicenter Trial of Subjects with Refractory Aggressive Non-Hodgkin’s Lymphoma (NHL) (ZUMA-1)

Date: Monday, April 18, 2016 1:00-5:00PM Central Time
Session: Adoptive Cell Therapy
Abstract Number: 2308
Location: Poster Hall, Section 25, Poster Board 20
Presenter: Marc Better, Ph.D., Kite Pharma, Santa Monica, CA

Title: Comparative Evaluation of Peripheral Blood T cells and Resultant Engineered Anti-CD19 CAR T Cell Products from Relapsed/Refractory Non-Hodgkin’s Lymphoma (NHL) Patients

Date: Monday, April 18, 2016 1:00-5:00PM Central Time
Session: Adoptive Cell Therapy
Abstract Number: 2305
Location: Poster Hall, Section 25, Poster Board 17
Presenter: Timothy J. Langer, Kite Pharma, Santa Monica, CA

About KTE-C19

KTE-C19 is an investigational therapy in which a patient’s T cells are genetically modified to express a CAR designed to target the antigen CD19, a protein expressed on the cell surface of B cell lymphomas and leukemias. Kite is currently enrolling four pivotal studies (also known as ZUMA studies) for KTE-C19 in patients with various B cell malignancies. The U.S. Food and Drug Administration has granted Breakthrough Therapy Designation status to KTE-C19, for the treatment of patients with refractory diffuse large B cell lymphoma, primary mediastinal B cell lymphoma, and transformed follicular lymphoma. KTE-C19 has also secured Orphan Drug Designation in the U.S. for DLBCL and in the EU for various hematological indications.

Bristol-Myers Squibb to Present New Overall Survival Data for Opdivo® (nivolumab) as Monotherapy and in Combination with Yervoy® (ipilimumab) at the AACR 2016 Annual Meeting

On March 16, 2016 Bristol-Myers Squibb Company (NYSE:BMY) reported that new clinical research data for two of its Immuno-Oncology medicines — Opdivo and Yervoy — will be presented at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) 2016 Annual Meeting in New Orleans, LA, from April 16-20 (Press release, Bristol-Myers Squibb, MAR 16, 2016, View Source [SID:1234509597]).

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Data to be presented for Opdivo, as a single-agent and in combination with Yervoy, illustrate the company’s commitment to expanding its Immuno-Oncology research portfolio to include additional tumor types and developing treatment options that have the potential to extend survival in hard-to-treat cancers in broad patient populations.

Jean Viallet, M.D., Global Clinical Research Lead, Oncology, Bristol-Myers Squibb, commented, "At this year’s AACR (Free AACR Whitepaper), we are excited to present, for the first time, overall survival data from the first pivotal Phase 3 trial of an Immuno-Oncology agent, Opdivo, in previously treated squamous cell carcinoma of the head and neck, a cancer that has had very few treatment advances over the past ten years. These head and neck cancer data represent the fifth tumor type with overall survival data for Opdivo compared to a standard of care. We will also be presenting overall survival data from CheckMate -069, which was the first randomized trial to evaluate the Opdivo + Yervoy Regimen in the first-line setting for advanced melanoma, and has been a foundational study in building our scientific understanding of combining these two Immuno-Oncology agents to treat this form of cancer."

Key data presentations include:

CheckMate -141: New, pivotal phase 3 data evaluating Opdivo versus investigator’s choice for recurrent or metastatic head and neck squamous cell carcinoma (Late-Breaking and Clinical Trial Abstract #CT099) will be presented as an oral presentation during the Immuno-Oncology Clinical Trials II Plenary Session on Tuesday, April 19, 10:30 AM – 12:15 PM CT.
CheckMate -069: First presentation of overall survival rates from a randomized phase 2 trial evaluating the Opdivo + Yervoy combination in patients with advanced melanoma (Late-Breaking and Clinical Trial Abstract #CT002) will be presented as an oral presentation during the Immuno-Oncology Clinical Trials I Plenary Session on Sunday, April 17, 2016, 2:15 – 4:00 PM CT
The full set of data to be presented by Bristol-Myers Squibb includes:

Melanoma

Initial report of overall survival rates from a randomized phase 2 trial evaluating the combination of nivolumab and ipilimumab in patients with advanced melanoma
Author: M. Postow
Abstract #CT002
Oral Presentation, Immuno-Oncology Clinical Trials I Plenary Session
Sunday, April 17, 2016, 2:15 – 4:00 PM CT, La Nouvelle Ballroom, Morial Convention Center

Durable, long-term survival in previously treated patients with advanced melanoma who received nivolumab monotherapy in a phase 1 trial
Author: F. S. Hodi
Abstract #CT001
Oral Presentation, Immuno-Oncology Clinical Trials I Plenary Session
Sunday, April 17, 2016, 2:15 – 4:00 PM CT, La Nouvelle Ballroom, Morial Convention Center

Association of programmed death-ligand 1 (PD-L1) and 2 (PD-L2) expression with nivolumab efficacy in advanced melanoma
Author: S. J. Rodig
Abstract #CT133
Oral Presentation, Early Clinical Trials Evaluating Cell-based Checkpoint Inhibitors, and Novel Immunotherapeutics Minisymposium
Tuesday, April 19, 2016, 3:00 – 5:00 PM CT, Room 343, Morial Convention Center

Squamous Cell Carcinoma of the Head and Neck

Nivolumab versus investigator’s choice for recurrent or metastatic head and neck squamous cell carcinoma: CheckMate -141
Author: M. Gillison
Abstract #CT099
Oral Presentation, Immuno-Oncology Clinical Trials II Plenary Session
Tuesday, April 19, 2016, 10:30 AM – 12:15 PM CT, Room 391, Morial Convention Center
Lung Cancer

Impact of baseline serum cytokines on survival in patients with advanced squamous non-small cell lung cancer treated with nivolumab or docetaxel: Exploratory analyses from CheckMate -063 and CheckMate -017
Author: B. Farsaci
Abstract #LB-072
Late-Breaking Minisymposium
Sunday, April 17, 2016, 4:15 – 6:15 PM CT, Room 275, Morial Convention Center

Characterization of the T-cell receptor repertoire in extensive disease small cell lung cancer
Author: Hussein
Abstract #4159
Poster Session, Immune Cell Activity Session
Tuesday, April 19, 2016, 1:00 – 5:00 PM CT, Convention Center, Halls G-J, Poster Section 31
Bristol-Myers Squibb & Immuno-Oncology: Advancing Oncology Research

At Bristol-Myers Squibb, we have a vision for the future of cancer care that is focused on Immuno-Oncology, now considered a major treatment choice alongside surgery, radiation, chemotherapy and targeted therapies for certain types of cancer.

We have a comprehensive clinical portfolio of investigational and approved Immuno-Oncology agents, many of which were discovered and developed by our scientists. Our ongoing Immuno-Oncology clinical program is looking at broad patient populations, across multiple solid tumors and hematologic malignancies, and lines of therapy and histologies, with the intent of powering our trials for overall survival and other important measures like durability of response. We pioneered the research leading to the first regulatory approval for the combination of two Immuno-Oncology agents, and continue to study the role of combinations in cancer.

We are also investigating other immune system pathways in the treatment of cancer including CTLA-4, CD-137, KIR, SLAMF7, PD-1, GITR, CSF1R, IDO, and LAG-3. These pathways may lead to potential new treatment options – in combination or monotherapy – to help patients fight different types of cancers.

Our collaboration with academia, as well as small and large biotech companies, to research the potential of Immuno-Oncology and non-Immuno-Oncology combinations, helps achieve our goal of providing new treatment options in clinical practice.

At Bristol-Myers Squibb, we are committed to changing survival expectations in hard-to-treat cancers and the way patients live with cancer.

About Opdivo

Cancer cells may exploit "regulatory" pathways, such as checkpoint pathways, to hide from the immune system and shield the tumor from immune attack. Opdivo is a PD-1 immune checkpoint inhibitor that binds to the checkpoint receptor PD-1 expressed on activated T-cells, and blocks the binding of PD-L1 and PD-L2, preventing the PD-1 pathway’s suppressive signaling on the immune system, including the interference with an anti-tumor immune response.

Opdivo’s broad global development program is based on Bristol-Myers Squibb’s understanding of the biology behind Immuno-Oncology. Our company is at the forefront of researching the potential of Immuno-Oncology to extend survival in hard-to-treat cancers. This scientific expertise serves as the basis for the Opdivo development program, which includes a broad range of Phase 3 clinical trials evaluating overall survival as the primary endpoint across a variety of tumor types. The Opdivo trials have also contributed toward the clinical and scientific understanding of the role of biomarkers and how patients may benefit from Opdivo across the continuum of PD-L1 expression. To date, the Opdivo clinical development program has enrolled more than 18,000 patients.

Opdivo was the first PD-1 immune checkpoint inhibitor to receive regulatory approval anywhere in the world in July 2014, and currently has regulatory approval in 48 countries including the United States, Japan, and in the European Union.

INDICATIONS

OPDIVO (nivolumab) as a single agent is indicated for the treatment of patients with BRAF V600 wild-type unresectable or metastatic melanoma.

OPDIVO (nivolumab) as a single agent is indicated for the treatment of patients with BRAF V600 mutation-positive unresectable or metastatic melanoma. This indication is approved under accelerated approval based on progression-free survival. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

OPDIVO (nivolumab), in combination with YERVOY (ipilimumab), is indicated for the treatment of patients with unresectable or metastatic melanoma. This indication is approved under accelerated approval based on progression-free survival. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

OPDIVO (nivolumab) is indicated for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) with progression on or after platinum-based chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving OPDIVO.

OPDIVO (nivolumab) is indicated for the treatment of patients with advanced renal cell carcinoma (RCC) who have received prior anti-angiogenic therapy.

IMPORTANT SAFETY INFORMATION

WARNING: IMMUNE-MEDIATED ADVERSE REACTIONS

YERVOY can result in severe and fatal immune-mediated adverse reactions. These immune-mediated reactions may involve any organ system; however, the most common severe immune-mediated adverse reactions are enterocolitis, hepatitis, dermatitis (including toxic epidermal necrolysis), neuropathy, and endocrinopathy. The majority of these immune-mediated reactions initially manifested during treatment; however, a minority occurred weeks to months after discontinuation of YERVOY.

Assess patients for signs and symptoms of enterocolitis, dermatitis, neuropathy, and endocrinopathy and evaluate clinical chemistries including liver function tests (LFTs), adrenocorticotropic hormone (ACTH) level, and thyroid function tests at baseline and before each dose.

Permanently discontinue YERVOY and initiate systemic high-dose corticosteroid therapy for severe immune-mediated reactions.

Immune-Mediated Pneumonitis

Immune-mediated pneumonitis, including fatal cases, occurred with OPDIVO treatment. Across the clinical trial experience with solid tumors, fatal immune-mediated pneumonitis occurred with OPDIVO. In addition, in Checkmate 069, there were six patients who died without resolution of abnormal respiratory findings. Monitor patients for signs with radiographic imaging and symptoms of pneumonitis. Administer corticosteroids for Grade 2 or greater pneumonitis. Permanently discontinue for Grade 3 or 4 and withhold until resolution for Grade 2. In Checkmate 069 and 067, immune-mediated pneumonitis occurred in 6% (25/407) of patients receiving OPDIVO with YERVOY: Fatal (n=1), Grade 3 (n=6), Grade 2 (n=17), and Grade 1 (n=1). In Checkmate 037, 066, and 067, immune-mediated pneumonitis occurred in 1.8% (14/787) of patients receiving OPDIVO: Grade 3 (n=2) and Grade 2 (n=12). In Checkmate 057, immune-mediated pneumonitis, including interstitial lung disease, occurred in 3.4% (10/287) of patients: Grade 3 (n=5), Grade 2 (n=2), and Grade 1 (n=3). In Checkmate 025, pneumonitis, including interstitial lung disease, occurred in 5% (21/406) of patients receiving OPDIVO and 18% (73/397) of patients receiving everolimus. Immune-mediated pneumonitis occurred in 4.4% (18/406) of patients receiving OPDIVO: Grade 4 (n=1), Grade 3 (n=4), Grade 2 (n=12), and Grade 1 (n=1).

Immune-Mediated Colitis

Immune-mediated colitis can occur with OPDIVO treatment. Monitor patients for signs and symptoms of colitis. Administer corticosteroids for Grade 2 (of more than 5 days duration), 3, or 4 colitis. As a single agent, withhold OPDIVO for Grade 2 or 3 and permanently discontinue for Grade 4 or recurrent colitis upon restarting OPDIVO. When administered with YERVOY, withhold OPDIVO for Grade 2 and permanently discontinue for Grade 3 or 4 or recurrent colitis upon restarting OPDIVO. In Checkmate 069 and 067, diarrhea or colitis occurred in 56% (228/407) of patients receiving OPDIVO with YERVOY. Immune-mediated colitis occurred in 26% (107/407) of patients: Grade 4 (n=2), Grade 3 (n=60), Grade 2 (n=32), and Grade 1 (n=13). In Checkmate 037, 066, and 067, diarrhea or colitis occurred in 31% (242/787) of patients receiving OPDIVO. Immune-mediated colitis occurred in 4.1% (32/787) of patients: Grade 3 (n=20), Grade 2 (n=10), and Grade 1 (n=2). In Checkmate 057, diarrhea or colitis occurred in 17% (50/287) of patients receiving OPDIVO. Immune-mediated colitis occurred in 2.4% (7/287) of patients: Grade 3 (n=3), Grade 2 (n=2), and Grade 1 (n=2). In Checkmate 025, diarrhea or colitis occurred in 25% (100/406) of patients receiving OPDIVO and 32% (126/397) of patients receiving everolimus. Immune-mediated diarrhea or colitis occurred in 3.2% (13/406) of patients receiving OPDIVO: Grade 3 (n=5), Grade 2 (n=7), and Grade 1 (n=1).

In a separate Phase 3 study of YERVOY 3 mg/kg, severe, life-threatening, or fatal (diarrhea of ≥7 stools above baseline, fever, ileus, peritoneal signs; Grade 3-5) immune-mediated enterocolitis occurred in 34 (7%) patients. Across all YERVOY-treated patients in that study (n=511), 5 (1%) developed intestinal perforation, 4 (0.8%) died as a result of complications, and 26 (5%) were hospitalized for severe enterocolitis.

Immune-Mediated Hepatitis

Immune-mediated hepatitis can occur with OPDIVO treatment. Monitor patients for abnormal liver tests prior to and periodically during treatment. Administer corticosteroids for Grade 2 or greater transaminase elevations. Withhold for Grade 2 and permanently discontinue for Grade 3 or 4 immune-mediated hepatitis. In Checkmate 069 and 067, immune-mediated hepatitis occurred in 13% (51/407) of patients receiving OPDIVO with YERVOY: Grade 4 (n=8), Grade 3 (n=37), Grade 2 (n=5), and Grade 1 (n=1). In Checkmate 037, 066, and 067, immune-mediated hepatitis occurred in 2.3% (18/787) of patients receiving OPDIVO: Grade 4 (n=3), Grade 3 (n=11), and Grade 2 (n=4). In Checkmate 057, one patient (0.3%) developed immune-mediated hepatitis. In Checkmate 025, there was an increased incidence of liver test abnormalities compared to baseline in AST (33% vs 39%), alkaline phosphatase (32% vs 32%), ALT (22% vs 31%), and total bilirubin (9% vs 3.5%) in the OPDIVO and everolimus arms, respectively. Immune-mediated hepatitis requiring systemic immunosuppression occurred in 1.5% (6/406) of patients receiving OPDIVO: Grade 3 (n=5) and Grade 2 (n=1).

In a separate Phase 3 study of YERVOY 3 mg/kg, severe, life-threatening, or fatal hepatotoxicity (AST or ALT elevations >5x the ULN or total bilirubin elevations >3x the ULN; Grade 3-5) occurred in 8 (2%) patients, with fatal hepatic failure in 0.2% and hospitalization in 0.4%.

Immune-Mediated Dermatitis

In a separate Phase 3 study of YERVOY 3 mg/kg, severe, life-threatening, or fatal immune-mediated dermatitis (eg, Stevens-Johnson syndrome, toxic epidermal necrolysis, or rash complicated by full thickness dermal ulceration, or necrotic, bullous, or hemorrhagic manifestations; Grade 3-5) occurred in 13 (2.5%) patients. 1 (0.2%) patient died as a result of toxic epidermal necrolysis. 1 additional patient required hospitalization for severe dermatitis.

Immune-Mediated Neuropathies

In a separate Phase 3 study of YERVOY 3 mg/kg, 1 case of fatal Guillain-Barré syndrome and 1 case of severe (Grade 3) peripheral motor neuropathy were reported.

Immune-Mediated Endocrinopathies

Hypophysitis, adrenal insufficiency, thyroid disorders, and type 1 diabetes mellitus can occur with OPDIVO treatment. Monitor patients for signs and symptoms of hypophysitis, signs and symptoms of adrenal insufficiency during and after treatment, thyroid function prior to and periodically during treatment, and hyperglycemia. Administer corticosteroids for Grade 2 or greater hypophysitis. Withhold for Grade 2 or 3 and permanently discontinue for Grade 4 hypophysitis. Administer corticosteroids for Grade 3 or 4 adrenal insufficiency. Withhold for Grade 2 and permanently discontinue for Grade 3 or 4 adrenal insufficiency. Administer hormone-replacement therapy for hypothyroidism. Initiate medical management for control of hyperthyroidism. Administer insulin for type 1 diabetes. Withhold OPDIVO for Grade 3 and permanently discontinue for Grade 4 hyperglycemia.

In Checkmate 069 and 067, hypophysitis occurred in 9% (36/407) of patients receiving OPDIVO with YERVOY: Grade 3 (n=8), Grade 2 (n=25), and Grade 1 (n=3). In Checkmate 037, 066, and 067, hypophysitis occurred in 0.9% (7/787) of patients receiving OPDIVO: Grade 3 (n=2), Grade 2 (n=3), and Grade 1 (n=2). In Checkmate 025, hypophysitis occurred in 0.5% (2/406) of patients receiving OPDIVO: Grade 3 (n=1) and Grade 1 (n=1). In Checkmate 069 and 067, adrenal insufficiency occurred in 5% (21/407) of patients receiving OPDIVO with YERVOY: Grade 4 (n=1), Grade 3 (n=7), Grade 2 (n=11), and Grade 1 (n=2). In Checkmate 037, 066, and 067, adrenal insufficiency occurred in 1% (8/787) of patients receiving OPDIVO: Grade 3 (n=2), Grade 2 (n=5), and Grade 1 (n=1). In Checkmate 057, 0.3% (1/287) of OPDIVO-treated patients developed adrenal insufficiency. In Checkmate 025, adrenal insufficiency occurred in 2.0% (8/406) of patients receiving OPDIVO: Grade 3 (n=3), Grade 2 (n=4), and Grade 1 (n=1). In Checkmate 069 and 067, hypothyroidism or thyroiditis occurred in 22% (89/407) of patients receiving OPDIVO with YERVOY: Grade 3 (n=6), Grade 2 (n=47), and Grade 1 (n=36). Hyperthyroidism occurred in 8% (34/407) of patients: Grade 3 (n=4), Grade 2 (n=17), and Grade 1 (n=13). In Checkmate 037, 066, and 067, hypothyroidism or thyroiditis occurred in 9% (73/787) of patients receiving OPDIVO: Grade 3 (n=1), Grade 2 (n=37), Grade 1 (n=35). Hyperthyroidism occurred in 4.4% (35/787) of patients receiving OPDIVO: Grade 3 (n=1), Grade 2 (n=12), and Grade 1 (n=22). In Checkmate 057, Grade 1 or 2 hypothyroidism, including thyroiditis, occurred in 7% (20/287) and elevated thyroid stimulating hormone occurred in 17% of patients receiving OPDIVO. Grade 1 or 2 hyperthyroidism occurred in 1.4% (4/287) of patients. In Checkmate 025, thyroid disease occurred in 11% (43/406) of patients receiving OPDIVO, including one Grade 3 event, and in 3.0% (12/397) of patients receiving everolimus. Hypothyroidism/thyroiditis occurred in 8% (33/406) of patients receiving OPDIVO: Grade 3 (n=2), Grade 2 (n=17), and Grade 1 (n=14). Hyperthyroidism occurred in 2.5% (10/406) of patients receiving OPDIVO: Grade 2 (n=5) and Grade 1 (n=5). In Checkmate 069 and 067, diabetes mellitus or diabetic ketoacidosis occurred in 1.5% (6/407) of patients: Grade 4 (n=3), Grade 3 (n=1), Grade 2 (n=1), and Grade 1 (n=1). In Checkmate 037, 066, and 067, diabetes mellitus or diabetic ketoacidosis occurred in 0.8% (6/787) of patients receiving OPDIVO: Grade 3 (n=2), Grade 2 (n=3), and Grade 1 (n=1). In Checkmate 025, hyperglycemic adverse events occurred in 9% (37/406) patients. Diabetes mellitus or diabetic ketoacidosis occurred in 1.5% (6/406) of patients receiving OPDIVO: Grade 3 (n=3), Grade 2 (n=2), and Grade 1 (n=1).

In a separate Phase 3 study of YERVOY 3 mg/kg, severe to life-threatening immune-mediated endocrinopathies (requiring hospitalization, urgent medical intervention, or interfering with activities of daily living; Grade 3-4) occurred in 9 (1.8%) patients. All 9 patients had hypopituitarism, and some had additional concomitant endocrinopathies such as adrenal insufficiency, hypogonadism, and hypothyroidism. 6 of the 9 patients were hospitalized for severe endocrinopathies.

Immune-Mediated Nephritis and Renal Dysfunction

Immune-mediated nephritis can occur with OPDIVO treatment. Monitor patients for elevated serum creatinine prior to and periodically during treatment. For Grade 2 or 3 increased serum creatinine, withhold and administer corticosteroids; if worsening or no improvement occurs, permanently discontinue. Administer corticosteroids for Grade 4 serum creatinine elevation and permanently discontinue. In Checkmate 069 and 067, immune-mediated nephritis and renal dysfunction occurred in 2.2% (9/407) of patients: Grade 4 (n=4), Grade 3 (n=3), and Grade 2 (n=2). In Checkmate 037, 066, and 067, nephritis and renal dysfunction of any grade occurred in 5% (40/787) of patients receiving OPDIVO. Immune-mediated nephritis and renal dysfunction occurred in 0.8% (6/787) of patients: Grade 3 (n=4) and Grade 2 (n=2). In Checkmate 057, Grade 2 immune-mediated renal dysfunction occurred in 0.3% (1/287) of patients receiving OPDIVO. In Checkmate 025, renal injury occurred in 7% (27/406) of patients receiving OPDIVO and 3.0% (12/397) of patients receiving everolimus. Immune-mediated nephritis and renal dysfunction occurred in 3.2% (13/406) of patients receiving OPDIVO: Grade 5 (n=1), Grade 4 (n=1), Grade 3 (n=5), and Grade 2 (n=6).

Immune-Mediated Rash

Immune-mediated rash can occur with OPDIVO treatment. Severe rash (including rare cases of fatal toxic epidermal necrolysis) occurred in the clinical program of OPDIVO. Monitor patients for rash. Administer corticosteroids for Grade 3 or 4 rash. Withhold for Grade 3 and permanently discontinue for Grade 4. In Checkmate 069 and 067, immune-mediated rash occurred in 22.6% (92/407) of patients receiving OPDIVO with YERVOY: Grade 3 (n=15), Grade 2 (n=31), and Grade 1 (n=46). In Checkmate 037, 066, and 067, immune-mediated rash occurred in 9% (72/787) of patients receiving OPDIVO: Grade 3 (n=7), Grade 2 (n=15), and Grade 1 (n=50). In Checkmate 057, immune-mediated rash occurred in 6% (17/287) of patients receiving OPDIVO including four Grade 3 cases. In Checkmate 025, rash occurred in 28% (112/406) of patients receiving OPDIVO and 36% (143/397) of patients receiving everolimus. Immune-mediated rash, defined as a rash treated with systemic or topical corticosteroids, occurred in 7% (30/406) of patients receiving OPDIVO: Grade 3 (n=4), Grade 2 (n=7), and Grade 1 (n=19).

Immune-Mediated Encephalitis

Immune-mediated encephalitis can occur with OPDIVO treatment. Withhold OPDIVO in patients with new-onset moderate to severe neurologic signs or symptoms and evaluate to rule out other causes. If other etiologies are ruled out, administer corticosteroids and permanently discontinue OPDIVO for immune-mediated encephalitis. In Checkmate 067, encephalitis was identified in one patient (0.2%) receiving OPDIVO with YERVOY. In Checkmate 057, fatal limbic encephalitis occurred in one patient (0.3%) receiving OPDIVO.

Other Immune-Mediated Adverse Reactions

Based on the severity of adverse reaction, permanently discontinue or withhold treatment, administer high-dose corticosteroids, and, if appropriate, initiate hormone-replacement therapy. In < 1.0% of patients receiving OPDIVO, the following clinically significant, immune-mediated adverse reactions occurred: uveitis, pancreatitis, facial and abducens nerve paresis, demyelination, polymyalgia rheumatica, autoimmune neuropathy, Guillain-Barré syndrome, hypopituitarism, systemic inflammatory response syndrome, gastritis, duodenitis, and sarcoidosis. Across clinical trials of OPDIVO as a single agent administered at doses of 3 mg/kg and 10 mg/kg, additional clinically significant, immune-mediated adverse reactions were identified: motor dysfunction, vasculitis, and myasthenic syndrome.

Infusion Reactions

Severe infusion reactions have been reported in <1.0% of patients in clinical trials of OPDIVO. Discontinue OPDIVO in patients with Grade 3 or 4 infusion reactions. Interrupt or slow the rate of infusion in patients with Grade 1 or 2. In Checkmate 069 and 067, infusion- related reactions occurred in 2.5% (10/407) of patients receiving OPDIVO with YERVOY: Grade 2 (n=6) and Grade 1 (n=4). In Checkmate 037, 066, and 067, Grade 2 infusion related reactions occurred in 2.7% (21/787) of patients receiving OPDIVO: Grade 3 (n=2), Grade 2 (n=8), and Grade 1 (n=11). In Checkmate 057, Grade 2 infusion reactions requiring corticosteroids occurred in 1.0% (3/287) of patients receiving OPDIVO. In Checkmate 025, hypersensitivity/infusion-related reactions occurred in 6% (25/406) of patients receiving OPDIVO and 1.0% (4/397) of patients receiving everolimus.

Embryo-fetal Toxicity

Based on their mechanisms of action, OPDIVO and YERVOY can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with an OPDIVO- or YERVOY- containing regimen and for at least 5 months after the last dose of OPDIVO.

Lactation

It is not known whether OPDIVO or YERVOY is present in human milk. Because many drugs, including antibodies, are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from an OPDIVO-containing regimen, advise women to discontinue breastfeeding during treatment. Advise women to discontinue nursing during treatment with YERVOY and for 3 months following the final dose.

Serious Adverse Reactions

In Checkmate 067, serious adverse reactions (73% and 37%), adverse reactions leading to permanent discontinuation (43% and 14%) or to dosing delays (55% and 28%), and Grade 3 or 4 adverse reactions (72% and 44%) all occurred more frequently in the OPDIVO plus YERVOY arm relative to the OPDIVO arm. The most frequent (≥10%) serious adverse reactions in the OPDIVO plus YERVOY arm and the OPDIVO arm, respectively, were diarrhea (13% and 2.6%), colitis (10% and 1.6%), and pyrexia (10% and 0.6%). In Checkmate 037, serious adverse reactions occurred in 41% of patients receiving OPDIVO. Grade 3 and 4 adverse reactions occurred in 42% of patients receiving OPDIVO. The most frequent Grade 3 and 4 adverse drug reactions reported in 2% to <5% of patients receiving OPDIVO were abdominal pain, hyponatremia, increased aspartate aminotransferase, and increased lipase. In Checkmate 066, serious adverse reactions occurred in 36% of patients receiving OPDIVO. Grade 3 and 4 adverse reactions occurred in 41% of patients receiving OPDIVO. The most frequent Grade 3 and 4 adverse reactions reported in ≥2% of patients receiving OPDIVO were gamma-glutamyltransferase increase (3.9%) and diarrhea (3.4%). In Checkmate 057, serious adverse reactions occurred in 47% of patients receiving OPDIVO. The most frequent serious adverse reactions reported in ≥2% of patients were pneumonia, pulmonary embolism, dyspnea, pleural effusion, and respiratory failure. In Checkmate 025, serious adverse reactions occurred in 47% of patients receiving OPDIVO. The most frequent serious adverse reactions reported in ≥2% of patients were acute kidney injury, pleural effusion, pneumonia, diarrhea, and hypercalcemia.

Common Adverse Reactions

In Checkmate 067, the most common (≥20%) adverse reactions in the OPDIVO plus YERVOY arm were fatigue (59%), rash (53%), diarrhea (52%), nausea (40%), pyrexia (37%), vomiting (28%), and dyspnea (20%). The most common (≥20%) adverse reactions in the OPDIVO arm were fatigue (53%), rash (40%), diarrhea (31%), and nausea (28%). In Checkmate 037, the most common adverse reaction (≥20%) reported with OPDIVO was rash (21%). In Checkmate 066, the most common adverse reactions (≥20%) reported with OPDIVO vs dacarbazine were fatigue (49% vs 39%), musculoskeletal pain (32% vs 25%), rash (28% vs 12%), and pruritus (23% vs 12%). In Checkmate 057, the most common adverse reactions (≥20%) reported with OPDIVO were fatigue (49%), musculoskeletal pain (36%), cough (30%), decreased appetite (29%), and constipation (23%). In Checkmate 025, the most common adverse reactions (≥20%) reported in patients receiving OPDIVO vs everolimus were asthenic conditions (56% vs 57%), cough (34% vs 38%), nausea (28% vs 29%), rash (28% vs 36%), dyspnea (27% vs 31%), diarrhea (25% vs 32%), constipation (23% vs 18%), decreased appetite (23% vs 30%), back pain (21% vs 16%), and arthralgia (20% vs 14%).

In a separate Phase 3 study of YERVOY 3 mg/kg, the most common adverse reactions (≥5%) in patients who received YERVOY at 3 mg/kg were fatigue (41%), diarrhea (32%), pruritus (31%), rash (29%), and colitis (8%).

6-K – Report of foreign issuer [Rules 13a-16 and 15d-16]

On March 16, 2016 Cellectis (Paris:ALCLS) (NASDAQ:CLLS) (Alternext: ALCLS – Nasdaq: CLLS), a biopharmaceutical company focused on developing immunotherapies based on gene edited CAR T-cells (UCART), and MabQuest SA, a biotech company focused on the development of antibody-based therapeutic interventions, reported that they have entered into a research collaboration and license agreement pertaining to the development of a new class of monoclonal antibodies targeting PD-1 (Filing, 6-K, Cellectis, MAR 16, 2016, View Source [SID:1234509593]). The action of these PD-1 antibodies is to promote the recovery of T-cells from exhaustion through a new mechanism of action. This new class of antibodies differs from currently approved anti-PD-1 mAbs in that they do not block the PD-1-PD-L1 interaction. These anti-PD-1 mAbs have potential uses for multiple indications in immunotherapy, including notably treatments for a variety of cancers. Cellectis plans to use this new class of anti-PD-1 antibodies either in combination therapy with its gene-edited UCART product candidates or single-agent or in combination with other already approved immunotherapy drugs.

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In vitro studies have shown that the combination of these novel PD-1 mAbs with currently approved anti-PD-1 mAbs enhances the recovery of T-cells from exhaustion. Due to their new mechanism of action, these anti-PD-1 mAbs may be used in combination with other PD-1/PD-L1 inhibitors, such as Nivolumab and Pembrolizumab, or other checkpoints inhibitors and immunotherapy approaches for boosting the therapeutic effects of single therapy. Furthermore, this novel class of anti-PD-1 mAbs may represent an alternative and effective therapeutic intervention in those cancer patients with tumors expressing low levels of PD-L1, with respect to the currently approved anti-PD-1 mAbs. In addition, Cellectis intend to combine these PD-1 mAbs with its gene-edited UCART product candidates to enhance their activity and increase their half-life.

The agreement includes a collaboration phase funded by Cellectis whereby Cellectis and MabQuest will jointly pursue preclinical research on several candidate antibodies; and a clinical development and commercialization phase of the best selected antibodies which will be led by Cellectis.

Under the agreement, MabQuest has granted an exclusive option to Cellectis. Upon exercise of the option, Cellectis would be granted worldwide exclusive rights over the family of PD-1 antagonist antibodies developed under the collaboration for all fields, and further potential derivatives of these antibodies.

"We are very pleased to have signed this agreement with MabQuest, with founders and lead scientists who have great expertise in the field of immunology and monoclonal antibodies," said André Choulika, Chairman and Chief Executive Officer of Cellectis. "This collaboration is an important building block for our gene-edited UCART product candidates and for our immunotherapy franchise. This new partnership fits perfectly into Cellectis’ strategy of expanding our focus in the cancer immunotherapy space with our CAR T-cell based approaches."

"The collaboration agreement with Cellectis is a tremendous opportunity for MabQuest to move into clinical development with this new class of anti-PD-1 mAbs. This collaboration will also boost MabQuest’s discovery program to develop additional antibody-based strategies to modulate the host immune system," said Dr. Giuseppe Pantaleo, President of MabQuest and Professor of Medicine and Chief of the Service of Immunology and Allergy at the Lausanne University Hospital, Lausanne, Switzerland.

Verastem to Present Data Supporting FAK/PYK2 Inhibition at the 2016 American Academy of Cancer Research Annual Meeting

On March 16, 2016 Verastem, Inc. (NASDAQ:VSTM), focused on discovering and developing drugs to treat cancer, reported the presentation of scientific data at the 2016 American Association of Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting being held April 16-20, 2016 in New Orleans, LA (Press release, Verastem, MAR 16, 2016, View Source;p=RssLanding&cat=news&id=2149075 [SID:1234509592]).

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"The data that will be presented at the upcoming 2016 AACR (Free AACR Whitepaper) Annual Meeting continue to build on the premise that focal adhesion kinase (FAK), and the related proline-rich tyrosine kinase 2 (PYK2), inhibition enhances the efficacy of standard of care treatments such as platinum, and notably, immune checkpoint inhibitors," said Dr. Jonathan Pachter, Verastem Head of Research. "Key immune-related observations include VS-6063 and VS-4718 dose-dependently stimulating proliferation of CD8+ cytotoxic T cells. This is in distinct contrast to other protein kinase inhibitors which impair the proliferation of CD8+ cytotoxic T cells. These data further extend the rationale for Verastem’s ongoing clinical trials testing FAK inhibitors in combination with the immune checkpoint inhibitors, pembrolizumab or avelumab."

Details for the AACR (Free AACR Whitepaper) presentations are as follows:

Poster Presentations

Title: FAK/PYK2 Inhibition Enhances Immune Checkpoint Inhibitor Efficacy
Session: Immunology: Immune Modulating Agents 1
Abstract No.: 568
Date and time: Sunday Apr 17, 2016 1:00 – 5:00 PM
Location: Convention Center, Halls G-J, Poster Section 26
Summary: Durable responses have been observed with single-agent immune checkpoint inhibitors, but combinations of immunotherapy agents with compounds that modulate the tumor microenvironment have the potential to overcome the mechanisms that tumor cells develop, which assist them in evading the immune attack. In addition to targeting cancer stem cells, Verastem’s dual FAK/PYK2 inhibitors, VS-6063 and VS-4718, have been shown to beneficially modulate the tumor microenvironment in squamous cell carcinoma models. In these study results, researchers at Verastem reported the findings from combinations of VS-6063 and VS-4718 with multiple immunotherapies.

The combination of VS-4718 with an anti-PD-1 monoclonal antibody (mAb) showed improved efficacy over anti-PD-1 mAb alone and extended survival in vivo. Analysis of the tumors at Day 12 of treatment revealed a significant increase in the CD8+ T cells/Treg ratios in tumors in the VS-4718 + anti-PD-1 combination group, providing a mechanistic understanding for the enhanced efficacy of this combination.

The combination of VS-4718 with anti-4-1BB was also tested in the same in vivo model. Consistent with what was observed with the anti-PD-1 combination, VS-4718 also enhanced the efficacy of the anti-4-1BB mAb. In in vitro T cell proliferation assays, VS-6063 and VS-4718 dose-dependently stimulated proliferation of CD8+ cytotoxic T cells isolated from healthy donors. In addition, both VS-4718 and VS-6063 decreased CD8+ T cell exhaustion markers, and increased T cell-mediated tumor cell killing in vitro. These data support the thesis that Verastem’s FAK/PYK2 inhibitors, VS-6063 and VS-4718, beneficially modulate the tumor microenvironment, and in combination with immune checkpoint inhibitors, may increase the breadth of responsive tumor types, increase the number of responders, and confer more durable anti-tumor responses.

Title: FAK Inhibition Re-sensitizes Platinum-resistant Serous Ovarian Cancer
Session: Novel targets: Experimental and Molecular Therapeutics
Abstract No.: 3811
Date and time: Tuesday Apr 19, 2016 1:00 – 5:00 PM
Location: Convention Center, Halls G-J, Poster Section 17
Summary: Ovarian cancer stem cell (CSC) resistance to chemotherapy treatment can give rise to tumor recurrence, which occurs in a high percentage of patients and is directly related to poor overall survival. FAK, an intracellular tyrosine kinase, has been linked to CSC survival in many cancers. In this study, researchers tested Verastem’s FAK inhibitor VS-4718 in certain ovarian cancer models.

In vitro results demonstrated that elevated FAK was present in platinum (CP)-resistant ovarian cancer cells and FAK tyrosine phosphorylation was increased after CP treatment of CP-sensitive ovarian cancer cells. VS-4718 selectively blocked CP-resistant ovarian carcinoma methylcellulose colony growth via cell cycle inhibition, but not apoptosis. In vivo, oral VS-4718 reduced CP-resistant orthotopic tumor burden with a simultaneous decrease in tumor-associated aldehyde dehydrogenase (ALDH) activity, a marker of ovarian CSCs. VS-4718 also reduced the expression of several other CSC-related biomarkers. These results suggest that FAK signaling facilitates ovarian carcinoma CSC phenotypes and support the testing of FAK inhibitors in combination with CP to prevent recurrent and chemo-resistant ovarian cancer.

A copy of the poster presentations will be available at http://bit.ly/R3M6wc following the respective presentation times of each poster.

About Focal Adhesion Kinase
Focal Adhesion Kinase (FAK) is a non-receptor tyrosine kinase encoded by the PTK-2 gene that is involved in cellular adhesion and, in cancer, metastatic capability. VS-6063 (defactinib) and VS-4718 are orally available compounds that are potent inhibitors of FAK. VS-6063 and VS-4718 utilize a multi-faceted approach to treat cancer by reducing cancer stem cells, enhancing anti-tumor immunity, and modulating the local tumor microenvironment. VS-6063 and VS-4718 are currently being studied in multiple clinical trials for their ability to improve patient outcome.