Bristol-Myers Squibb and Five Prime Present Phase 1a/1b Data Evaluating Cabiralizumab (anti-CSF-1 receptor antibody) with Opdivo (nivolumab) in Patients with Advanced Solid Tumors

Study marks the first clinical experience evaluating an anti-CSF-1 receptor antibody with an anti-PD-1/PD-L1 therapy

Early efficacy signal observed in heavily pretreated patients with advanced pancreatic cancer with microsatellite stable (MSS) disease

PRINCETON, NJ & SOUTH SAN FRANCISCO, CA, USA I Bristol-Myers Squibb Company (NYSE:BMY) and Five Prime Therapeutics, Inc. (NASDAQ:FPRX) today announced preliminary results from a dose escalation and expansion study evaluating the safety, pharmacokinetics and pharmacodynamics of cabiralizumab in combination with Opdivo (nivolumab) in patients with advanced solid tumors. This is the first disclosure of a clinical experience evaluating an anti-CSF-1 receptor antibody, which depletes immunosuppressive tumor associated macrophages (TAMs), in combination with an anti-PD-1 antibody. Preliminary results show that the safety profile of cabiralizumab plus Opdivo was generally consistent with that of Opdivo monotherapy, and that the combination results in dose-related decreases in circulating monocytes. In a cohort of heavily pre-treated patients with advanced pancreatic cancer (n=31 evaluable patients), a patient population that is generally insensitive to immunotherapy, durable clinical benefit was observed in five patients (16%), including confirmed objective responses in three patients with microsatellite-stable (MSS) disease (objective response rate 10%). The data will be presented Saturday, November 11 at the Society for Immunotherapy of Cancer (SITC) 32nd Annual Meeting in a late-breaking oral presentation (abstract #O42) during Clinical Trials: Novel Combinations from 4:30 – 4:45 p.m. ET.

More cancer patients are being treated with immunotherapy, but most patients with advanced pancreatic cancer remain resistant to anti-PD-1/PD-L1 therapy and typically have poor outcomes, with an average one-year survival rate of only 16 percent and five-year survival of less than 3 percent.1-3 Pancreatic cancer is known to be associated with TAM infiltration and higher TAM infiltration is in turn associated with worse prognosis, suggesting that suppressed immune response contributes to tumor progression in this patient population. These data show for the first time that combining an anti-CSF-1 receptor antibody with Opdivo may help restore T cell function by a simultaneous reduction of TAMs and inhibition of PD-1 signaling.

“In our robust Immuno-Oncology clinical program, we are focused on discovering ways to leverage the complex tumor microenvironment to help restore the body’s natural ability to fight cancer,” said Fouad Namouni, M.D., head of development, Oncology, Bristol-Myers Squibb. “These preliminary results support our additional evaluation of the combination of cabiralizumab and Opdivo in patients with advanced pancreatic cancer.”

“Cabiralizumab depletes immunosuppressive TAMs that regulate T cells in the tumor microenvironment. TAM depletion may be synergistic to PD-1 blockade,” said Helen Collins, chief medical officer, Five Prime Therapeutics. “While early, we are encouraged by these results, which are supportive of continued development of this combination in pancreatic cancer.”

About the Study

NCT02526017 is a Phase 1a/1b open-label study to evaluate safety, tolerability, pharmacokinetics (PK), and clinical benefit of cabiralizumab in combination with Opdivo in patients with advanced cancers in single-arm cohorts. In the expansion cohorts, patients received cabiralizumab 4mg/kg plus Opdivo 3mg/kg intravenous (IV) once every two weeks in a 3+3+3 design.

As of data cut-off, 229 patients have been treated, including 205 patients in the combination dose expansion cohorts in advanced solid tumors, of which 33 were pancreatic cancer patients. Cabiralizumab PK activity appears similar as a monotherapy and in combination with Opdivo. The PK of cabiralizumab ≥ 4 mg/kg Q2W approaches the linear dose range, suggesting saturation of target-mediated clearance. Cabiralizumab alone or in combination with Opdivo results in dose-related decreases in circulating monocytes. Treatment-related adverse events (TRAEs) of any grade occurred in 90 percent (n=184) of patients treated with cabiralizumab and Opdivo, with 49 percent (n=100) of patients experiencing Grade 3/4 adverse events. Of the 24 patients in the monotherapy group, 63 percent (n=15) experienced TRAEs of any grade, and 54 percent (n=13) experienced Grade 3/4 adverse events. The most common TRAEs were elevations in creatine kinase and serum liver enzymes.

The efficacy data reported at SITC pertain to an expansion cohort in pancreatic cancer. The ongoing Phase 1a/1b trial has started to enroll and treat an additional 30 pancreatic cancer patients to further evaluate the combination in this patient population in a total of 60 patients. Further, Bristol-Myers Squibb is launching a new study of cabiralizumab plus Opdivo to provide additional insight into the potential benefit of the combination in pancreatic cancer. Additional details on this trial are available on clinicaltrials.gov.

About CSF1R and Cabiralizumab

Colony-stimulating factor 1 receptor (CSF1R) is a cell-surface tyrosine kinase receptor expressed by macrophages and other cells of the myeloid lineage. The CSF1R tyrosine kinase is activated when bound by its ligands, CSF-1 and IL-34. High levels of CSF1 in tumors stimulate more M2-like macrophages, which further tumor progression through suppressing effector T cell functions. High levels of TAMs in tumors are associated with poor prognostic outcomes, and preclinical research suggests that a blockade of CSF1R or inhibition of kinase activity may reduce the tumor burden, with a net effect of promotion of antitumor immunologic effects. Preclinical studies suggest that targeting the CSF1R pathway in combination with other potentially complementary immune pathways, like PD-1, may be a key strategy to more effectively activate the antitumor immune response.

Bristol-Myers Squibb and Five Prime are evaluating cabiralizumab in combination with Opdivo in a variety of advanced solid tumors. In 2015, Bristol-Myers Squibb and Five Prime entered into an exclusive worldwide license and collaboration agreement for the development and commercialization of Five Prime’s CSF1R antibody program, which includes cabiralizumab. Five Prime will continue to conduct the current Phase 1a/1b trial evaluating the combination of Opdivo and cabiralizumab in six tumor types, which was announced as part of the Companies’ initial clinical collaboration in November 2014, through to completion. Bristol-Myers Squibb will be responsible for subsequent development studies and for global commercialization, and Five Prime will retain rights to a U.S. co-promotion option.

Bristol-Myers Squibb & Immuno-Oncology: Advancing Oncology Research

At Bristol-Myers Squibb, patients are at the center of everything we do. Our vision for the future of cancer care is focused on researching and developing transformational Immuno-Oncology (I-O) medicines for hard-to-treat cancers that could potentially improve outcomes for these patients.

We are leading the scientific understanding of I-O through our extensive portfolio of investigational compounds and approved agents. Our differentiated clinical development program is studying broad patient populations across more than 50 types of cancers with more than 15 clinical-stage programs designed to target different immune system pathways. Our deep expertise and innovative clinical trial designs position us to advance I-O/I-O, I-O/chemotherapy, I-O/targeted therapies and I-O/radiation therapies across multiple tumors and potentially deliver the next wave of therapies with a sense of urgency. We also continue to pioneer research that will help facilitate a deeper understanding of the role of immune biomarkers and how patients’ tumor biology can be used as a guide for treatment decisions throughout their journey.

We understand making the promise of I-O a reality for the many patients who may benefit from these therapies requires not only innovation on our part but also close collaboration with leading experts in the field. Our partnerships with academia, government, advocacy and biotech companies support our collective goal of providing new treatment options to advance the standards of clinical practice.

About Opdivo

Opdivo is a programmed death-1 (PD-1) immune checkpoint inhibitor that is designed to uniquely harness the body’s own immune system to help restore anti-tumor immune response. By harnessing the body’s own immune system to fight cancer, Opdivo has become an important treatment option across multiple cancers.

Opdivo’s leading global development program is based on Bristol-Myers Squibb’s scientific expertise in the field of Immuno-Oncology and includes a broad range of clinical trials across all phases, including Phase 3, in a variety of tumor types. To date, the Opdivo clinical development program has enrolled more than 25,000 patients. The Opdivo trials have contributed to gaining a deeper understanding of the potential role of biomarkers in patient care, particularly regarding how patients may benefit from Opdivo across the continuum of PD-L1 expression.

In July 2014, Opdivo was the first PD-1 immune checkpoint inhibitor to receive regulatory approval anywhere in the world. Opdivo is currently approved in more than 60 countries, including the United States, the European Union and Japan. In October 2015, the company’s Opdivo and Yervoy combination regimen was the first Immuno-Oncology combination to receive regulatory approval for the treatment of metastatic melanoma and is currently approved in more than 50 countries, including the United States and the European Union.

U.S. FDA-APPROVED INDICATIONS FOR OPDIVO®

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

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.

OPDIVO® (nivolumab) is indicated for the treatment of adult patients with classical Hodgkin lymphoma (cHL) that has relapsed or progressed after autologous hematopoietic stem cell transplantation (HSCT) and brentuximab vedotin or after 3 or more lines of systemic therapy that includes autologous HSCT. This indication is approved under accelerated approval based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

OPDIVO® (nivolumab) is indicated for the treatment of patients with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) with disease progression on or after platinum-based therapy.

OPDIVO® (nivolumab) is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy or have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

OPDIVO® (nivolumab) is indicated for the treatment of adult and pediatric (12 years and older) patients with microsatellite instability high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer (CRC) that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan. This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

OPDIVO® (nivolumab) is indicated for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

About the Bristol-Myers Squibb and Ono Pharmaceutical Co., Ltd. Collaboration

In 2011, through a collaboration agreement with Ono Pharmaceutical Co., Ltd. (Ono), Bristol-Myers Squibb expanded its territorial rights to develop and commercialize Opdivo globally except in Japan, South Korea and Taiwan, where Ono had retained all rights to the compound at the time. On July 23, 2014, Bristol-Myers Squibb and Ono further expanded the companies’ strategic collaboration agreement to jointly develop and commercialize multiple immunotherapies – as single agents and combination regimens – for patients with cancer in Japan, South Korea and Taiwan.

About Bristol-Myers Squibb

Bristol-Myers Squibb is a global biopharmaceutical company whose mission is to discover, develop and deliver innovative medicines that help patients prevail over serious diseases. For more information about Bristol-Myers Squibb, visit us at BMS.com or follow us on LinkedIn, Twitter, YouTube and Facebook.

SOURCE: Bristol-Myers Squibb

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