ONO PHARMACEUTICAL : Phase 1/2 Data Combining Urelumab with Opdivo (nivolumab) in Hematologic and Solid Tumors Suggest Increased Antitumor Effect in Patients with Melanoma (164KB)

November 18, 2016

Phase 1/2 Data Combining Urelumab with Opdivo (nivolumab) in Hematologic and Solid Tumors Suggest Increased Antitumor Effect in Patients with Melanoma

(PRINCETON, N.J., November 12, 2016) - Bristol-Myers Squibb Company (NYSE:BMY) announced safety and efficacy data from a Phase 1/2 study of urelumab in combination with Opdivo (nivolumab) in patients with hematologic and solid tumors, including biomarker analyses by level of PD-L1 expression. The combination of urelumab and Opdivo showed encouraging efficacy among 46 evaluable melanoma patients with an objective response rate (ORR) of 50% (23/46 with 18 confirmed and 5 unconfirmed). ORR was a secondary endpoint as measured by Response Evaluation Criteria In Solid Tumors (RECIST). Similar response was seen in both PD-L1 positive and PD-L1 negative melanoma patients, with ORR of 50% (10/20) and 47% (8/17) in those with >1% and

Bristol-Myers Squibb (BMS) has a robust clinical development program in Opdivo monotherapy and in combination therapy with other therapeutic drugs in a variety of tumor types overseas, including Glioblastoma, Small Cell Lung Cancer, Urothelial Cancer, Hepatocellular Carcinoma, Esophageal Cancer, Colorectal Cancer, Gastric Cancer, Blood Cancer, etc.

In Japan, Ono Pharmaceutical Co., Ltd. (ONO) launched Opdivo for the treatment of unresectable melanoma in September 2014. ONO received an approval for additional indication of unresectable, advanced or recurrent non-small cell lung cancer in December 2015 and unresectable or metastatic renal cell cancer in August 2016. In addition, ONO has submitted supplemental applications for additional indications of Hodgkin Lymphoma and Head and Neck Cancer, and is conducting clinical development program including Gastric Cancer, Esophageal Cancer, Small Cell Lung Cancer, Hepatocellular Carcinoma, Glioblastoma, Ovarian Cancer, Urothelial Cancer, Malignant Pleural Mesothelioma, Biliary Tract Cancer, etc.

In Japan, ONO and BMS (and BMS Japan subsidiary BMSKK) have formed a strategic partnership that includes co-development, co-commercialization, and co-promotion of multiple immunotherapies for patients with cancer.

Attached from the following page is the press release made by BMS for your information.

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ONO PHARMACEUTICAL CO., LTD.

Corporate Communications public_relations@ono.co.jp

Phase 1/2 Data Combining Urelumab with Opdivo (nivolumab) in Hematologic and Solid Tumors Suggest Increased Antitumor Effect in Patients with Melanoma

(PRINCETON, N.J., November 12, 2016) - Bristol-Myers Squibb Company (NYSE:BMY) today announced safety and efficacy data from a Phase 1/2 study of urelumab in combination with Opdivo (nivolumab) in patients with hematologic and solid tumors, including biomarker analyses by level of PD-L1 expression. The combination of urelumab and Opdivo showed encouraging efficacy among 46 evaluable melanoma patients with an objective response rate (ORR) of 50% (23/46 with 18 confirmed and 5 unconfirmed). ORR was a secondary endpoint as measured by Response Evaluation Criteria In Solid Tumors (RECIST). Similar response was seen in both PD-L1 positive and PD-L1 negative melanoma patients, with ORR of 50% (10/20) and 47% (8/17) in those with >1% and no significant added toxicity was observed with urelumab in combination with Opdivo over Opdivo monotherapy. These data were presented at an oral presentation (poster number 239) at the Society for Immunotherapy of Cancer (SITC) 31 Annual Meeting on November 12 at 10:40 a.m. EST in National Harbor, Maryland.

The overall rate of treatment-related adverse events (TRAEs) was 63% (n=87), with the most common being fatigue (31%), ALT increased (11%), anemia (10%), and AST increased (9%). No additional signals were seen with the combination therapy compared to Opdivo monotherapy. The rate of Grade 3-4 TRAEs was 17% (n=23). The rate of discontinuations due to TRAEs was 6% (n=8).

Urelumab is a fully human monoclonal IgG4k antibody agonist of CD137, a tumor necrosis factor (TNF) family receptor expressed primarily on activated T cells and activated natural killer (NK) cells. Opdivo blocks the inhibitory function of the PD-1 receptor on T cells.

"These results suggest that urelumab in combination with Opdivo may offer an antitumor benefit in patients with melanoma, in both PD-L1 expressors and non-expressors," said Erminia Massarelli, MD, PhD, MS, Associate Clinical Professor at the City of Hope Comprehensive Cancer Center. "While there have been major advances in melanoma treatment over the past five years, some patients continue to need additional options to treat the disease, which is one of deadliest forms of cancer."

"We are committed to exploring complementary immune pathways and mechanisms and look forward to continued study of urelumab in combination with multiple Immuno- Oncology agents across various tumor types and personalized to patient biologies," said Tim Reilly, head of Oncology Early Assets Development at Bristol-Myers Squibb.

About the Study

The Phase 1/2 study of urelumab administered in combination with Opdivo evaluated which doses are safe and tolerable. Efficacy was evaluated in advanced/metastatic melanoma (n=46), diffuse large B-cell lymphoma (DLBCL, n=19), NSCLC patients who had progressed on a

PD-1/PD-L1 therapy (n=14), NSCLC patients who had not previously received a PD-1/PD-L1 therapy (n=20), SCCHN (n=22) and other tumors (n=3). The ORR for these cohorts was 50%, 0%, 0%, 5%, 5% and 0%, respectively, and the disease control rate (DCR) was 70%, 21%,

21%, 35%, 23% and 33%, respectively.

After an initial phase where patients received urelumab 3 mg IV every four weeks plus Opdivo 3 mg/kg IV every two weeks, patients were treated with urelumab 8 mg IV every four weeks plus Opdivo 3 mg/kg IV every two weeks. Cohort expansion, during which patients with specific tumor types received urelumab 8 mg IV every four weeks plus Opdivo 240 mg IV every two weeks, was initiated after completion of the required safety monitoring period.

The primary endpoint of the Phase 1/2 study is safety, as measured by the rate of adverse events (AEs) and serious adverse events (SAEs). All subjects who received at least one (full or partial) dose of urelumab or Opdivo were evaluated for safety during treatment and for up

to 100 days follow-up (n=138). Secondary outcome measures include best overall response, ORR, duration of response and progression free survival rate.

About Metastatic Melanomai

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 for at least 30 years. Approximately 73,870 melanoma cases were estimated to be diagnosed in the U.S. in 2015. Melanoma is mostly curable when treated in its early stages. However, in its late stages, 5-year and 10-year survival rates in the U.S. average 15-20% and 10-15%, respectively.

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 57 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 47 countries, including the United States and the European Union.