ONO PHARMACEUTICAL : Updated Results Presented for the Opdivo (nivolumab) and Yervoy (ipilimumab) Combination in Metastatic Renal Cell Carcinoma From Phase 1 Study (151KB)

October 11, 2016

Updated Results Presented for the Opdivo (nivolumab) and Yervoy (ipilimumab) Combination in Metastatic Renal Cell Carcinoma From Phase 1 Study

(PRINCETON, NJ, October 9, 2016) - Bristol-Myers Squibb Company (NYSE: BMY) announced updated results from the Phase 1 CheckMate -016 trial, which evaluated the safety and tolerability (primary endpoint) of Opdivo at different doses as part of a regimen with Yervoy, sunitinib or pazopanib in previously treated and treatment-naïve patients with metastatic renal cell carcinoma (mRCC). These updated results include findings for the Opdivo and Yervoy combinations [Opdivo 3 mg/kg plus Yervoy 1 mg/kg arm and Opdivo 1 mg/kg plus Yervoy 3 mg/kg arm] with approximately two-years of follow-up, which showed the overall response rate (ORR; secondary endpoint) was 40. 4% (n=47) in both arms. Of the 38 responders in both treatment arms, 39.5% (n=15) had an ongoing response, with a median duration of response of 20.4 months (95% CI: 8.54 - NE) in the Opdivo 3 mg/kg plus Yervoy 1 mg/kg arm and 19.7 months (95% CI: 8.08 - NE) in the Opdivo 1 mg/kg plus Yervoy 3 mg/kg arm. The overall survival rate at 12 months was 81% and 85% for Opdivo 3 mg/kg plus Yervoy 1 mg/kg arm and Opdivo 1 mg/kg plus Yervoy 3 mg/kg arm, respectively, and at 24 months was 67% and 70%, respectively. There were fewer grade 3/4 treatment-related adverse events reported in the Opdivo 3 mg/kg plus Yervoy 1 mg/kg arm (38.3%) than with Opdivo 1 mg/kg plus Yervoy 3 mg/kg (61.7%).

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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Updated Results Presented for the Opdivo (nivolumab) and Yervoy (ipilimumab) Combination in Metastatic Renal Cell Carcinoma From Phase 1 Study

• Durable responses observed with the Opdivo and Yervoy combination in an updated analysis of CheckMate -016

• Confirmed objective response rate for both combination regimen cohorts was 40.4%

• The safety profile of the Opdivo and Yervoy combination in metastatic renal cell carcinoma patients is consistent with previous reports of the regimen in other studies

(PRINCETON, NJ, October 9, 2016) - Bristol-Myers Squibb Company (NYSE: BMY) announced today updated results from the Phase 1 CheckMate -016 trial, which evaluated the safety and tolerability (primary endpoint) of Opdivo at different doses as part of a regimen with Yervoy, sunitinib or pazopanib in previously treated and treatment-naïve patients with metastatic renal cell carcinoma (mRCC). These updated results include findings for the Opdivo and Yervoy combinations [Opdivo 3 mg/kg plus Yervoy 1 mg/kg arm and Opdivo 1 mg/kg plus Yervoy 3 mg/kg arm] with approximately two-years of follow-up, which showed the overall response rate (ORR; secondary endpoint) was 40. 4% (n=47) in both arms. Of the 38 responders in both treatment arms, 39.5% (n=15) had an ongoing response, with a median duration of response of 20.4 months (95% CI: 8.54 - NE) in the Opdivo 3 mg/kg plus Yervoy 1 mg/kg arm and 19.7 months (95% CI: 8.08 - NE) in the Opdivo 1 mg/kg plus

Yervoy 3 mg/kg arm. The overall survival rate at 12 months was 81% and 85% for Opdivo 3 mg/kg plus Yervoy 1 mg/kg arm and Opdivo 1 mg/kg plus Yervoy 3 mg/kg arm, respectively, and at 24 months was 67% and 70%, respectively. There were fewer grade 3/4 treatment- related adverse events reported in the Opdivo 3 mg/kg plus Yervoy 1 mg/kg arm (38.3%) than with Opdivo 1 mg/kg plus Yervoy 3 mg/kg (61.7%).

These results will be presented at the 2016 European Society for Medical Oncology (ESMO) Congress during a poster session on Sunday, October 9 from 1:00 - 2:00 p.m. CEST (Abstract #1062P).

"There remains a significant unmet need for treatment options that offer ongoing responses and increase survival for patients with renal cell carcinoma, the most common type of kidney cancer," said Asim Amin, M.D., Ph.D., Levine Cancer Institute, Carolinas HealthCare System. "The results from CheckMate -016 are encouraging and warrant further

study, as they show with nearly two years of follow-up, patients in each Opdivo and Yervoy

combination arm had a response that is ongoing in 40.4% of the patients."

Nearly a third of renal cell carcinoma (RCC) diagnoses occur once the disease has metastasized, or spread, to other parts of the body. At Stage IV, survival rates are low, with approximately 12% of advanced kidney cancer patients alive at five years.

"The findings reported at ESMO for CheckMate -016 validate our approach to studying the combination of our two Immuno-Oncology agents, Opdivo and Yervoy, to improve patient outcomes in metastatic renal cell carcinoma," said Vicki Goodman, M.D., development lead, Melanoma and Genitourinary Cancers, Bristol-Myers Squibb. "Our Phase 3 program for the Opdivo and Yervoy combination in the first line metastatic renal cell carcinoma is ongoing, and we hope to confirm these early findings through our continued research."

About CheckMate -016

CheckMate -016 is a multicenter, open-label, Phase 1 trial of Opdivo in combination with Yervoy, sunitinib or pazopanib in previously treated and treatment-naïve patients with metastatic renal cell carcinoma (mRCC). In the arms evaluating the combination regimen of Opdivo and Yervoy, which included 47 patients each, patients were randomized to receive Opdivo 3 mg/kg and Yervoy 1 mg/kg or Opdivo 1 mg/kg and Yervoy 3 mg/kg by intravenous infusion every three weeks for four doses, followed by Opdivo 3 mg/kg by intravenous infusion every two weeks until progression or toxicity. Prior systemic therapy was administered in 46.8% and 55.3% in the Opdivo 3 mg/kg plus Yervoy 1 mg/kg and Opdivo 1 mg/kg plus Yervoy 3 mg/kg arms, respectively. The primary endpoints were to assess the safety and tolerability, and secondary endpoints were to assess objective response rate (ORR), duration of response (DOR), overall survival (OS) and progression-free survival (PFS).

In the study, fewer patients in the Opdivo 3 mg/kg and Yervoy 1 mg/kg arm experienced grade 3/4 treatment-related adverse events (AEs) than those in the Opdivo 1 mg/kg plus Yervoy 3 mg/kg arm (38.3% and 61.7%). Increased lipase was the most common grade 3/4 treatment-related AE in both arms (14.9% with Opdivo 3 mg/kg and Yervoy 1 mg/kg; and 27.7% with Opdivo 1 mg/kg and Yervoy 3 mg/kg). Grade 3/4 treatment-related select AEs in the Opdivo 3 mg/kg and Yervoy 1 mg/kg and Opdivo 1 mg/kg and Yervoy 3 mg/kg arms were, respectively, gastrointestinal (4.3% and 23.4%), hepatic (6.4% and 21.3%),

renal (4.3% and 4.3%), endocrinopathy (4.3% and 0.0%) and skin (0.0% and 2.1%). Discontinuations due to treatment-related AEs included five and 13 patients in the Opdivo 3

mg/kg and Yervoy 1 mg/kg and Opdivo 1 mg/kg and Yervoy 3 mg/kg arms, respectively. Treatment-related AEs leading to discontinuation in >5% of patients were increased alanine aminotransferase (ALT; 10.6%) and colitis (6.4%) in the Opdivo 1 mg/kg and Yervoy 3 mg/kg arm. No treatment-related deaths occurred in either arm. Based on these results, further development of the Opdivo 1 mg/kg and Yervoy 3 mg/kg regimen was not pursued. .

Key efficacy results in previously treated and treatment-naive mRCC patients are summarized below.

Opdivo 3 mg/kg plus Yervoy 1 mg/kg (n=47)		Opdivo 1 mg/kg plus Yervoy 3 mg/kg (n=47)
Confirmed ORR, n (%); 95%	19 (40.4)	19 (40.4)
CI	26.4 - 55.7	26.4 - 55.7
Best overall response,a n (%)
Complete response	5 (10.6)	0 (0.0)
Partial response	14 (29.8)	19 (40.4)
Stable disease	19 (40.4)	17 (36.2)
Disease progression	8 (17.0)	8 (17.0)
Median DOR, mos. (range)	20.4	19.7
(95% CI: 8.54 - NE)	(95% CI: 8.08 - NE)
12-month OS rate (%)	81	85
24-month OS rate	67	70
Median OS, mos. (range);	Not reached	32.6 (25.99-NE)
95% CI
Median PFS, mos. (range)	6.6 (3.55 - 14.9)	9.1 (5.62 - 15.67)

a Best overall response was indeterminate in one patient (2.1%) in the Opdivo 3 mg/kg plus Yervoy 1 mg/kg arm and in two patients (4.3%) in the Opdivo 1 mg/kg plus Yervoy 3 mg/kg arm.

About Renal Cell Carcinoma

Renal cell carcinoma (RCC) is the most common type of kidney cancer in adults, accounting for more than 100,000 deaths worldwide each year. Clear-cell RCC is the most prevalent type of RCC and constitutes 80% to 90% of all cases. Renal cell carcinoma is approximately twice as common in men as it is in women, with the highest rates of the disease found in North America and Europe. Globally, the five-year survival rate for those diagnosed with advanced kidney cancer is 12%.

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