ONO PHARMACEUTICAL : Opdivo® (nivolumab) Granted First Approval of a PD-1 Inhibitor in Hematology for the Treatment of Classical Hodgkin Lymphoma Patients Who Have Relapsed or Progressed After Auto-HSCT and Post-transplantation Brentuximab Vedotin by the FDA (156KB)

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May 20, 2016

Opdivo® (nivolumab) Granted First Approval of a PD-1 Inhibitor in Hematology for the Treatment of Classical Hodgkin Lymphoma Patients Who Have Relapsed or Progressed After Auto-HSCT and Post-transplantation Brentuximab Vedotin by the FDA

(PRINCETON, NJ, May 17, 2016) - Bristol-Myers Squibb Company (NYSE: BMY) announced the

(PRINCETON, NJ, May 17, 2016) - Bristol-Myers Squibb Company (NYSE: BMY) today announced the U.S. Food and Drug Administration (FDA) has approved

Opdivo® (nivolumab) for the treatment of patients with classical Hodgkin lymphoma (cHL) who

have relapsed or progressed after autologous hematopoietic stem cell transplantation (auto- HSCT) and post-transplantation brentuximab vedotin.1 This accelerated approval is based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. This first approval of a PD-1 inhibitor for cHL patients who have relapsed or progressed after auto-HSCT and post-transplantation brentuximab vedotin is based on a combined analysis of data from the Phase 2 CheckMate -205 and the Phase 1 CheckMate -039 trials.1 Based on this analysis (n=95), Opdivo delivered a high

response rate, with an objective response rate (ORR) of 65% (CI 95%: 55-75; 62/95 patients).1

The percentage of patients with a complete response was 7% (CI 95%: 3-15; 7/95 patients), and the percentage of patients with a partial response was 58% (CI 95%: 47-68; 55/95 patients).1 Among responders, the duration of response was maintained over time for a median of 8.7 months (CI 95%: 6.8-NE; range 0.0+, 23.1+).1

Opdivo is associated with the following Warnings and Precautions including immune- mediated: pneumonitis, colitis, hepatitis, endocrinopathies, nephritis and renal dysfunction, rash,

encephalitis, other adverse reactions; infusion reactions; complications of allogeneic HSCT after

Opdivo; and embryo-fetal toxicity.1 Please see the Important Safety Information section below. "As a classical Hodgkin lymphoma patient who has tried multiple therapies, I know

firsthand what it's like to not have a clear next step," said Matt Kludt, a patient enrolled in a nivolumab clinical trial. "When I started on Opdivo, I was hopeful about the potential for this new treatment. Now, I'm proud to be able to say I was one of several patients who have helped contribute to the approval of a new therapy that may offer other patients like me the possibility of a high response rate."

"Today's approval of Opdivo delivers a transformational and exciting new option for these patients and the hematologists who treat them. By expanding this Immuno-Oncology therapy into a hematologic malignancy, we continue to deliver upon our unwavering commitment to provide treatments that work directly with the body's immune system for patients who are in need of new options," said Chris Boerner, Head of U.S. Commercial, Bristol-Myers Squibb. "This is our second Immuno-Oncology agent in blood cancer in less than a year for patients impacted by diseases with a deep unmet need. This approval of Opdivo represents how we are continually working towards the goal of helping patients, like Matt, by offering them a new chance in their fight against this disease."

The efficacy of Opdivo in patients (n=95) with cHL after failure of auto-HSCT and post- transplantation brentuximab vedotin was evaluated in the combined analysis from two studies.1 CheckMate -205 is a Phase 2, single-arm, open-label, multicenter, multicohort study.1 The results of this trial will be presented at the American Society of Clinical Oncology Annual Meeting in June 2016. CheckMate -039 is a Phase 1, open-label, multicenter, dose escalation study.1 In the combined analysis, efficacy was evaluated by ORR, and an additional outcome measure was duration of response. Objective response rate was assessed by an independent radiographic review committee.1

Both studies excluded patients with an Eastern Cooperative Oncology Group (ECOG) performance status of two or higher, autoimmune disease, symptomatic interstitial lung disease, hepatic transaminases more than three times the upper limit of normal (ULN), creatinine clearance less than 40 mL/min, prior allogeneic HSCT or chest irradiation within 24 weeks.1 In addition, both studies required an adjusted diffusion capacity of the lungs for carbon monoxide (DLCO) of more than 60% in patients with prior pulmonary toxicity.1 Patients received 3 mg/kg

of single-agent Opdivo administered as an intravenous infusion over 60 minutes every two weeks until disease progression, maximal clinical benefit or unacceptable toxicity.1

The median age was 37 years (range: 18-72), and the majority were male (64%) and white (87%).1 Patients had received a median of five prior systemic regimens (range: 3-15) and received a median of 17 doses of Opdivo (range: 3-48), with a median duration of therapy of 8.3 months (range: 1.9-24 months).1 In adults with cHL who have relapsed or progressed after auto- HSCT and post-transplantation brentuximab vedotin (n=95), Opdivo demonstrated impressive response rates: ORR was 65% (CI 95%: 55-75; 62/95 patients), including a 7% complete response rate (CI 95%: 3-15; 7/95 patients) and a 58% partial response rate (CI 95%: 47-68; 55/95 patients).1 The median time to response was 2.1 months (range: 0.7-5.7).1 Among responders, Opdivo demonstrated an 8.7 month median duration of response (95% CI: 6.8-NE; range 0.0+, 23.1+).1

The safety of Opdivo in cHL was evaluated in 263 adult patients from the CheckMate

-205 (n=240) and -039 (n=23) trials.1 Among these patients (safety population: n=263) serious adverse reactions occurred in 21% of patients.1 The most frequent serious adverse reactions reported in ≥1% of patients were infusion-related reaction, pneumonia, pleural effusion, pyrexia, rash and pneumonitis.1 Ten patients died from causes other than disease progression, including 6 who died from complications of allogeneic HSCT.1 In the safety population, 4.2% discontinued treatment due to adverse reactions, and 23% of patients had a dose delay for an adverse reaction.1 In the subset of patients in the efficacy population (n=95), serious adverse reactions occurred in 27% of the patients.1 In CheckMate -205 and -039, among all patients (safety population: n=263) and the subset of patients in the efficacy population (n=95), respectively, the most common

adverse reactions (reported in at least 20%) were fatigue (32% and 43%), upper respiratory tract infection (28% and 48%), pyrexia (24% and 35%), diarrhea (23% and 30%), and cough (22% and 35%).1 In the subset of patients in the efficacy population (n=95), the most common adverse reactions also included rash (31%), musculoskeletal pain (27%), pruritus (25%), nausea (23%),

arthralgia (21%), and peripheral neuropathy (21%).1

"It is important to have new treatment options for patients with difficult-to-treat diseases who have exhausted the current available options. Because of the unique pathology and biology of classical Hodgkin lymphoma,2 it makes sense from a scientific standpoint to investigate a PD- 1 inhibitor," said Anas Younes, M.D., medical oncologist and chief of Lymphoma Service,