On June 5, 2016 Bristol-Myers Squibb Company (NYSE:BMY) reported new long-term overall survival (OS) results from two dose-ranging studies, the Phase 1 CA209-003 study and the Phase 2 CA209-010 study, evaluating Opdivo in patients with previously treated advanced renal cell carcinoma (RCC) (Press release, Bristol-Myers Squibb, JUN 5, 2016, View Source [SID:1234513000]). Findings include the first report of four- and five-year survival data from the advanced RCC cohort (n=34) of study -003, in which OS was an exploratory endpoint. In study -003, 38% of patients were alive at four years, and 34% of patients were alive at five years. In study -010 (n=167), in which OS was a secondary endpoint, 29% of patients were alive at four years. The long-term safety profile of Opdivo in studies -003 and -010 was consistent with previously reported studies, with no new safety signals identified after more than four years of follow-up.

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Bristol-Myers Squibb is also presenting additional analyses of health-related quality of life data, a secondary endpoint, from the pivotal, Phase 3 study, CheckMate -025, which evaluated Opdivo versus everolimus in patients with advanced RCC who received prior anti-angiogenic therapy. In this study, 55.4% of patients treated with Opdivo experienced a clinically meaningful improvement in disease-related symptoms, as defined in the study, versus 36.7% of patients treated with everolimus (HR=1.66 [95% CI: 1.33-2.08; p<0.001]).

Dr. Bernard Escudier, Chair of the Genitourinary Oncology Committee, Institut Gustave Roussy in Villejuif, France, commented, "Historically, five-year survival rates for patients diagnosed with advanced kidney cancer have been less than 12%. Building on the survival results seen in the Phase 3 study, CheckMate -025, research evaluating whether Opdivo may provide long-term survival has been of interest to physicians. Data from studies -003 and -010 report, for the first time, longer than four-year survival with Opdivo in previously treated advanced renal cell carcinoma. These findings offer additional important information about the role of Opdivo as a treatment option for these patients."

The results from studies -003 and -010 will be presented today, Sunday, June 5, at the 52nd Annual Meeting of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) during an oral presentation from 10:24 AM – 10:36 AM CDT (Abstract #4507). Data from CheckMate -025 will be presented during a poster session on Monday, June 6, from 1:00 PM – 4:30 PM CDT (Abstract #4549).

"We are excited to share the overall survival results from studies -010 and -003, as these data provide new insights into the long-term efficacy and safety of Opdivo in previously treated advanced renal cell carcinoma," said Vicki Goodman, M.D., Development Lead, Melanoma and Genitourinary Cancers, Bristol-Myers Squibb. "Additionally, with Opdivo, a meaningful improvement in health-related quality of life, an important factor in cancer care and patient well-being, was observed compared to everolimus, based on new data from CheckMate -025. We look forward to further evaluating our Immuno-Oncology agents across different tumor types, including the Opdivo and Yervoy combination, with the goal of improving long-term survival and quality of life for RCC patients."

About CA209-003

Study -003, is a Phase 1b open-label, multicenter, multidose, dose-escalation study evaluating Opdivo in 306 patients with select advanced or recurrent malignancies. The primary endpoint was safety and tolerability. Secondary endpoints included objective response rate (ORR). Overall survival (OS) was an exploratory endpoint.

The results from study -003 presented at the 2016 ASCO (Free ASCO Whitepaper) Annual Meeting focus on the cohort of patients with advanced renal cell carcinoma (RCC, n=34) who had received one to five prior systemic therapies, and were treated with Opdivo 1 mg/kg or 10 mg/kg intravenously every two weeks.

At four years, the OS rate for patients treated with Opdivo was 38%, with a median OS of 22.4 months (95% CI: 12.5-NE), and the five-year survival rate was 34%, with a minimum follow-up of 50.5 months. The long-term safety profile of Opdivo in study -003 was consistent with previous studies, with no new safety signals identified after more than four years of follow-up. Grade 3-4 treatment-related adverse events (AEs) occurred in 17.6% of patients. Any grade treatment-related AEs leading to discontinuation occurred in 8.8% of patients.

About CA209-010

Study -010 is a Phase 2, randomized, dose-ranging study evaluating Opdivo in 167 patients with previously treated advanced renal cell carcinoma (RCC). In the study, patients with advanced RCC who had received prior treatment with one to three therapies (at least one being an anti-angiogenic agent) were treated with Opdivo (0.3, 2 or 10 mg/kg) every three weeks administered intravenously. The primary endpoint was dose-response by progression-free survival (PFS). Secondary endpoints included objective response rate (ORR), overall survival (OS) and safety.

At four years, the OS rate for patients treated with Opdivo was 29%, with a median OS of 23.4 months (95% CI: 17.7-26.9), at a minimum follow-up of 49.2 months. In the study, the ORR was 21.6% (95% CI: 15.6-28.6) with a median duration of response lasting 23 months. Median time to response was 2.8 months (1.2-10.0).

The long-term safety profile of Opdivo in study -010 was consistent with previous studies, with no new safety signals identified after approximately four years of follow-up. Grade 3-4 treatment-related adverse events (AEs) occurred in 14.4% of patients in study -010. Any grade treatment-related AEs leading to discontinuation occurred in 9.6% of patients.

About CheckMate -025

CheckMate -025 is an open-label, randomized Phase 3 study of Opdivo versus everolimus in previously treated patients with advanced clear-cell renal cell carcinoma (RCC) after prior anti-angiogenic therapy. Patients were randomized to receive Opdivo (n=410) 3 mg/kg administered intravenously every two weeks or everolimus (n=411) 10 mg administered orally once daily. The primary endpoint of the study was overall survival (OS). Secondary endpoints include objective response rate (ORR), progression-free survival (PFS), quality of life (QoL) and safety. Patient-reported QoL was measured using the kidney specific, Functional Assessment of Cancer Therapy–Kidney Symptom Index–Disease Related Symptoms (FKSI-DRS) scale, and European Quality of Life (EuroQol)-5 Dimensions (EQ-5D) questionnaire. Quality of life was measured at baseline among approximately 361 patients randomized for treatment with Opdivo and 343 patients randomized for treatment with everolimus.

A higher proportion of patients treated with Opdivo experienced a clinically meaningful improvement in health-related QoL (defined as a 2-point increase from baseline using FKSI-DRS) compared to patients treated with everolimus (200 [55.4%] of 361 vs. 126 [36.7%] of 343, respectively; (HR=1.66 [95% CI: 1.33-2.08; p<0.001]). Median time to improvement in disease-related symptoms occurred at 4.7 months (95% CI: 3.7-7.5) with Opdivo and was not estimable with everolimus due to a limited number of patients who experienced improvement.

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. RCC 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%.

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 51 countries including the United States, Japan, and in 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 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.

OPDIVO (nivolumab) is indicated for the treatment of patients with classical Hodgkin lymphoma (cHL) that has relapsed or progressed after autologous hematopoietic stem cell transplantation (HSCT) and post- transplantation brentuximab vedotin. 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.

Please refer to the end of the Important Safety Information for a brief description of the patient populations studied in the Checkmate trials.

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). In Checkmate 205 and 039, pneumonitis, including interstitial lung disease, occurred in 4.9% (13/263) of patients receiving OPDIVO. Immune-mediated pneumonitis occurred in 3.4% (9/263) of patients receiving OPDIVO: Grade 3 (n=1) and Grade 2 (n=8).

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 Checkmate 205 and 039, diarrhea or colitis occurred in 30% (80/263) of patients receiving OPDIVO. Immune-mediated diarrhea (Grade 3) occurred in 1.1% (3/263) of patients.

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 Checkmate 205 and 039, hepatitis occurred in 11% (30/263) of patients receiving OPDIVO. Immune-mediated hepatitis occurred in 3.4% (9/263): Grade 3 (n=7) and Grade 2 (n=2).

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 205 and 039, adrenal insufficiency (Grade 2) occurred in 0.4% (1/263) of patients receiving OPDIVO. 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 205 and 039, hypothyroidism/thyroiditis occurred in 12% (32/263) of patients receiving OPDIVO: Grade 2 (n=18) and Grade 1: (n=14). Hyperthyroidism occurred in 1.5% (4/263) of patients receiving OPDIVO: Grade 2: (n=3) and Grade 1 (n=1). 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 Checkmate 205 and 039, diabetes mellitus occurred in 0.8% (2/263) of patients receiving OPDIVO: Grade 3 (n=1) 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). In Checkmate 205 and 039, nephritis and renal dysfunction occurred in 4.9% (13/263) of patients treated with OPDIVO. This included one reported case (0.3%) of Grade 3 autoimmune nephritis.

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). In Checkmate 205 and 039, rash occurred in 22% (58/263) of patients receiving OPDIVO. Immune-mediated rash occurred in 7% (18/263) of patients on OPDIVO: Grade 3 (n=4), Grade 2 (n=3), and Grade 1 (n=11).

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. In Checkmate 205 and 039, encephalitis occurred in 0.8% (2/263) of patients after allogeneic HSCT after 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, iritis, 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. In Checkmate 205 and 039, hypersensitivity/infusion- related reactions occurred in 16% (42/263) of patients receiving OPDIVO: Grade 3 (n=2), Grade 2 (n=24), and Grade 1 (n=16).

Complications of Allogeneic HSCT after OPDIVO

Complications, including fatal events, occurred in patients who received allogeneic HSCT after OPDIVO. Outcomes were evaluated in 17 patients from Checkmate 205 and 039, who underwent allogeneic HSCT after discontinuing OPDIVO (15 with reduced-intensity conditioning, 2 with myeloablative conditioning). Thirty-five percent (6/17) of patients died from complications of allogeneic HSCT after OPDIVO. Five deaths occurred in the setting of severe or refractory GVHD. Grade 3 or higher acute GVHD was reported in 29% (5/17) of patients. Hyperacute GVHD was reported in 20% (n=2) of patients. A steroid-requiring febrile syndrome, without an identified infectious cause, was reported in 35% (n=6) of patients. Two cases of encephalitis were reported: Grade 3 (n=1) lymphocytic encephalitis without an identified infectious cause, and Grade 3 (n=1) suspected viral encephalitis. Hepatic veno-occlusive disease (VOD) occurred in one patient, who received reduced-intensity conditioned allogeneic SCT and died of GVHD and multi-organ failure. Other cases of hepatic VOD after reduced-intensity conditioned allogeneic HSCT have also been reported in patients with lymphoma who received a PD-1 receptor blocking antibody before transplantation. Cases of fatal hyperacute GVHD have also been reported. These complications may occur despite intervening therapy between PD-1 blockade and allogeneic HSCT.

Follow patients closely for early evidence of transplant-related complications such as hyperacute GVHD, severe (Grade 3 to 4) acute GVHD, steroid-requiring febrile syndrome, hepatic VOD, and other immune- mediated adverse reactions, and intervene promptly.

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. In Checkmate 205 and 039, among all patients (safety population [n=263]), adverse reactions leading to discontinuation (4.2%) or to dosing delays (23%) occurred. The most frequent serious adverse reactions reported in ≥1% of patients were infusion-related reaction, pneumonia, pleural effusion, pyrexia, rash and pneumonitis. Ten patients died from causes other than disease progression, including 6 who died from complications of allogeneic HSCT. Serious adverse reactions occurred in 21% of patients in the safety population (n=263) and 27% of patients in the subset of patients evaluated for efficacy (efficacy population [n=95]).

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 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%). 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%).

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%).

CHECKMATE Trials and Patient Populations

Checkmate 069 and 067 – advanced melanoma alone or in combination with YERVOY; Checkmate 037 and 066 – advanced melanoma; Checkmate 057 – non-squamous non-small cell lung cancer (NSCLC); Checkmate 025 – renal cell carcinoma; Checkmate 205/039 – classical Hodgkin lymphoma

On June 05, 2016 Adaptimmune Therapeutics plc (Nasdaq:ADAP), a leader in T-cell therapy to treat cancer, reported a poster presentation of updated data on its lead clinical program, an affinity enhanced SPEAR T-cell receptor therapy targeting the NY-ESO-1 cancer antigen, in patients with advanced tumors at the 2016 Annual American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Meeting (Press release, Adaptimmune, JUN 5, 2016, View Source;p=RssLanding&cat=news&id=2175118 [SID:1234512999]).

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Also being presented are an overview of cytokine release syndrome (CRS) in patients treated with NY-ESO SPEAR T-cells, and preclinical safety assessment of Adaptimmune’s next SPEAR T-cell therapy product directed at alpha fetoprotein (AFP); enrollment in a clinical trial of this AFP SPEAR T-cell therapy is expected to initiate later this year.

"Our goal is to develop our broad pipeline of targets and affinity enhanced SPEAR T-cells in an effort to develop a panel of TCR T-cell therapies to offer patients suffering from a wide variety of cancers the hope of a cure," said Dr. Rafael Amado, Adaptimmune’s Chief Medical Officer. "To that end, the clinical data described to date help clarify that our technology can be used to develop SPEAR T-cells against cancer targets that are capable of generating strong responses in the context of an acceptable benefit:risk profile. Further, we have developed and are utilizing a proprietary target validation and in vitro preclinical safety package that we believe can generate affinity enhanced TCRs against many cancers with reduced risk of safety events."

In the poster presentation entitled, "Genetically Engineered NY-ESO-1 Specific T-Cells in HLA-A:0201 positive Patients with Advanced Tumors," Crystal Mackall, M.D., Professor of Pediatrics and Medicine; Associate Director of the Stanford Cancer Institute, provided an update to the clinical experience of the NY-ESO SPEAR T-cell therapeutic in patients across cancer indications. The authors of the poster concluded:

NY-ESO SPEAR T-cells demonstrated robust clinical responses in solid and hematologic tumors, including a 50 percent (6/12) response rate in synovial sarcoma, and a 91 percent (20/22) response rate in multiple myeloma at day 100;
Preliminary data show responses to NY-ESO SPEAR T-cells in patients with low level of NY-ESO expression;
To date, no objective clinical responses have been reported in the initial patients enrolled in the ovarian cancer and melanoma cohorts. These melanoma and ovarian cancer patients were enrolled using different screening assays from those included in the synovial sarcoma and multiple myeloma studies, and did not include fludarabine in the preconditioning regimes. All patients in the melanoma study had failed prior check point inhibitor therapy. Both trials will continue to enroll patients using revised protocols with standardized NY-ESO screening and using optimized conditioning regimens. In addition, a new melanoma study protocol is being designed to incorporate standard checkpoint inhibitor therapy in combination with NY-ESO SPEAR T-cells;
NY-ESO SPEAR T-cells have been generally well tolerated with an acceptable benefit:risk profile in patients to date. The most common adverse events include rash, diarrhea, pyrexia, and fatigue. Grade 3/4 cytokine release syndrome was observed in four patients, which can be monitored and managed with supportive care measures;
NY-ESO SPEAR T-cells exhibited durable persistence without the requirement for IL-2 support in vivo, with cells detectable for up to three years. Additionally, NY-ESO-T cytotoxic function was detected over time without accumulation of multiple exhaustion markers. Poor persistence appears to correlate with a lack of clinical response and pre-conditioning with Cytoxan alone in the ovarian and melanoma studies.

In the poster presentation entitled, "Cytokine Release Syndrome (CRS) in patients treated with NY-ESO-1c259 SPEAR T cells," Crystal Mackall, M.D. presented a review of CRS including evaluation of concurrent AEs and reported symptoms, cytokine levels and CRP in patients treated with NY-ESO SPEAR T-cells:

Of 53 patients treated with NY-ESO SPEAR T-cells as of January 27, 2016, eight were diagnosed with CRS: One patient was diagnosed with Grade 1, three patients with Grade 2, three patients with Grade 3 and one patient with Grade 4;
Symptoms generally manifest in the first two weeks and have been effectively managed with supportive care measures. In these patients the onset of CRS coincided with T-cell expansion, and elevated IL-6 and IL-8 were observed during CRS;
According to the authors, while there are differences in the patient populations, the incidence of CRS with NY-ESO SPEAR T-cell therapy appears to be of lower frequency and severity than reported with CD19 CAR-T therapy.

In the poster presentation entitled, "Targeting alpha fetoprotein with SPEAR T-cells in hepatocellular carcinoma," Andrew Gerry, Ph.D., Adaptimmune’s Director of Preclinical Research, presented data describing the selection and screening of a SPEAR T-cell candidate targeting AFP:

Adaptimmune’s extensive preclinical safety package comprised of molecular mapping, human cell testing, and potency testing is capable of validating TCRs with enhanced affinity for target proteins, but without marked recognition of non-cancerous tissue or safety concerns that would preclude clinical development;
Target validation results indicated that AFP could be a very attractive target for HCC, with a potential therapeutic window for the TCR to recognize highly positive hepatocellular cancer tissue without marked recognition of non-cancerous tissue;
No safety concerns were identified for AFP SPEAR T-cell reactivity, and no off-target AFP T-cell responses of concern were observed against a variety of cell types from a variety of organ systems. Alloreactivity was detected in a subset of HLA subtypes, which will be included in the exclusion criteria of the clinical study.

Adaptimmune’s SPEAR T-cell candidates are novel cancer immunotherapies that have been engineered to target and destroy cancer cells by strengthening a patient’s natural T-cell response. T-cells are a type of white blood cell that play a central role in a person’s immune response. Adaptimmune’s goal is to harness the power of the T-cell and, through its multiple therapeutic candidate, significantly impact cancer treatment and clinical outcomes of patients with solid and hematologic cancers.

On June 4, 2016 Genus Oncology reported that it collaborates with leaders in leukemia research at Harvard’s Dana-Farber Cancer Institute and Beth Israel Deaconess Medical Center on an investigator-initiated Phase 1b/2a trial of GO-203 in combination with Decitabine for the treatment of patients with relapsed/refractory AML (Press release, Genus Oncology, JUN 4, 2016, View Source [SID:SID1234515226]).

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On June 4, 2016 Merck (NYSE: MRK), known as MSD outside the United States and Canada, reported new data, including updated response rates, progression-free survival (PFS) and overall survival (OS) with KEYTRUDA (pembrolizumab), the company’s anti-PD-1 therapy, as a monotherapy in patients with advanced non-small cell lung cancer (NSCLC) whose tumors express PD-L1 from two studies: KEYNOTE-010 and KEYNOTE-001 (Press release, Merck & Co, JUN 4, 2016, View Source [SID:1234513113]). The findings are being presented at the 52nd Annual Meeting of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) in Chicago (Abstracts #9015 and #9026).

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A sub-analysis from the phase 2/3 KEYNOTE-010 trial includes OS data with KEYTRUDA compared to chemotherapy in previously treated patients with advanced NSCLC based on varying levels of PD-L1 expression; other data from KEYNOTE-010 are currently under review by the U.S. Food and Drug Administration (FDA) and are intended to serve as the basis for the full approval of KEYTRUDA in lung cancer in patients whose tumors express PD-L1. Additionally, updated findings from the phase 1b KEYNOTE-001 trial, the study that supported the accelerated approval of KEYTRUDA in NSCLC, include overall response rate (ORR), PFS, safety and two-year survival data.

"We are particularly excited by the results we are seeing with KEYTRUDA in lung cancer from both studies including longer term follow-up data in KEYNOTE-001 that continues to demonstrate durable responses in treatment-naïve and treatment-experienced patients," said Dr. Roger Dansey, senior vice president and therapeutic area head, oncology late-stage development, Merck Research Laboratories. "The KEYNOTE-010 data show that there is a correlation between increased levels of PD-L1 expression and improved benefit, which further underscores the importance of understanding a patient’s PD-L1 expression when determining a specific treatment plan."

Merck has a robust clinical development program for KEYTRUDA (pembrolizumab) in lung cancer, with five registration-enabling studies currently underway. The KEYTRUDA clinical development program includes more than 30 tumor types in more than 270 clinical trials, including more than 100 trials that combine KEYTRUDA with other cancer treatments.

Findings from KEYNOTE-010 (Abstract #9015)

KEYNOTE-010 is a global, open-label, randomized, pivotal phase 2/3 study evaluating KEYTRUDA (2 mg/kg or 10 mg/kg every three weeks) compared to standard of care chemotherapy (docetaxel, 75 mg/m2 every three weeks) in patients with previously treated advanced NSCLC. The primary endpoints were OS and PFS and were assessed based on patients whose tumors express high levels of PD-L1 (greater than or equal to 50 percent) and in patients with any level of PD-L1 expression (greater than or equal to one percent) – as reflected by tumor proportion scores (TPS). KEYNOTE-010 is the first study of its kind to evaluate the potential of an immunotherapy compared to chemotherapy based on prospective measurement of PD-L1 expression in patients with advanced NSCLC. As previously announced, the study met its primary objective showing that KEYTRUDA significantly improved OS compared to chemotherapy in patients with any level of PD-L1 expression. Findings were similar in patients who received the FDA-approved dose of KEYTRUDA (2 mg/kg every three weeks) and the investigational dose of KEYTRUDA (10 mg/kg every three weeks). These findings also served as the basis for the KEYTRUDA application currently under review by the FDA.

Findings from abstract #9015 were based on a sub-analysis of patient outcomes across four PD-L1 expression categories as determined by TPS (one to 24 percent; 25 to 49 percent; 50 to 74 percent; and greater than or equal to 75 percent) (n=1,033). Results showed that the OS, PFS, and overall response rate (ORR) generally increased with increasing levels of PD-L1 expression in those patients treated with KEYTRUDA, but not chemotherapy (docetaxel) – with the longest OS and PFS and highest ORR observed in patients who were in the highest PD-L1 TPS category.

In patients treated with KEYTRUDA (pembrolizumab), median OS was 16.6 months in patients in the highest PD-L1 TPS category (95% CI, 11.2-NR) and 9.7 months in patients in the lowest PD-L1 TPS category (95% CI, 8.9-11.6); median PFS was 6.2 months in patients in the highest PD-L1 TPS category (95% CI, 4.2-8.2) and 2.6 months in the lowest PD-L1 TPS category (95% CI, 2.1-3.4); ORR was 33.7 percent in patients in the highest PD-L1 TPS category and 8.6 percent in the lowest PD-L1 TPS category.

In patients treated with chemotherapy, median OS was 8.2 months in patients in the highest PD-L1 TPS category (95% CI, 5.8-10.9) and 8.5 months in patients in the lowest PD-L1 TPS category (95% CI, 7.5-9.9); median PFS was 4.0 months in patients in the highest PD-L1 TPS category (95% CI, 2.2-4.5) and 4.0 months in the lowest PD-L1 TPS category (95% CI, 2.3-5.5); ORR was 7.0 percent in patients in the highest PD-L1 TPS category and 10.9 percent in the lowest PD-L1 TPS category.

The safety profile of KEYTRUDA was consistent with that observed in previously reported studies of KEYTRUDA.

On June 4, these data will be presented in a poster session from 8:00 – 11:30 a.m. CDT (Location: Hall A) and in a poster discussion from 3:00 – 4:15 p.m. CDT (Location: E354b).

Findings from KEYNOTE-001 (Abstract #9026)

KEYNOTE-001 is a multicenter, open-label, multi-cohort, activity-estimating phase 1b trial evaluating KEYTRUDA (2 mg/kg every three weeks or 10 mg/kg every two or three weeks) in various advanced cancers, including lung cancer. The lung cancer cohort included treatment-naïve and previously treated patients with advanced NSCLC. The primary efficacy outcome measure was confirmed ORR as assessed by blinded independent central review using RECIST v1.1. Tumor response was assessed every nine weeks. The secondary outcome measures included PFS, OS, and duration of response. Findings from this study supported the accelerated approval of KEYTRUDA in previously treated NSCLC based on ORR and safety data.

Primary outcome measures observed in treatment-naïve patients (n=101) showed ORR of 58.3 percent (TPS greater than or equal to 50 percent), 17.4 percent (TPS of one to 49 percent), and 10.0 percent (TPS of less than one percent); and ORR in previously treated patients (n=449) of 38.3 percent (TPS greater than or equal to 50 percent), 12.9 percent (TPS of one to 49 percent), and 9.9 percent (TPS of less than one percent). Data at ASCO (Free ASCO Whitepaper) also assessed secondary outcome measures, including OS. In treatment-naïve patients, results showed a median OS of 22.1 months (95% CI, 16.8-27.2) with an 18-month OS rate of 58.1 percent and a 24-month OS rate of 44.5 percent. In previously treated patients, results showed a median OS of 10.6 months (95% CI, 8.6-13.3) with an 18-month OS rate of 36.6 percent and a 24-month OS rate of 30.4 percent.

Outcomes were further assessed based on three PD-L1 TPS categories (greater than or equal to 50 percent; one to 49 percent; and less than one percent). Results of this analysis showed that while a benefit was observed across all PD-L1 categories, the greatest benefit was observed in treatment-naïve patients with higher levels of PD-L1 expression (greater than or equal to 50 percent of cells expressing PD-L1). In this group, the 18-month OS rate was 72.7 percent and the 24-month OS rate was 60.6 percent; the median OS had not been reached at the time of analysis.

The safety profile of KEYTRUDA (pembrolizumab) was consistent with that observed in previously reported KEYTRUDA studies. Immune-mediated adverse events of Grade 3-5 were hypothyroidism, pneumonitis, hyperthyroidism, severe skin toxicities, colitis, adrenal insufficiency, and hypophysitis. There were two treatment-related deaths (one case each of interstitial lung disease and cardiopulmonary arrest).

These data will be presented in a poster session on June 4, 8:00 – 11:30 a.m. CDT (Location: Hall A).

About KEYTRUDA (pembrolizumab) Injection 100 mg

KEYTRUDA is a humanized monoclonal antibody that works by increasing the ability of the body’s immune system to help detect and fight tumor cells. KEYTRUDA blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, thereby activating T lymphocytes which may affect both tumor cells and healthy cells.

KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic melanoma.

KEYTRUDA is also indicated for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors express PD-L1 as determined by an FDA-approved test with disease progression on or after platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving KEYTRUDA. This indication is approved under accelerated approval based on tumor response rate and durability of response. An improvement in survival or disease-related symptoms has not yet been established. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

KEYTRUDA (pembrolizumab) is administered at a dose of 2 mg/kg as an intravenous infusion over 30 minutes every three weeks for the approved indications.

Selected Important Safety Information for KEYTRUDA (pembrolizumab)

Immune-mediated pneumonitis occurred in 19 (3.5%) of 550 patients, including Grade 2 (1.1%), 3 (1.3%), 4 (0.4%), or 5 (0.2%) pneumonitis and occurred more frequently in patients with a history of asthma/chronic obstructive pulmonary disease (5.4%) or prior thoracic radiation (6.0%). Monitor patients for signs and symptoms of pneumonitis. Evaluate suspected pneumonitis with radiographic imaging. Administer corticosteroids for Grade 2 or greater pneumonitis. Withhold KEYTRUDA for Grade 2; permanently discontinue KEYTRUDA for Grade 3 or 4 or recurrent Grade 2 pneumonitis.

Immune-mediated colitis occurred in 4 (0.7%) of 550 patients, including Grade 2 (0.2%) or 3 (0.4%) colitis. Monitor patients for signs and symptoms of colitis. Administer corticosteroids for Grade 2 or greater colitis. Withhold KEYTRUDA for Grade 2 or 3; permanently discontinue KEYTRUDA for Grade 4 colitis.

Immune-mediated hepatitis occurred in patients receiving KEYTRUDA. Monitor patients for changes in liver function. Administer corticosteroids for Grade 2 or greater hepatitis and, based on severity of liver enzyme elevations, withhold or discontinue KEYTRUDA.

Hypophysitis occurred in 1 (0.2%) of 550 patients, which was Grade 3 in severity. Monitor patients for signs and symptoms of hypophysitis (including hypopituitarism and adrenal insufficiency). Administer corticosteroids and hormone replacement as clinically indicated. Withhold KEYTRUDA for Grade 2; withhold or discontinue for Grade 3 or 4 hypophysitis.

Hyperthyroidism occurred in 10 (1.8%) of 550 patients, including Grade 2 (0.7%) or 3 (0.3%) hyperthyroidism. Hypothyroidism occurred in 38 (6.9%) of 550 patients, including Grade 2 (5.5%) or 3 (0.2%) hypothyroidism. Thyroid disorders can occur at any time during treatment. Monitor patients for changes in thyroid function (at the start of treatment, periodically during treatment, and as indicated based on clinical evaluation) and for clinical signs and symptoms of thyroid disorders. Administer replacement hormones for hypothyroidism and manage hyperthyroidism with thionamides and beta-blockers as appropriate. Withhold or discontinue KEYTRUDA for Grade 3 or 4 hyperthyroidism.

Type 1 diabetes mellitus, including diabetic ketoacidosis, occurred in 3 (0.1%) of 2117 patients. Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Administer insulin for type 1 diabetes, and withhold KEYTRUDA and administer anti-hyperglycemics in patients with severe hyperglycemia.

Immune-mediated nephritis occurred in patients receiving KEYTRUDA (pembrolizumab). Monitor patients for changes in renal function. Administer corticosteroids for Grade 2 or greater nephritis. Withhold KEYTRUDA for Grade 2; permanently discontinue KEYTRUDA for Grade 3 or 4 nephritis.

Other clinically important immune-mediated adverse reactions can occur. For suspected immune-mediated adverse reactions, ensure adequate evaluation to confirm etiology or exclude other causes. Based on the severity of the adverse reaction, withhold KEYTRUDA and administer corticosteroids. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Based on limited data from clinical studies in patients whose immune-related adverse reactions could not be controlled with corticosteroid use, administration of other systemic immunosuppressants can be considered. Resume KEYTRUDA when the adverse reaction remains at Grade 1 or less following corticosteroid taper. Permanently discontinue KEYTRUDA for any Grade 3 immune-mediated adverse reaction that recurs and for any life-threatening immune-mediated adverse reaction.

The following clinically significant, immune-mediated adverse reactions occurred in less than 1% of 550 patients: rash, vasculitis, hemolytic anemia, serum sickness, and myasthenia gravis.

Severe and life-threatening infusion-related reactions have been reported in 3 (0.1%) of 2117 patients. Monitor patients for signs and symptoms of infusion-related reactions including rigors, chills, wheezing, pruritus, flushing, rash, hypotension, hypoxemia, and fever. For Grade 3 or 4 reactions, stop infusion and permanently discontinue KEYTRUDA.

Based on its mechanism of action, KEYTRUDA can cause fetal harm when administered to a pregnant woman. If used during pregnancy, or if the patient becomes pregnant during treatment, apprise the patient of the potential hazard to a fetus. Advise females of reproductive potential to use highly effective contraception during treatment and for 4 months after the last dose of KEYTRUDA.

KEYTRUDA was discontinued due to adverse reactions in 14% of 550 patients. Serious adverse reactions occurred in 38% of patients. The most frequent serious adverse reactions reported in at least 2% of patients were pleural effusion, pneumonia, dyspnea, pulmonary embolism, and pneumonitis. The most common adverse reactions (reported in at least 20% of patients) were fatigue (44%), cough (29%), decreased appetite (25%), and dyspnea (23%).

No formal pharmacokinetic drug interaction studies have been conducted with KEYTRUDA.

It is not known whether KEYTRUDA (pembrolizumab) is excreted in human milk. Because many drugs are excreted in human milk, instruct women to discontinue nursing during treatment with KEYTRUDA and for 4 months after the final dose.

Safety and effectiveness of KEYTRUDA have not been established in pediatric patients.

Our Focus on Cancer

Our goal is to translate breakthrough science into innovative oncology medicines to help people with cancer worldwide. At Merck Oncology, helping people fight cancer is our passion and supporting accessibility to our cancer medicines is our commitment. Our focus is on pursuing research in immuno-oncology and we are accelerating every step in the journey – from lab to clinic – to potentially bring new hope to people with cancer.

As part of our focus on cancer, Merck is committed to exploring the potential of immuno-oncology with one of the fastest-growing development programs in the industry. We are currently executing an expansive research program that includes more than 270 clinical trials evaluating our anti-PD-1 therapy across more than 30 tumor types. We also continue to strengthen our immuno-oncology portfolio through strategic acquisitions and are prioritizing the development of several promising immunotherapeutic candidates with the potential to improve the treatment of advanced cancers.

For more information about our oncology clinical trials, visit www.merck.com/clinicaltrials.

On June 04, 2016 TESARO, Inc. (NASDAQ:TSRO), an oncology-focused biopharmaceutical company, reported an update on its clinical development pipeline during an investor briefing and webcast held in conjunction with the American Society for Clinical Oncology (ASCO) (Free ASCO Whitepaper) 2016 annual meeting (Press release, TESARO, JUN 4, 2016, View Source [SID:1234513083]).

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During the investor briefing, TESARO announced that the U.S. Food and Drug Administration (FDA) has accepted for review the New Drug Application (NDA) for an intravenous (IV) formulation of rolapitant. The FDA has set a target action date under the Prescription Drug User Fee Act (PDUFA) of January 11, 2017. The NDA for rolapitant IV is supported by data from a clinical program of approximately 350 subjects, and included a bioequivalence study and several other supportive non-clinical and clinical studies.

TESARO also provided an update on its Phase 3 NOVA trial of niraparib in patients with ovarian cancer. A sufficient number of progression free survival (PFS) events has been reached to trigger data analysis for both cohorts. Data cleaning is underway in preparation for database lock and release of top-line results. Finally, TESARO announced FDA clearance of its Investigational New Drug (IND) application for TSR-022, its anti-TIM-3 antibody candidate. A Phase 1 study for TSR-022 is planned to begin in mid-2016.

"We continue to make significant progress with our pipeline of oncology product candidates. The acceptance of the rolapitant IV NDA and clearance of TSR-022 IND are important milestones for TESARO and demonstrate our commitment to advancing new therapeutic options for patients," said Mary Lynne Hedley, Ph.D., President and COO of TESARO. "Our NOVA study results will be the first data from a prospectively designed, randomized, Phase 3 trial of a PARP inhibitor, and we look forward to sharing these data later this quarter."

About Intravenous Rolapitant
Rolapitant IV is a potent and selective NK-1 receptor antagonist with an extended plasma half-life that is being developed for the prevention of chemotherapy-induced nausea and vomiting (CINV). NK-1 receptors are highly concentrated in the brain and bind the neurokinin substance P. Activation of NK-1 receptors plays a central role in nausea and vomiting induced by emetogenic stimuli, including certain cancer chemotherapies. NK-1 receptor antagonists have been demonstrated to improve the management of nausea and vomiting experienced by cancer patients undergoing emetogenic chemotherapy. TESARO licensed exclusive rights for the development, manufacture, commercialization, and distribution of rolapitant from OPKO Health, Inc.

About Niraparib
Niraparib is a potent, oral PARP inhibitor that is currently being evaluated in four ongoing pivotal trials. TESARO is building a robust niraparib franchise by assessing activity across multiple tumor types and by evaluating several potential combinations of niraparib with other therapeutics. The ongoing monotherapy development program for niraparib includes a Phase 3 trial in patients with ovarian cancer (the NOVA trial), a registrational Phase 2 treatment trial in patients with ovarian cancer (the QUADRA trial), a Phase 3 trial for the treatment of patients with BRCA-positive breast cancer (the BRAVO trial), and a Phase 3 trial in patients with first-line ovarian cancer (the PRIMA trial). Several combination studies are also underway, including trials of niraparib plus pembrolizumab, bevacizumab, and temozolomide.

About TSR-022

TSR-022 is a monoclonal antibody candidate targeting TIM-3 and was developed as part of a collaboration between TESARO and AnaptysBio, Inc. This collaboration was initiated in March of 2014, and is focused on the development of monospecific antibody drug candidates targeting PD-1 (TSR-042), TIM-3 (TSR-022), and LAG-3 (TSR-033), and bi-specific antibody drug candidates targeting PD-1/TIM-3 and PD-1/LAG-3, in addition to a novel bi-specific antibody candidate designed to target undisclosed targets.