Europese Commissie keurt Opdivo (nivolumab) van Bristol-Myers Squibb goed voor eerder behandeld, lokaal gevorderd niet-reseceerbaar of gemetastaseerd urotheliaal carcinoom bij volwassenen na falen van een behandeling op basis van platines

02/06/17

 Opdivo is het eerste en enige immuno-oncologische middel dat Europese goedkeuring krijgt voor de behandeling van dit type blaaskanker

Nu is Opdivo goedgekeurd in de Europese Unie voor acht indicaties in zes verschillende tumortypes

    (PRINCETON, NJ, 2 juni 2017) – Bristol-Myers Squibb Company (NYSE: BMY) kondigde vandaag aan dat de Europese Commissie (EC) Opdivo (nivolumab) heeft goedgekeurd voor de behandeling van lokaal gevorderd niet-reseceerbaar of gemetastaseerd urotheliaal carcinoom (metastatic urothelial carcinoma, mUC) bij volwassenen na falen van een behandeling op basis van platines. Door deze beslissing is Opdivo het eerste en enige immuno-oncologische middel dat in de Europese Unie is goedgekeurd voor de behandeling van patiënten met dit vaak voorkomende type van blaaskanker.

    “Naar schatting worden er in Europa jaarlijks 151.000 nieuwe gevallen van blaaskanker vastgesteld, maar toch is er in de afgelopen decennia weinig vooruitgang geboekt in de behandeling van gevorderde blaaskanker,” aldus Prof. Dr. med. Margitta Retz, senior arts, hoofd Urologische Oncologie aan de Urological Clinic and Polyclinic, Technical University te Munchen. “De goedkeuring van nivolumab door de Europese Commissie is een aanzienlijke sprong vooruit, met een opvallend objectief responspercentage, en biedt een belangrijke optie om patiënten met eerder behandelde, lokaal gevorderde niet-reseceerbare of gemetastaseerde urotheliale kanker te helpen.”

    De goedkeuring was gebaseerd op resultaten van CheckMate -275, een open-label, multicentrisch fase 2-onderzoek met één onderzoeksarm dat Opdivo evalueerde bij patiënten met lokaal gevorderd of mUC die ziekteprogressie vertoonden tijdens of na behandeling met platinumhoudende chemotherapie of die ziekteprogressie vertoonden in de 12 maanden van neoadjuvante of adjuvante behandeling met platinumhoudende chemotherapie. In deze studie kregen 270 patiënten Opdivo 3 mg/kg om de twee weken intraveneus toegediend totdat ziekteprogressie of onaanvaardbare toxiciteit optrad. Het primaire eindpunt van het onderzoek was het objectieve responspercentage (objective response rate, ORR). De secundaire eindpunten waren de progressievrije overleving (progression-free survival, PFS) en de totale overleving (overall survival, OS). In het onderzoek reageerde 20,0% (95% BI: 15,4-25,3; 54/270) van de patiënten op behandeling met Opdivo. Het percentage patiënten dat een complete respons vertoonde bedroeg 3,0% (8/270) en het percentage patiënten met een partiële respons bedroeg 17% (46/270).

    “Wij zijn verheugd dat de Europese Commissie Opdivo heeft goedgekeurd voor patiënten met eerder behandeld, lokaal gevorderd niet-reseceerbaar of gemetastaseerd urotheliaal carcinoom, want velen van hen hebben nood aan een bijkomende behandelingsoptie,” aldus Murdo Gordon, executive vice president en chief commercial officer van Bristol-Myers Squibb. “Deze tweede goedkeuring van Opdivo binnen de EU in twee maanden toont aan dat Bristol-Myers Squibb zich inzet om aan onbeantwoorde behoeften van kankerpatiënten te voldoen. Wij willen nauw met de Europese gezondheidsautoriteiten samenwerken zodat Opdivo zo snel mogelijk beschikbaar wordt voor patiënten met deze vaak voorkomende vorm van blaaskanker.”

    De helft van de totale patiëntenpopulatie (46%) in CheckMate -275 had een tumor PD-L1 expressie van minstens 1% en het middel was werkzaam bij proefpersonen met of zonder tumor PD-L1 expressie. Het responspercentage was 25% bij patiënten met een tumor PD-L1 expressie ≥1% (95% BI: 17,7-33,6) en 15,8% (95% BI: 10,3-22,7) bij patiënten met een tumor PD-L1 expressie <1%. Bij alle behandelde patiënten bedroeg de mediane PFS 2,0 maanden, was de OS na 12 maanden gelijk aan 41% (95% BI: 34,8-47,1) en bedroeg de mediane OS 8,6 maanden (95% BI: 6,1-11,3).

    Van de 270 patiënten die Opdivo kregen in CheckMate -275, trad bij 17,8% een graad 3 of 4 behandelingsgerelateerde bijwerking op (adverse event, AE). De vaakst gemelde behandelingsgerelateerde bijwerking van eender welke graad waren vermoeidheid (16,7%), jeuk (9,3%), diarree (8,9%), verminderde eetlust (8,1%), hypothyreoïdie (7,8%), misselijkheid (7,0%), asthenie (5,9%), huiduitslag (5,9%) en koorts (5,6%). De meest frequente voorkomende behandelingsgerelateerde bijwerkingen van graad 3 of 4 waren vermoeidheid (1,9%), diarree (1,9%), asthenie (1,5%) en huiduitslag (1,1%). Algemeen genomen, stopte 4,8% van de patiënten met de behandeling wegens behandelingsgerelateerde bijwerkingen van eender welke graad, en 3,0% stopte met de behandeling wegens behandelingsgerelateerde bijwerkingen van graad 3 of 4. Behandelingsgerelateerd overlijden trad op bij vier patiënten als gevolg van pneumonitis of cardiovasculair falen.

Over blaaskanker

Blaaskanker, die gewoonlijk ontstaat in de cellen die de binnenkant van de blaas bekleden, is de vijfde meest vastgestelde kanker in Europa. Naar schatting worden er elk jaar 151.000 nieuwe gevallen vastgesteld en zijn er meer dan 52.000 sterfgevallen. Urotheliaal carcinoom is het meest voorkomend type blaaskanker en vertegenwoordigt ongeveer 90% van de gevallen. De meeste gevallen van blaaskanker worden in een vroeg stadium vastgesteld, maar het recidiefpercentage en progressiepercentage zijn hoog en ongeveer 78% van de patiënten zal binnen de vijf jaar recidiveren. De overlevingspercentages hangen af van het stadium, de type kanker en het moment van diagnose. Voor blaaskanker van stadium IV bedraagt het overlevingspercentage na vijf jaar 15%.

Over Opdivo

Opdivo is een “programmed death-1 (PD-1) immune checkpoint inhibitor” (remmer van de geprogrammeerde celdood-1-receptor) die ontwikkeld is om het eigen immuunsysteem op unieke wijze te wapenen teneinde de anti-tumor immuunrespons te helpen herstellen. Doordat Opdivo het eigen immuunsysteem wapent om kanker te bestrijden, vormt het een belangrijke behandelingsoptie voor meerdere kankertypes.

Het toonaangevende globale ontwikkelingsprogramma voor Opdivo is gebaseerd op de wetenschappelijke expertise van Bristol-Myers Squibb inzake immuno-oncologie en bestaat uit een brede waaier van klinische onderzoeken in alle fasen, waaronder fase 3, bij allerhande tumortypes. Tot dusver hebben meer dan 25.000 patiënten aan het klinische ontwikkelingsprogramma voor Opdivo deelgenomen. De onderzoeken met Opdivo hebben bijgedragen tot een beter inzicht in de mogelijke rol van biomerkers bij patiëntenzorg, vooral wat betreft de manier waarop zij voordeel uit Opdivo kunnen halen tijdens de volledige expressie van PD-L1.

In juli 2014 was Opdivo de eerste PD-1 immune checkpoint inhibitor die door regelgevende instanties wereldwijd werd goedgekeurd. Nu is Opdivo goedgekeurd in meer dan 60 landen, waaronder de Verenigde Staten, de Europese Unie en Japan. In oktober 2015 hebben regelgevende instanties de combinatietherapie Opdivo en Yervoy van het bedrijf als eerste immuno-oncologische combinatie goedgekeurd voor de behandeling van gemetastaseerde melanomen. Momenteel is ze goedgekeurd in meer dan 50 landen, waaronder de Verenigde Staten en de Europese Unie.

DOOR DE AMERIKAANSE FDA GOEDGEKEURDE INDICATIES VOOR OPDIVO®

OPDIVO® (nivolumab) als monotherapie is geïndiceerd voor de behandeling van patiënten met een niet- reseceerbaar of gemetastaseerd melanoom met een BRAF V600 mutatie. Deze indicatie is goedgekeurd volgens een versnelde goedkeuringsprocedure op basis van de progressievrije overleving. Een definitieve goedkeuring voor deze indicatie is mogelijk na verificatie en beschrijving van het klinisch voordeel in de bevestigende onderzoeken.

OPDIVO® (nivolumab) als monotherapie is geïndiceerd voor de behandeling van patiënten met een niet- reseceerbaar of gemetastaseerd melanoom met het BRAF V600 wild type.

OPDIVO® (nivolumab), in combinatie met YERVOY® (ipilimumab), is geïndiceerd voor de behandeling van patiënten met een niet-reseceerbaar of gemetastaseerd melanoom. Deze indicatie is goedgekeurd volgens een versnelde goedkeuringsprocedure op basis van de progressievrije overleving. Een definitieve goedkeuring voor deze indicatie is mogelijk na verificatie en beschrijving van het klinisch voordeel in de bevestigende onderzoeken.

OPDIVO® (nivolumab) is geïndiceerd voor de behandeling van patiënten met gemetastaseerd niet- kleincellig longcarcinoom (non-small cell lung cancer, NSCLC) die tijdens of na platinumhoudende chemotherapie progressie vertonen. Patiënten met EGFR of ALK genomische tumorafwijkingen moeten voorafgaand aan de toediening van OPDIVO ziekteprogressie vertonen tijdens een door de FDA goedgekeurde behandeling voor deze afwijkingen.

OPDIVO® (nivolumab) is geïndiceerd voor de behandeling van patiënten met gevorderd niercelcarcinoom (renal cell carcinoma, RCC) die voordien anti-angiogene therapie hebben gekregen.

OPDIVO® (nivolumab) is geïndiceerd voor de behandeling van patiënten met klassiek Hodgkin lymfoom (classical Hodgkin lymphoma, cHL) dat recidiveert of progressie vertoont na autologe hematopoëtische stamceltransplantatie (HSCT) en behandeling met brentuximab vedotin na de transplantatie. Deze indicatie is goedgekeurd volgens een versnelde goedkeuringsprocedure op basis van het totale responspercentage. Een definitieve goedkeuring voor deze indicatie is mogelijk na verificatie en beschrijving van het klinisch voordeel in de bevestigende onderzoeken.

OPDIVO® (nivolumab) geïndiceerd voor de behandeling van patiënten met recidiverend of gemetastaseerd plaveiselcelcarcinoom van het hoofd-halsgebied (squamous cell carcinoma of the head and neck, SCCHN) die tijdens of na platinumhoudende therapie progressie vertonen.

OPDIVO® (nivolumab) is geïndiceerd voor de behandeling van patiënten met lokaal gevorderd of gemetastaseerd urotheliaal carcinoom die tijdens of na platinumhoudende chemotherapie of binnen de 12 maanden na neoadjuvante of adjuvante behandeling platinumhoudende chemotherapie progressie vertonen. Deze indicatie is goedgekeurd volgens een versnelde goedkeuringsprocedure op basis van het tumorresponspercentage en de duur van de respons. Een definitieve goedkeuring voor deze indicatie is mogelijk na verificatie en beschrijving van het klinisch voordeel in de bevestigende onderzoeken.

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

OPDIVO can cause immune-mediated pneumonitis. Fatal cases have been reported. Monitor patients for signs with radiographic imaging and for symptoms of pneumonitis. Administer corticosteroids for Grade 2 or more severe pneumonitis. Permanently discontinue for Grade 3 or 4 and withhold until resolution for Grade 2. In patients receiving OPDIVO monotherapy, fatal cases of immune-mediated pneumonitis have occurred. Immune-mediated pneumonitis occurred in 3.1% (61/1994) of patients. In patients receiving OPDIVO with YERVOY, immune-mediated pneumonitis occurred in 6% (25/407) of patients.

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

OPDIVO can cause immune-mediated colitis. Monitor patients for signs and symptoms of colitis. Administer corticosteroids for Grade 2 (of more than 5 days duration), 3, or 4 colitis. Withhold OPDIVO monotherapy for Grade 2 or 3 and permanently discontinue for Grade 4 or recurrent colitis upon re-initiation of OPDIVO. When administered with YERVOY, withhold OPDIVO and YERVOY for Grade 2 and permanently discontinue for Grade 3 or 4 or recurrent colitis. In patients receiving OPDIVO monotherapy, immune-mediated colitis occurred in 2.9% (58/1994) of patients. In patients receiving OPDIVO with YERVOY, immune-mediated colitis occurred in 26% (107/407) of patients including three fatal cases.

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

OPDIVO can cause immune-mediated hepatitis. 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 patients receiving OPDIVO monotherapy, immune-mediated hepatitis occurred in 1.8% (35/1994) of patients. In patients receiving OPDIVO with YERVOY, immune-mediated hepatitis occurred in 13% (51/407) of patients.

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 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

OPDIVO can cause immune-mediated hypophysitis, immune-mediated adrenal insufficiency, autoimmune thyroid disorders, and Type 1 diabetes mellitus. Monitor patients for signs and symptoms of hypophysitis, signs and symptoms of adrenal insufficiency, thyroid function prior to and periodically during treatment, and hyperglycemia. Administer hormone replacement as clinically indicated and 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. Withhold OPDIVO for Grade 3 and permanently discontinue for Grade 4 hyperglycemia.

In patients receiving OPDIVO monotherapy, hypophysitis occurred in 0.6% (12/1994) of patients. In patients receiving OPDIVO with YERVOY, hypophysitis occurred in 9% (36/407) of patients. In patients receiving OPDIVO monotherapy, adrenal insufficiency occurred in 1% (20/1994) of patients. In patients receiving OPDIVO with YERVOY, adrenal insufficiency occurred in 5% (21/407) of patients. In patients receiving OPDIVO monotherapy, hypothyroidism or thyroiditis resulting in hypothyroidism occurred in 9% (171/1994) of patients. Hyperthyroidism occurred in 2.7% (54/1994) of patients receiving OPDIVO monotherapy. In patients receiving OPDIVO with YERVOY, hypothyroidism or thyroiditis resulting in hypothyroidism occurred in 22% (89/407) of patients. Hyperthyroidism occurred in 8% (34/407) of patients receiving OPDIVO with YERVOY. In patients receiving OPDIVO monotherapy, diabetes occurred in 0.9% (17/1994) of patients. In patients receiving OPDIVO with YERVOY, diabetes occurred in 1.5% (6/407) of patients.

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

OPDIVO can cause immune-mediated nephritis. Monitor patients for elevated serum creatinine prior to and periodically during treatment. Administer corticosteroids for Grades 2-4 increased serum creatinine. Withhold OPDIVO for Grade 2 or 3 and permanently discontinue for Grade 4 increased serum creatinine. In patients receiving OPDIVO monotherapy, immune-mediated nephritis and renal dysfunction occurred in 1.2% (23/1994) of patients. In patients receiving OPDIVO with YERVOY, immune-mediated nephritis and renal dysfunction occurred in 2.2% (9/407) of patients.

Immune-Mediated Skin Adverse Reactions and Dermatitis
OPDIVO can cause immune-mediated rash, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), some cases with fatal outcome. Administer corticosteroids for Grade 3 or 4 rash. Withhold for Grade 3 and permanently discontinue for Grade 4 rash. For symptoms or signs of SJS or TEN, withhold OPDIVO and refer the patient for specialized care for assessment and treatment; if confirmed, permanently discontinue. In patients receiving OPDIVO monotherapy, immune-mediated rash occurred in 9% (171/1994) of patients. In patients receiving OPDIVO with YERVOY, immune- mediated rash occurred in 22.6% (92/407) of patients.

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 Encephalitis

OPDIVO can cause immune-mediated encephalitis. Evaluation of patients with neurologic symptoms may include, but not be limited to, consultation with a neurologist, brain MRI, and lumbar puncture. 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 patients receiving OPDIVO monotherapy, encephalitis occurred in 0.2% (3/1994) of patients. Fatal limbic encephalitis occurred in one patient after 7.2 months of exposure despite discontinuation of OPDIVO and administration of corticosteroids. Encephalitis occurred in one patient receiving OPDIVO with YERVOY (0.2%) after 1.7 months of exposure.

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. Across clinical trials of OPDIVO the following clinically significant immune-mediated adverse reactions occurred in <1.0% of patients receiving OPDIVO: uveitis, iritis, pancreatitis, facial and abducens nerve paresis, demyelination, polymyalgia rheumatica, autoimmune neuropathy, Guillain-Barré syndrome, hypopituitarism, systemic inflammatory response syndrome, gastritis, duodenitis, sarcoidosis, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), myositis, myocarditis, rhabdomyolysis, motor dysfunction, vasculitis, and myasthenic syndrome.

Infusion Reactions

OPDIVO can cause severe infusion reactions, which have been reported in <1.0% of patients in clinical trials. 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 patients receiving OPDIVO monotherapy, infusion-related reactions occurred in 6.4% (127/1994) of patients. In patients receiving OPDIVO with YERVOY, infusion-related reactions occurred in 2.5% (10/407) of patients.

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 HSCT 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 037, serious adverse reactions occurred in 41% of patients receiving OPDIVO (n=268). 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 (n=206). 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 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 (n=313) relative to the OPDIVO arm (n=313). 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 017 and 057, serious adverse reactions occurred in 46% of patients receiving OPDIVO (n=418). The most frequent serious adverse reactions reported in at least 2% of patients receiving OPDIVO were pneumonia, pulmonary embolism, dyspnea, pyrexia, pleural effusion, pneumonitis, and respiratory failure. In Checkmate 025, serious adverse reactions occurred in 47% of patients receiving OPDIVO (n=406). 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]). In Checkmate 141, serious adverse reactions occurred in 49% of patients receiving OPDIVO. The most frequent serious adverse reactions reported in at least 2% of patients receiving OPDIVO were pneumonia, dyspnea, respiratory failure, respiratory tract infections, and sepsis. In Checkmate 275, serious adverse reactions occurred in 54% of patients receiving OPDIVO (n=270). The most frequent serious adverse reactions reported in at least 2% of patients receiving OPDIVO were urinary tract infection, sepsis, diarrhea, small intestine obstruction, and general physical health deterioration.

Common Adverse Reactions

In Checkmate 037, the most common adverse reaction (≥20%) reported with OPDIVO (n=268) was rash (21%). In Checkmate 066, the most common adverse reactions (≥20%) reported with OPDIVO (n=206) vs dacarbazine (n=205) were fatigue (49% vs 39%), musculoskeletal pain (32% vs 25%), rash (28% vs 12%), and pruritus (23% vs 12%). In Checkmate 067, the most common (≥20%) adverse reactions in the OPDIVO plus YERVOY arm (n=313) 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 (n=313) arm were fatigue (53%), rash (40%), diarrhea (31%), and nausea (28%). In Checkmate 017 and 057, the most common adverse reactions (≥20%) in patients receiving OPDIVO (n=418) were fatigue, musculoskeletal pain, cough, dyspnea, and decreased appetite. In Checkmate 025, the most common adverse reactions (≥20%) reported in patients receiving OPDIVO (n=406) vs everolimus (n=397) 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 (≥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 Checkmate 141, the most common adverse reactions (≥10%) in patients receiving OPDIVO were cough and dyspnea at a higher incidence than investigator’s choice. In Checkmate 275, the most common adverse reactions (≥ 20%) reported in patients receiving OPDIVO (n=270) were fatigue (46%), musculoskeletal pain (30%), nausea (22%), and decreased appetite (22%).

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 067 - advanced melanoma alone or in combinationwith YERVOY; Checkmate 037 and 066 - advanced melanoma; Checkmate 017 - squamous non-small cell lung cancer (NSCLC); Checkmate 057 - non-squamous NSCLC; Checkmate 025 - renal cell carcinoma; Checkmate 205/039 - classical Hodgkin lymphoma; Checkmate 141 – squamous cell carcinoma of the head and neck; Checkmate 275 - urothelial carcinoma.

Please see U.S. Full Prescribing Information for OPDIVO and YERVOY, including Boxed WARNING regarding immune-mediated adverse reactions for YERVOY.

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.

Bristol-Myers Squibb Forward-Looking Statement

This press release contains "forward-looking statements" as that term is defined in the Private Securities Litigation Reform Act of 1995 regarding the research, development and commercialization of pharmaceutical products. Such forward-looking statements are based on current expectations and involve inherent risks and uncertainties, including factors that could delay, divert or change any of them, and could cause actual outcomes and results to differ materially from current expectations. No forward-looking statement can be guaranteed. Forward-looking statements in this press release should be evaluated together with the many uncertainties that affect Bristol-Myers Squibb's business, particularly those identified in the cautionary factors discussion in Bristol-Myers Squibb's Annual Report on Form 10-K for the year ended December 31, 2016 in our Quarterly Reports on Form 10-Q and our Current Reports on Form 8-K. Bristol-Myers Squibb undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events or otherwise.

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Contacts

Media:
Audrey Abernathy, 919-605-4521
audrey.abernathy@bms.com

Investors:
Tim Power, 609-252-7509
timothy.power@bms.com


Bill Szablewski, 609-252-5894
william.szablewski@bms.com