FDA action removes partial hold on CheckMate -602, the last of holds pre­vi­ously placed on three Opdivo-based com­bi­na­tion trials in re­lapsed or refractory multiple myeloma

Princeton, NJ (Press Release) – Bristol-Myers Squibb Company (NYSE: BMY) today announced that the U.S. Food and Drug Admin­istra­tion (FDA) lifted a partial clin­i­cal hold placed on CA209-602 (CheckMate -602), a ran­domized, open-label Phase 3 study eval­u­ating the addi­tion of Opdivo (nivolumab) to poma­lido­mide and dexa­meth­a­sone in patients with re­lapsed or refractory multiple myeloma. The de­ci­sion follows consultation with the FDA and agree­ment on amendments to the study protocol.

Three trials eval­u­ating Opdivo-based com­bi­na­tions in re­lapsed or refractory multiple myeloma were placed on partial clin­i­cal hold in September 2017 as an FDA precaution fol­low­ing risks identified in trials studying another anti–PD-1 agent, pem­bro­lizu­mab, in patients with multiple myeloma. CheckMate -602 is the last of the three trials to have its partial clin­i­cal hold lifted fol­low­ing a similar FDA action announced in December 2017, when the agency lifted partial holds on CA209-039 (CheckMate -039) and CA204-142.

Bristol-Myers Squibb is committed to im­prov­ing out­comes for patients with multiple myeloma.

About Opdivo

Opdivo is a pro­grammed death-1 (PD-1) immune checkpoint inhibitor that is designed to uniquely harness the body’s own immune system to help restore anti-tumor immune response. By harnessing the body’s own immune system to fight cancer, Opdivo has become an im­por­tant treat­ment option across multiple cancers.

Opdivo’s leading global devel­op­ment pro­gram is based on Bristol-Myers Squibb’s scientific expertise in the field of Immuno-Oncology and in­cludes a broad range of clin­i­cal trials across all phases, in­­clud­ing Phase 3, in a variety of tumor types. To date, the Opdivo clin­i­cal devel­op­ment pro­gram has enrolled more than 25,000 patients. The Opdivo trials have con­trib­uted to gaining a deeper under­stand­ing of the poten­tial role of bio­­markers in patient care, particularly re­gard­ing how patients may benefit from Opdivo across the con­tin­uum of PD-L1 ex­pres­sion.

In July 2014, Opdivo was the first PD-1 immune checkpoint inhibitor to receive regu­la­tory approval any­where in the world. Opdivo is cur­rently approved in more than 60 countries, in­­clud­ing the United States, the European Union and Japan. In October 2015, the Company’s Opdivo and Yervoy com­bi­na­tion regi­men was the first Immuno-Oncology com­bi­na­tion to receive regu­la­tory approval for the treat­ment of metastatic mel­anoma and is cur­rently approved in more than 50 countries, in­­clud­ing the United States and 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 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 the con­firmatory trials.

OPDIVO® (nivolumab) as a single agent is indicated for the treat­ment of patients with BRAF V600 wild-type unresectable or metastatic mel­anoma.

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), in com­bi­na­tion with YERVOY® (ipilimumab), is indicated for the treat­ment of patients with intermediate or poor-risk, pre­vi­ously untreated ad­vanced renal cell carcinoma (RCC).

OPDIVO® (nivolumab) is indicated for the treat­ment of adult patients with classical Hodgkin lym­phoma (cHL) that has re­lapsed or progressed after au­tol­o­gous hema­to­poietic stem cell trans­plan­ta­tion (HSCT) and brentuximab vedotin or after 3 or more lines of systemic ther­apy that in­cludes au­tol­o­gous HSCT. 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.

OPDIVO® (nivolumab) is indicated for the treat­ment of patients with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) with disease pro­gres­sion on or after platinum-based ther­apy.

OPDIVO® (nivolumab) is indicated for the treat­ment of patients with locally ad­vanced or metastatic urothelial carcinoma who have disease pro­gres­sion during or fol­low­ing platinum-containing chemo­ther­apy or have disease pro­gres­sion within 12 months of neoadjuvant or adjuvant treat­ment with platinum-containing chemo­ther­apy. This indi­ca­tion is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indi­ca­tion may be contingent upon veri­fi­ca­tion and description of clin­i­cal benefit in con­firmatory trials.

OPDIVO® (nivolumab) is indicated for the treat­ment of adult and pediatric (12 years and older) patients with microsatellite instability high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer (CRC) that has progressed fol­low­ing treat­ment with a fluoropyrimidine, oxaliplatin, and irinotecan. This indi­ca­tion is approved under accelerated approval based on over­all response rate and duration of response. Continued approval for this indi­ca­tion may be contingent upon veri­fi­ca­tion and description of clin­i­cal benefit in con­firmatory trials.

OPDIVO® (nivolumab) is indicated for the treat­ment of patients with hepato­cellular carcinoma (HCC) who have been pre­vi­ously treated with sorafenib. This indi­ca­tion is approved under accelerated approval based on tumor response rate and durability of response. 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 adjuvant treat­ment of patients with mel­anoma with involvement of lymph nodes or metastatic disease who have undergone com­plete resection.

OPDIVO® (10 mg/mL) is an injection for in­tra­venous (IV) use.

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 1 mg/kg with YERVOY 3 mg/kg, immune-mediated pneu­mo­nitis occurred in 6% (25/407) of patients. In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, immune-mediated pneu­mo­nitis occurred in 4.4% (24/547) of patients.

In Checkmate 205 and 039, pneu­mo­nitis, in­­clud­ing interstitial lung disease, occurred in 6.0% (16/266) of patients receiving OPDIVO. Immune-mediated pneu­mo­nitis occurred in 4.9% (13/266) of patients receiving OPDIVO: Grade 3 (n=1) and Grade 2 (n=12).

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 1 mg/kg with YERVOY 3 mg/kg, immune-mediated colitis occurred in 26% (107/407) of patients in­­clud­ing three fatal cases. In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, immune-mediated colitis occurred in 10% (52/547) 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

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. For patients without HCC, withhold OPDIVO for Grade 2 and perma­nently dis­con­tinue OPDIVO for Grade 3 or 4. For patients with HCC, withhold OPDIVO and admin­ister corticosteroids if AST/ALT is within normal limits at base­line and in­­creases to >3 and up to 5 times the upper limit of normal (ULN), if AST/ALT is >1 and up to 3 times ULN at base­line and in­­creases to >5 and up to 10 times the ULN, and if AST/ALT is >3 and up to 5 times ULN at base­line and in­­creases to >8 and up to 10 times the ULN. Permanently dis­con­tinue OPDIVO and admin­ister corticosteroids if AST or ALT in­­creases to >10 times the ULN or total bilirubin in­­creases >3 times the ULN. In patients receiving OPDIVO mono­therapy, immune-mediated hepatitis occurred in 1.8% (35/1994) of patients. In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg, immune-mediated hepatitis occurred in 13% (51/407) of patients. In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, immune-mediated hepatitis occurred in 7% (38/547) of patients.

In Checkmate 040, immune-mediated hepatitis requiring systemic corticosteroids occurred in 5% (8/154) of patients receiving OPDIVO.

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 1 mg/kg with YERVOY 3 mg/kg, hypophysitis occurred in 9% (36/407) of patients. In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, hypophysitis occurred in 4.6% (25/547) of patients In patients receiving OPDIVO mono­therapy, adrenal insufficiency occurred in 1% (20/1994) of patients. In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg, adrenal insufficiency occurred in 5% (21/407) of patients. In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, adrenal insufficiency occurred in 7% (41/547) 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 1 mg/kg with YERVOY 3 mg/kg, hypo­thy­roid­ism or thyroiditis resulting in hypo­thy­roid­ism occurred in 22% (89/407) of patients. Hyperthyroidism occurred in 8% (34/407) of patients receiving this dose of OPDIVO with YERVOY. In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, hypo­thy­roid­ism or thyroiditis resulting in hypo­thy­roid­ism occurred in 22% (119/547) of patients. Hyperthyroidism occurred in 12% (66/547) of patients receiving this dose of OPDIVO with YERVOY. In patients receiving OPDIVO mono­therapy, diabetes occurred in 0.9% (17/1994) of patients. In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg, diabetes occurred in 1.5% (6/407) of patients. In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, diabetes occurred in 2.7% (15/547) 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 1 mg/kg with YERVOY 3 mg/kg, immune-mediated nephritis and renal dysfunction occurred in 2.2% (9/407) of patients. In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, immune-mediated nephritis and renal dysfunction occurred in 4.6% (25/547) 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 1 mg/kg with YERVOY 3 mg/kg, immune-mediated rash occurred in 22.6% (92/407) of patients. In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, immune-mediated rash occurred in 16.6% (91/547) 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 1 mg/kg with YERVOY 3 mg/kg (0.2%) after 1.7 months of exposure. Encephalitis occurred in one patient receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg (0.2%) after approx­i­mately 4 months of exposure.

Other Immune-Mediated Adverse Reactions

Based on the severity of the adverse reac­tion, perma­nently dis­con­tinue or withhold OPDIVO, admin­ister high-dose corticosteroids, and, if appro­pri­ate, ini­ti­ate hormone-replacement ther­apy. Across clin­i­cal trials of OPDIVO mono­therapy or in com­bi­na­tion with YERVOY, the fol­low­ing clin­i­cally sig­nif­i­cant immune-mediated adverse reac­tions, some with fatal out­come, occurred in <1.0% of patients receiving OPDIVO: myocarditis, rhabdomyolysis, myositis, 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), motor dysfunction, vasculitis, aplastic anemia, pericarditis, and myasthenic syn­drome.

If uveitis occurs in com­bi­na­tion with other immune-mediated adverse reac­tions, con­sider a Vogt-Koyanagi-Harada-like syn­drome, which has been observed in patients receiving OPDIVO and may require treat­ment with systemic steroids to reduce the risk of perma­nent vision loss.

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 as a 60-minute infusion, infusion-related reac­tions occurred in 6.4% (127/1994) of patients. In a separate study in which patients received OPDIVO mono­therapy as a 60-minute infusion or a 30-minute infusion, infusion-related reac­tions occurred in 2.2% (8/368) and 2.7% (10/369) of patients, re­spec­tive­ly. Additionally, 0.5% (2/368) and 1.4% (5/369) of patients, re­spec­tive­ly, ex­peri­enced adverse reac­tions within 48 hours of infusion that led to dose delay, perma­nent dis­con­tinu­a­tion or withholding of OPDIVO. In patients receiving OPDIVO 1 mg/kg with ipilimumab 3 mg/kg every 3 weeks, infusion-related reac­tions occurred in 2.5% (10/407) of patients. In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, infusion-related reac­tions occurred in 5.1% (28/547) 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 breastfeeding 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 214, serious adverse reac­tions occurred in 59% of patients receiving OPDIVO plus YERVOY and in 43% of patients receiving sunitinib. The most frequent serious adverse reac­tions reported in at least 2% of patients were diarrhea, pyrexia, pneu­monia, pneu­mo­nitis, hypophysitis, acute kidney injury, dyspnea, adrenal insufficiency, and colitis; in patients treated with sunitinib, they were pneu­monia, pleural effusion, and dyspnea. In Checkmate 205 and 039, adverse reac­tions leading to dis­con­tinu­a­tion occurred in 7% and dose delays due to adverse reac­tions occurred in 34% of patients (n=266). Serious adverse reac­tions occurred in 26% of patients. The most frequent serious adverse reac­tions reported in ≥1% of patients were pneu­monia, infusion-related reac­tion, pyrexia, colitis or diarrhea, pleural effusion, pneu­mo­nitis, and rash. Eleven patients died from causes other than disease pro­gres­sion: 3 from adverse reac­tions within 30 days of the last OPDIVO dose, 2 from in­fec­tion 8 to 9 months after com­plet­ing OPDIVO, and 6 from com­pli­ca­tions of allo­geneic HSCT. In Checkmate 141, serious adverse reac­tions occurred in 49% of patients receiving OPDIVO (n=236). The most frequent serious adverse reac­tions reported in at least 2% of patients receiving OPDIVO were pneu­monia, dyspnea, res­pira­tory failure, res­pira­tory tract in­fec­tion, 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. In Checkmate 040, serious adverse reac­tions occurred in 49% of patients (n=154). The most frequent serious adverse reac­tions reported in at least 2% of patients were pyrexia, ascites, back pain, general physical health deterioration, abdominal pain, and pneu­monia. In Checkmate 238, Grade 3 or 4 adverse reac­tions occurred in 25% of OPDIVO-treated patients (n=452). The most frequent Grade 3 and 4 adverse reac­tions reported in at least 2% of OPDIVO-treated patients were diarrhea and in­­creased lipase and amylase. Serious adverse reac­tions occurred in 18% of OPDIVO-treated patients.

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 fatigue (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 214, the most common adverse reac­tions (≥20%) reported in patients treated with OPDIVO plus YERVOY (n=547) vs sunitinib (n=535) were fatigue (58% vs 69%), rash (39% vs 25%), diarrhea (38% vs 58%), mus­cu­lo­skel­etal pain (37% vs 40%), pruritus (33% vs 11%), nausea (30% vs 43%), cough (28% vs 25%), pyrexia (25% vs 17%), arthralgia (23% vs 16%), and de­creased appetite (21% vs 29%). In Checkmate 205 and 039, the most common adverse reac­tions (≥20%) reported in patients receiving OPDIVO (n=266) were upper res­pira­tory tract in­fec­tion (44%), fatigue (39%), cough (36%), diarrhea (33%), pyrexia (29%), mus­cu­lo­skel­etal pain (26%), rash (24%), nausea (20%) and pruritus (20%). In Checkmate 141, the most common adverse reac­tions (≥10%) in patients receiving OPDIVO (n=236) 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 Checkmate 040, the most common adverse reac­tions (≥20%) in patients receiving OPDIVO (n=154) were fatigue (38%), mus­cu­lo­skel­etal pain (36%), abdominal pain (34%), pruritus (27%), diarrhea (27%), rash (26%), cough (23%), and de­creased appetite (22%). In Checkmate 238, the most common adverse reac­tions (≥20%) reported in OPDIVO-treated patients (n=452) vs ipilimumab-treated patients (n=453) were fatigue (57% vs 55%), diarrhea (37% vs 55%), rash (35% vs 47%), mus­cu­lo­skel­etal pain (32% vs 27%), pruritus (28% vs 37%), headache (23% vs 31%), nausea (23% vs 28%), upper res­pira­tory in­fec­tion (22% vs 15%), and abdominal pain (21% vs 23%). The most common immune-mediated adverse reac­tions were rash (16%), diarrhea/colitis (6%), and hepatitis (3%). The most common adverse reac­tions (≥20%) in patients who received OPDIVO as a single agent were fatigue, rash, mus­cu­lo­skel­etal pain, pruritus, diarrhea, nausea, asthenia, cough, dyspnea, con­sti­pa­tion, de­creased appetite, back pain, arthralgia, upper res­pira­tory tract in­fec­tion, pyrexia, headache, and abdominal pain.

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 com­bi­na­tion with YERVOY® (ipilimumab); 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; Checkmate 040 – hepato­cellular carcinoma, Checkmate 238 – adjuvant treat­ment of mel­anoma.

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. Among other risks, there can be no guar­an­tee that Opdivo will receive regu­la­tory approval for the indi­ca­tions described herein. 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, 2017 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.

Source: Bristol Myers-Squibb.