Princeton, NJ (Press Release) – The U.S. Food and Drug Admin­istra­tion (FDA) has placed a partial clin­i­cal hold on CA209602 (CheckMate-602), CA209039 (CheckMate-039) and CA204142, three clin­i­cal trials in­vesti­gating Opdivo (nivolumab)-based com­bi­na­tions in patients with re­lapsed or refractory multiple myeloma.

This partial clin­i­cal hold is related to risks identified in trials studying another anti–PD-1 agent, pem­bro­lizu­mab, in patients with multiple myeloma. The FDA determined data cur­rently avail­able from non-Opdivo studies indicate the risks of PD-1/PD-L1 treat­ment plus poma­lido­mide or lena­lido­mide and possibly PD-1/PD-L1 treat­ments alone or with other com­bi­na­tions outweigh poten­tial benefit for patients with multiple myeloma.

As part of the terms of the partial clin­i­cal hold, patients cur­rently enrolled in CheckMate-602, CheckMate-039 and CA204142 who are experiencing clin­i­cal benefit can con­tinue treat­ment. No new patients will enroll in the studies at this time.

Bristol-Myers Squibb remains steadfast in our commitment to im­prove out­comes for patients with multiple myeloma, and will work closely with the FDA to address con­cerns.

The fol­low­ing trials are on partial clin­i­cal hold:

• CheckMate-602: An Open-Label, Randomized Phase 3 Trial of Combinations of Nivolumab, Elotuzumab, Pomalidomide and Dexamethasone in Relapsed and Refractory Multiple Myeloma
• CheckMate-039: A Phase 1 study to establish the tolerability of nivolumab and the combination of nivolumab and daratumumab, with or without IMiD (pomalidomide and dexamethasone), in subjects with relapsed or refractory MM
• CA204142: A Phase 2, Multiple Cohort Study of Elotuzumab in Combination With Pomalidomide and Low-Dose Dexamethasone (EPd), and in Combination With Nivolumab (EN), in Patients With Multiple Myeloma Relapsed or Refractory to Prior Treatment With Lenalidomide

Other studies of Opdivo outside of multiple myeloma will con­tinue as planned. Empliciti (elotuzumab) is approved in the US in com­bi­na­tion with lena­lido­mide and dexa­meth­a­sone, for the treat­ment of patients with multiple myeloma who have received one to three prior ther­a­pies

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) 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 adults 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.

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 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 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, 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. 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.

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, 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 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%).. 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.

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; 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 Empliciti

Empliciti is an immunostimulatory anti­body that specifically targets Signaling Lymphocyte Activation Molecule Family member 7 (SLAMF7), a cell-surface glycoprotein. SLAMF7 is expressed on myeloma cells independent of cytogenetic ab­nor­mal­i­ties. SLAMF7 also is expressed on Natural Killer cells, plasma cells and at lower levels on specific immune cell subsets of dif­fer­en­ti­ated cells within the hema­to­poietic lineage.

Empliciti has a dual mech­a­nism-of-action. It directly activates the immune system through Natural Killer cells via the SLAMF7 path­way. Empliciti also targets SLAMF7 on myeloma cells, tagging these malignant cells for Natural Killer cell-mediated destruction via anti­body-dependent cellular toxicity.

Bristol-Myers Squibb and AbbVie are co-developing Empliciti, with Bristol-Myers Squibb solely responsible for commercial activities.

U.S. FDA-APPROVED INDICATION FOR EMPLICITI™

EMPLICITI™ (elotuzumab) is indicated in com­bi­na­tion with lena­lido­mide and dexa­meth­a­sone for the treat­ment of patients with multiple myeloma who have received one to three prior ther­a­pies.

IMPORTANT SAFETY INFORMATION

Infusion Reactions

EMPLICITI can cause infusion reac­tions. Common symp­toms in­clude fever, chills, and hyper­tension. Bradycardia and hypo­­tension also developed during infusions. In the trial, 5% of patients required inter­rup­tion of the admin­istra­tion of EMPLICITI for a median of 25 minutes due to infusion reac­tions, and 1% of patients dis­con­tinued due to infusion reac­tions. Of the patients who ex­peri­enced an infusion reac­tion, 70% (23/33) had them during the first dose. If a Grade 2 or higher infusion reac­tion occurs, interrupt the EMPLICITI infusion and institute appro­pri­ate medical and sup­port­ive measures. If the infusion reac­tion recurs, stop the EMPLICITI infusion and do not restart it on that day. Severe infusion reac­tions may require perma­nent dis­con­tinu­a­tion of EMPLICITI ther­apy and emergency treat­ment.

Premedicate with dexa­meth­a­sone, H1 Blocker, H2 Blocker, and acetaminophen prior to infusing with EMPLICITI.

Infections

In a clin­i­cal trial of patients with multiple myeloma (N=635), in­fec­tions were reported in 81.4% of patients in the EMPLICITI with lena­lido­mide/dexamethasone arm (ERd) and 74.4% in the lena­lido­mide/dexamethasone arm (Rd). Grade 3-4 in­fec­tions were 28% (ERd) and 24.3% (Rd). Opportunistic in­fec­tions were reported in 22% (ERd) and 12.9% (Rd). Fungal in­fec­tions were 9.7% (ERd) and 5.4% (Rd). Herpes zoster was 13.5% (ERd) and 6.9% (Rd). Discontinuations due to in­fec­tions were 3.5% (ERd) and 4.1% (Rd). Fatal in­fec­tions were 2.5% (ERd) and 2.2% (Rd). Monitor patients for devel­op­ment of in­fec­tions and treat promptly.

Second Primary Malignancies

In a clin­i­cal trial of patients with multiple myeloma (N=635), in­­vasive second pri­mary malig­nan­cies (SPM) were 9.1% (ERd) and 5.7% (Rd). The rate of hema­to­logic malig­nan­cies were the same be­tween ERd and Rd treat­ment arms (1.6%). Solid tumors were reported in 3.5% (ERd) and 2.2% (Rd). Skin cancer was reported in 4.4% (ERd) and 2.8% (Rd). Monitor patients for the devel­op­ment of SPMs.

Hepatotoxicity

Elevations in liver enzymes (AST/ALT greater than 3 times the upper limit, total bilirubin greater than 2 times the upper limit, and alkaline phosphatase less than 2 times the upper limit) con­sis­tent with hepato­tox­ic­ity were 2.5% (ERd) and 0.6% (Rd). Two patients experiencing hepato­tox­ic­ity dis­con­tinued treat­ment; how­ever, 6 out of 8 patients had resolution and con­tinued treat­ment. Monitor liver enzymes periodically. Stop EMPLICITI upon Grade 3 or higher elevation of liver enzymes. After return to base­line values, con­tin­u­a­tion of treat­ment may be con­sidered.

Interference with Determination of Complete Response

EMPLICITI is a humanized IgG kappa mono­clonal anti­body that can be detected on both the serum protein electrophoresis and immuno­fix­a­tion assays used for the clin­i­cal monitoring of endogenous M-protein. This inter­fer­ence can impact the deter­mi­na­tion of com­plete response and possibly relapse from com­plete response in patients with IgG kappa myeloma protein.

Pregnancy/Females and Males of Reproductive Potential

There are no studies with EMPLICITI with pregnant women to inform any drug asso­ci­ated risks.

There is a risk of fetal harm, in­­clud­ing severe life-threatening human birth defects asso­ci­ated with lena­lido­mide and it is con­tra­in­di­cated for use in pregnancy. Refer to the lena­lido­mide full pre­scrib­ing in­­for­ma­tion for require­ments re­gard­ing con­tra­cep­tion and the prohibitions against blood and/or sperm donation due to presence and transmission in blood and/or semen and for addi­tional in­­for­ma­tion.

Adverse Reactions

Infusion reac­tions were reported in approx­i­mately 10% of patients treated with EMPLICITI with lena­lido­mide and dexa­meth­a­sone. All reports of infusion reac­tion were Grade 3 or lower. Grade 3 infusion reac­tions occurred in 1% of patients.

Serious adverse reac­tions were 65.4% (ERd) and 56.5% (Rd). The most frequent serious adverse reac­tions in the ERd arm compared to the Rd arm were: pneu­monia (15.4%, 11%), pyrexia (6.9%, 4.7%), res­pira­tory tract in­fec­tion (3.1%, 1.3%), anemia (2.8%, 1.9%), pul­mo­nary embolism (3.1%, 2.5%), and acute renal failure (2.5%, 1.9%).

The most common adverse reac­tions in ERd and Rd, re­spec­tive­ly (>20%) were fatigue (61.6%, 51.7%), diarrhea (46.9%, 36.0%), pyrexia (37.4%, 24.6%), con­sti­pa­tion (35.5%, 27.1%), cough (34.3%, 18.9%), periph­eral neu­rop­athy (26.7%, 20.8%), nasopharyngitis (24.5%, 19.2%), upper res­pira­tory tract in­fec­tion (22.6%, 17.4%), de­creased appetite (20.8%, 12.6%), and pneu­monia (20.1%, 14.2%).

Please see the full Prescribing Information for EMPLICITI.

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 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 or Empliciti will receive regu­la­tory approval for an addi­tional indi­ca­tion. Forward-looking state­ments in this ma­teri­al 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.

Source: Bristol-Myers Squibb.