Bristol Myers Squibb Receives European Commission Approval for the Subcutaneous Formulation of Opdivo® (nivolumab) Across Multiple Solid Tumor Indications

Opdivo is the first and only PD-1 inhibitor approved for subcutaneous (SC) use in the European Union

Approval is based on results from the Phase 3 CheckMate -67T clinical trial which demonstrated noninferiority in the co-primary endpoints of C_avgd28 and C_minss, and consistent efficacy in the secondary endpoint of overall response rate, for the subcutaneous formulation of Opdivo (Opdivo SC) vs. its intravenous formulation (IV Opdivo)

PRINCETON, N.J.--(BUSINESS WIRE)-- Bristol Myers Squibb (NYSE: BMY) today announced that the European Commission (EC) has approved a new Opdivo^® (nivolumab) formulation associated with a new route of administration (subcutaneous use [SC]), a new pharmaceutical form (solution for injection) and a new strength (600 mg/vial). Opdivo SC, or nivolumab for subcutaneous use co-formulated with recombinant human hyaluronidase (rHuPH20), has been approved for use across multiple adult solid tumors as monotherapy, monotherapy maintenance following completion of intravenous nivolumab plus Yervoy^® (ipilimumab) combination therapy, or in combination with chemotherapy or cabozantinib.

“The EC’s decision to approve Opdivo SC ushers in a new era of cancer care in which we are able to deliver a 3- to 5-minute injection of a treatment that has shown consistent efficacy and comparable safety to intravenous Opdivo, which changed the cancer treatment landscape over a decade ago,” said Dana Walker, M.D., M.S.C.E., Opdivo global program lead, Bristol Myers Squibb. “BMS is committed to advancing medicines that help improve the patient experience, and with the approval of Opdivo SC in the European Union, we are delivering on this goal.”

The positive EC decision is based on results from the CheckMate -67T clinical trial and additional data that demonstrated comparable pharmacokinetics (PK) and safety profiles between Opdivo SC and IV Opdivo. The CheckMate –67T clinical trial showed noninferiority of PK primary endpoints, C_avgd28 (time-averaged Opdivo serum concentration over 28 days) and C_minss (trough serum concentration at steady state), with Opdivo SC vs. IV Opdivo in adult patients with advanced or metastatic clear cell renal cell carcinoma (ccRCC) who had received no more than two prior lines of systemic therapy but had not received prior immuno-oncology therapy. The geometric mean ratio (GMR) for C_avgd28 was 2.10 (90% CI: 2.00-2.20) and the GMR for C_minss was 1.77 (90% CI: 1.63-1.93). Additionally, as a key powered secondary endpoint, the objective response rate (ORR) in the Opdivo SC arm (n=248) was 24% (95% CI: 19-30), compared with 18% (95% CI: 14-24) in the IV Opdivo arm (n=247), showing that Opdivo SC has similar efficacy compared to IV Opdivo. The safety profile of Opdivo SC remained consistent with the IV formulation.

The pharmacokinetics, efficacy and safety results from CheckMate -67T were presented at the 2024 American Society of Clinical Oncology (ASCO^®) Genitourinary Cancers Symposium. Additional analyses were presented at the 2024 ASCO Annual Meeting, the 2024 European Society for Medical Oncology (ESMO) Congress, and published in the Annals of Oncology.

“As the first and only subcutaneously administered PD-1 inhibitor approved in the European Union, subcutaneous nivolumab is helping to transform the treatment landscape for eligible patients by giving them a new way to potentially receive the same benefits of the IV formulation of nivolumab, in a more convenient manner,” said Laurence Albiges, M.D., Ph.D., a professor of medical oncology at Université Paris-Saclay, and head of the Department of Oncology at Gustave Roussy, Villejuif, France. “This approval provides eligible patients and their doctors a new way to tailor treatment plans for each individual’s needs and to improve the efficiency with which nivolumab can be administered from a patient perspective as well as in the organization of our healthcare resources.”

The approval by the EC is valid in all 27 member states of the European Union (EU), as well as Iceland, Liechtenstein and Norway.

On December 27, 2024, subcutaneous nivolumab and hyaluronidase-nvhy, marketed under the brand name Opdivo Qvantig^TM, was approved by the U.S. Food and Drug Administration (FDA). Bristol Myers Squibb thanks the patients and investigators involved in the CheckMate -67T clinical trial.

About CheckMate -67T

CheckMate -67T was a Phase 3, randomized, open-label, noninferiority trial evaluating Opdivo Qvantig compared to intravenous (IV) Opdivo, in adult patients with advanced or metastatic clear cell renal cell carcinoma (ccRCC) who received prior systemic therapy. A total of 495 patients were randomized to receive either Opdivo Qvantig (1,200 mg of nivolumab and 20,000 units of hyaluronidase) every 4 weeks subcutaneously (n = 248), or Opdivo 3 mg/kg every 2 weeks intravenously (n = 247). The coprimary endpoints were time-averaged concentration over 28 days (C_avgd28) and minimum concentration at steady state (C_minss). The key powered secondary endpoint was overall response rate, as assessed by blinded independent central review.

Select Safety Profile from CheckMate -67T

Serious adverse reactions occurred in 28% of patients receiving Opdivo Qvantig (n=247). The most frequent serious adverse reactions reported in >1% of patients who received Opdivo Qvantig were pleural effusion (1.6%), pneumonitis (1.6%), hyperglycemia (1.2%), hyperkalemia (1.2%), hemorrhage (1.2%) and diarrhea (1.2%). The most common adverse reactions (≥10%) in patients treated with Opdivo Qvantig (n=247) were musculoskeletal pain (31%), fatigue (20%), pruritus (16%), rash (15%), hypothyroidism (12%), diarrhea (11%), cough (11%), and abdominal pain (10%). Fatal adverse reactions occurred in 3 (1.2%) patients who received Opdivo Qvantig; these included myocarditis, myositis, and colitis complications. Study therapy was discontinued in 10% of patients due to adverse reactions. The safety profile of Opdivo Qvantig was comparable with the safety profile of IV Opdivo.

About Subcutaneous Administration

Subcutaneous administration is delivery of treatment beneath the skin and is an alternative to IV infusion. There are several potential benefits of subcutaneous administration: it may offer the flexibility to provide and receive treatment where it is best for the healthcare provider and patient, may impact infusion chair capacity, and may reduce time spent preparing and administering treatment. It may also simplify administering treatment for patients who have difficult-to-access veins or do not want a port. Subcutaneous treatment has the potential to be administered by a healthcare professional without site of care restrictions.

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 treated more than 35,000 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 65 countries, including the United States, the European Union, Japan and China. 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.

INDICATIONS

OPDIVO QVANTIG™ (nivolumab and hyaluronidase-nvhy), as monotherapy, is indicated for the first-line treatment of adult patients with intermediate- or poor-risk advanced renal cell carcinoma (RCC), following treatment with intravenous nivolumab and ipilimumab combination therapy.

Limitations of Use: OPDIVO QVANTIG is not indicated in combination with ipilimumab for the treatment of renal cell carcinoma.

OPDIVO QVANTIG™ (nivolumab and hyaluronidase-nvhy), in combination with cabozantinib, is indicated for the first-line treatment of adult patients with advanced renal cell carcinoma (RCC).

OPDIVO QVANTIG™ (nivolumab and hyaluronidase-nvhy), as monotherapy, is indicated for the treatment of adult patients with advanced renal cell carcinoma (RCC) who have received prior anti-angiogenic therapy.

OPDIVO QVANTIG™ (nivolumab and hyaluronidase-nvhy), as monotherapy, is indicated for the treatment of adult patients with unresectable or metastatic melanoma.

OPDIVO QVANTIG™ (nivolumab and hyaluronidase-nvhy), as monotherapy, is indicated for the treatment of adult patients with unresectable or metastatic melanoma following treatment with intravenous nivolumab and ipilimumab combination therapy.

Limitations of Use: OPDIVO QVANTIG is not indicated in combination with ipilimumab for treatment of unresectable or metastatic melanoma.

OPDIVO QVANTIG™ (nivolumab and hyaluronidase-nvhy), as monotherapy, is indicated for the adjuvant treatment of adult patients with completely resected Stage IIB, Stage IIC, Stage III, or Stage IV melanoma.

OPDIVO QVANTIG™ (nivolumab and hyaluronidase-nvhy), in combination with platinum-doublet chemotherapy, is indicated as neoadjuvant treatment of adult patients with resectable (tumors ≥4 cm or node positive) non-small cell lung cancer (NSCLC).

OPDIVO QVANTIG™ (nivolumab and hyaluronidase-nvhy), in combination with platinum-doublet chemotherapy, is indicated for the neoadjuvant treatment of adult patients with resectable (tumors ≥4 cm or node positive) non-small cell lung cancer (NSCLC) and no known epidermal growth factor receptor (EGFR) mutations or anaplastic lymphoma kinase (ALK) rearrangements, followed by OPDIVO QVANTIG as monotherapy in the adjuvant setting after surgical resection.

OPDIVO QVANTIG™ (nivolumab and hyaluronidase-nvhy), as monotherapy, is indicated for the treatment of adult 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 QVANTIG.

Limitations of Use: OPDIVO QVANTIG is not indicated in combination with ipilimumab for the treatment of metastatic NSCLC.

OPDIVO QVANTIG™ (nivolumab and hyaluronidase-nvhy), as monotherapy, is indicated for the treatment of adult patients with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) with disease progression on or after platinum-based therapy.

OPDIVO QVANTIG™ (nivolumab and hyaluronidase-nvhy), as monotherapy, is indicated for the adjuvant treatment of adult patients with urothelial carcinoma (UC) who are at high risk of recurrence after undergoing radical resection of UC.

OPDIVO QVANTIG™ (nivolumab and hyaluronidase-nvhy), in combination with cisplatin and gemcitabine, is indicated for the first-line treatment of adult patients with unresectable or metastatic urothelial carcinoma (UC).

OPDIVO QVANTIG™ (nivolumab and hyaluronidase-nvhy), as monotherapy, is indicated for the treatment of adult patients with locally advanced or metastatic urothelial carcinoma (UC) 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.

OPDIVO QVANTIG™ (nivolumab and hyaluronidase-nvhy), as monotherapy following treatment with intravenous nivolumab and ipilimumab combination therapy, is indicated for the treatment of adult patients with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer (CRC) that has progressed following treatment with fluoropyrimidine, oxaliplatin, and irinotecan.

Limitations of Use: OPDIVO QVANTIG is not indicated in combination with ipilimumab for the treatment of MSI-H or dMMR metastatic CRC.

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 QVANTIG™ (nivolumab and hyaluronidase-nvhy), as a monotherapy, is indicated for the treatment of adult patients with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic 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 QVANTIG™ (nivolumab and hyaluronidase-nvhy), as monotherapy, is indicated for the treatment of adult patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib and following treatment with intravenous nivolumab and ipilimumab.

Limitations of Use: OPDIVO QVANTIG is not indicated in combination with ipilimumab for the treatment of patients with HCC.

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 the confirmatory trials.

OPDIVO QVANTIG™ (nivolumab and hyaluronidase-nvhy), as monotherapy, is indicated for the adjuvant treatment of completely resected esophageal or gastroesophageal junction cancer with residual pathologic disease in adult patients who have received neoadjuvant chemoradiotherapy (CRT).

OPDIVO QVANTIG™ (nivolumab and hyaluronidase-nvhy), in combination with fluoropyrimidine- and platinum-containing chemotherapy, is indicated for the first-line treatment of adult patients with unresectable advanced or metastatic esophageal squamous cell carcinoma (ESCC).

Limitations of Use: OPDIVO QVANTIG is not indicated in combination with ipilimumab for the treatment of patients with unresectable advanced or metastatic ESCC.

OPDIVO QVANTIG™ (nivolumab and hyaluronidase-nvhy), as monotherapy, is indicated for the treatment of adult patients with unresectable advanced, recurrent or metastatic esophageal squamous cell carcinoma (ESCC) after prior fluoropyrimidine- and platinum-based chemotherapy.

OPDIVO QVANTIG™ (nivolumab and hyaluronidase-nvhy), in combination with fluoropyrimidine- and platinum-containing chemotherapy, is indicated for the treatment of adult patients with advanced or metastatic gastric cancer, gastroesophageal junction cancer, and esophageal adenocarcinoma.

IMPORTANT SAFETY INFORMATION

Severe and Fatal Immune-Mediated Adverse Reactions

Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue. While immune-mediated adverse reactions usually manifest during treatment, they can also occur after discontinuation of OPDIVO QVANTIG. Early identification and management are essential to ensure safe use of OPDIVO QVANTIG. Monitor for signs and symptoms that may be clinical manifestations of underlying immune-mediated adverse reactions. Evaluate clinical chemistries including liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. In cases of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate.

Withhold or permanently discontinue OPDIVO QVANTIG depending on severity (please see Section 2 Dosage and Administration in the accompanying Full Prescribing Information). In general, if OPDIVO QVANTIG interruption or discontinuation is required, administer systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over for at least 1 month. Consider administration of other systemic immunosuppressants in patients whose immune-mediated adverse reactions are not controlled with corticosteroid therapy.

Toxicity management guidelines for adverse reactions that do not necessarily require systemic steroids (e.g., endocrinopathies and dermatologic reactions) are discussed below.

Immune-Mediated Pneumonitis

OPDIVO QVANTIG can cause immune-mediated pneumonitis. The incidence of pneumonitis is higher in patients who have received prior thoracic radiation.

Immune-mediated pneumonitis occurred in 2.8% (7/247) of patients receiving OPDIVO QVANTIG, including Grade 3 (0.8%) and Grade 2 (2.0%) adverse reactions.

Immune-Mediated Colitis

OPDIVO QVANTIG can cause immune-mediated colitis. A common symptom included in the definition of colitis was diarrhea. Cytomegalovirus (CMV) infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies.

Immune-mediated colitis occurred in 2.8% (7/247) of patients receiving OPDIVO QVANTIG, including Grade 3 (0.4%) and Grade 2 (2.4%) adverse reactions.

Immune-Mediated Hepatitis and Hepatotoxicity

OPDIVO QVANTIG can cause immune-mediated hepatitis.

Immune-mediated hepatitis occurred in 2.4% (6/247) of patients receiving OPDIVO QVANTIG, including Grade 3 (1.6%), and Grade 2 (0.8%) adverse reactions.

Intravenous nivolumab in combination with cabozantinib can cause hepatic toxicity with higher frequencies of Grade 3 and 4 ALT and AST elevations compared to intravenous nivolumab alone. Consider more frequent monitoring of liver enzymes as compared to when the drugs are administered as single agents. With the combination of intravenous nivolumab and cabozantinib, Grades 3 and 4 increased ALT or AST were seen in 11% (35/320) of patients.

Immune-Mediated Endocrinopathies

OPDIVO QVANTIG can cause primary or secondary adrenal insufficiency, immune-mediated hypophysitis, immune-mediated thyroid disorders, and Type 1 diabetes mellitus, which can present with diabetic ketoacidosis. Withhold OPDIVO QVANTIG depending on severity (please see section 2 Dosage and Administration in the accompanying Full Prescribing Information). For Grade 2 or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement as clinically indicated. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field defects. Hypophysitis can cause hypopituitarism; initiate hormone replacement as clinically indicated. Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism; initiate hormone replacement or medical management as clinically indicated. Monitor patients for hyperglycemia or other signs and symptoms of diabetes; initiate treatment with insulin as clinically indicated.

Adrenal insufficiency occurred in 2% (5/247) of patients receiving OPDIVO QVANTIG, including Grade 3 (0.8%) and Grade 2 (1.2%) adverse reactions.

Adrenal insufficiency occurred in 4.7% (15/320) of patients with RCC who received intravenous nivolumab with cabozantinib, including Grade 3 (2.2%) and Grade 2 (1.9%) adverse reactions.

Hypophysitis occurred in 0.6% (12/1994) of patients treated with single agent intravenous nivolumab, including Grade 3 (0.2%) and Grade 2 (0.3%). Thyroiditis occurred in 0.4% (1/247) of patients receiving OPDIVO QVANTIG, including a Grade 1 (0.4%) adverse reaction.

Hyperthyroidism occurred in 0.8% (2/247) of patients receiving OPDIVO QVANTIG, including Grade 2 (0.4%) adverse reactions. Hypothyroidism occurred in 9% (23/247) of patients receiving OPDIVO QVANTIG, including Grade 2 (5.7%) adverse reactions.

Grade 3 diabetes occurred in 0.4% (1/247) of patients receiving OPDIVO QVANTIG.

Immune-Mediated Nephritis with Renal Dysfunction

OPDIVO QVANTIG can cause immune-mediated nephritis.

Grade 2 immune-mediated nephritis and renal dysfunction occurred in 1.2% (3/247) of patients receiving OPDIVO QVANTIG.

Immune-Mediated Dermatologic Adverse Reactions

OPDIVO QVANTIG can cause immune-mediated rash or dermatitis. Exfoliative dermatitis, including Stevens-Johnson Syndrome, toxic epidermal necrolysis (TEN), and DRESS (drug rash with eosinophilia and systemic symptoms), has occurred with PD-1/PD-L1 blocking antibodies. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate non-exfoliative rashes. Withhold or permanently discontinue OPDIVO QVANTIG depending on severity (please see section 2 Dosage and Administration in the accompanying Full Prescribing Information).

Immune-mediated rash occurred in 7% (17/247) of patients, including Grade 3 (0.8%) and Grade 2 (2.8%) adverse reactions.

Other Immune-Mediated Adverse Reactions

The following clinically significant immune-mediated adverse reactions occurred at an incidence of <1% (unless otherwise noted) in patients who received OPDIVO QVANTIG or intravenous nivolumab as single agent or in combination with chemotherapy or immunotherapy, or were reported with the use of other PD-1/PD-L1 blocking antibodies. Severe or fatal cases have been reported for some of these adverse reactions: cardiac/vascular: myocarditis, pericarditis, vasculitis; nervous system: meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis (including exacerbation), Guillain-Barré syndrome, nerve paresis, autoimmune neuropathy; ocular: uveitis, iritis, and other ocular inflammatory toxicities can occur; gastrointestinal: pancreatitis to include increases in serum amylase and lipase levels, gastritis, duodenitis; musculoskeletal and connective tissue: myositis/polymyositis, rhabdomyolysis, and associated sequelae including renal failure, arthritis, polymyalgia rheumatica; endocrine: hypoparathyroidism; other (hematologic/immune): hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis (HLH), systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, solid organ transplant rejection, other transplant (including corneal graft) rejection.

Some ocular IMAR cases can be associated with retinal detachment. Various grades of visual impairment, including blindness, can occur. If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Harada–like syndrome, as this may require treatment with systemic corticosteroids to reduce the risk of permanent vision loss.

Complications of Allogeneic Hematopoietic Stem Cell Transplantation

Fatal and other serious complications can occur in patients who receive allogeneic hematopoietic stem cell transplantation (HSCT) before or after being treated with OPDIVO QVANTIG. Transplant-related complications include hyperacute graft-versus-host disease (GVHD), acute GVHD, chronic GVHD, hepatic veno-occlusive disease (VOD) after reduced intensity conditioning, and steroid-requiring febrile syndrome (without an identified infectious cause). These complications may occur despite intervening therapy between OPDIVO QVANTIG and allogeneic HSCT.

Follow patients closely for evidence of transplant-related complications and intervene promptly. Consider the benefit versus risks of treatment with OPDIVO QVANTIG prior to or after an allogeneic HSCT.

Embryo-Fetal Toxicity

Based on its mechanism of action and data from animal studies, OPDIVO QVANTIG can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of nivolumab to cynomolgus monkeys from the onset of organogenesis through delivery resulted in increased abortion and premature infant death. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with OPDIVO QVANTIG and for 5 months after the last dose.

Increased Mortality in Patients with Multiple Myeloma when Nivolumab Is Added to a Thalidomide Analogue and Dexamethasone

In randomized clinical trials in patients with multiple myeloma, the addition of a PD-1 blocking antibody, including intravenous nivolumab, to a thalidomide analogue plus dexamethasone, a use for which no PD-1 or PD-L1 blocking antibody is indicated, resulted in increased mortality. Treatment of patients with multiple myeloma with a PD-1 or PD-L1 blocking antibody in combination with a thalidomide analogue plus dexamethasone is not recommended outside of controlled clinical trials.

Lactation

There are no data on the presence of nivolumab or hyaluronidase in human milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in the breastfed child, advise women not to breastfeed during treatment and for 5 months after the last dose of OPDIVO QVANTIG.

Serious Adverse Reactions

In Checkmate 67T, serious adverse reactions occurred in 28% of patients who received OPDIVO QVANTIG (n=247). Serious adverse reactions in >1% of patients included pleural effusion (1.6%), pneumonitis (1.6%), hyperglycemia (1.2%), hyperkalemia (1.2%), hemorrhage (1.2%) and diarrhea (1.2%). Fatal adverse reactions occurred in 3 patients (1.2%) who received OPDIVO QVANTIG and included myocarditis, myositis, and colitis complications.

In Checkmate 037, serious adverse reactions occurred in 41% of patients receiving intravenous nivolumab (n=268). Grade 3 and 4 adverse reactions occurred in 42% of patients receiving intravenous nivolumab. The most frequent Grade 3 and 4 adverse drug reactions reported in 2% to <5% of patients receiving intravenous nivolumab were abdominal pain, hyponatremia, increased aspartate aminotransferase, and increased lipase. In Checkmate 066, serious adverse reactions occurred in 36% of patients receiving intravenous nivolumab (n=206). Grade 3 and 4 adverse reactions occurred in 41% of patients receiving intravenous nivolumab. The most frequent Grade 3 and 4 adverse reactions reported in ≥2% of patients receiving intravenous nivolumab were gamma-glutamyltransferase increase (3.9%) and diarrhea (3.4%). In Checkmate 067, the most frequent (≥10%) serious adverse reactions in the intravenous nivolumab arm (n=313) were diarrhea (2.2%), colitis (1.9%), and pyrexia (1.0%). In Checkmate 067, serious adverse reactions (74% and 44%), adverse reactions leading to permanent discontinuation (47% and 18%) or to dosing delays (58% and 36%), and Grade 3 or 4 adverse reactions (72% and 51%) all occurred more frequently in the intravenous nivolumab plus intravenous ipilimumab arm (n=313) relative to the intravenous nivolumab arm (n=313). The most frequent (≥10%) serious adverse reactions in the intravenous nivolumab plus intravenous ipilimumab arm and the intravenous nivolumab arm, respectively, were diarrhea (13% and 2.2%), colitis (10% and 1.9%), and pyrexia (10% and 1.0%).

In Checkmate 816, serious adverse reactions occurred in 30% of patients (n=176) who were treated with intravenous nivolumab in combination with platinum-doublet chemotherapy. Serious adverse reactions in >2% included pneumonia and vomiting. No fatal adverse reactions occurred in patients who received intravenous nivolumab in combination with platinum-doublet chemotherapy.

In Checkmate 77T, serious adverse reactions occurred in 21% of patients who received intravenous nivolumab in combination with platinum-doublet chemotherapy as neoadjuvant treatment (n=228). The most frequent (≥2%) serious adverse reactions was pneumonia. Fatal adverse reactions occurred in 2.2% of patients, due to cerebrovascular accident, COVID-19 infection, hemoptysis, pneumonia, and pneumonitis (0.4% each). In the adjuvant phase of Checkmate 77T, 22% of patients experienced serious adverse reactions (n=142). The most frequent serious adverse reaction was pneumonitis/ILD (2.8%). One fatal adverse reaction due to COVID-19 occurred.

In Checkmate 017 and 057, serious adverse reactions occurred in 46% of patients receiving intravenous nivolumab (n=418). The most frequent serious adverse reactions reported in ≥2% of patients receiving intravenous nivolumab were pneumonia, pulmonary embolism, dyspnea, pyrexia, pleural effusion, pneumonitis, and respiratory failure. In Checkmate 057, fatal adverse reactions occurred; these included events of infection (7 patients, including one case of Pneumocystis jirovecii pneumonia), pulmonary embolism (4 patients), and limbic encephalitis (1 patient).

In Checkmate 214, serious adverse reactions occurred in 59% of patients receiving intravenous nivolumab plus intravenous ipilimumab (n=547). The most frequent serious adverse reactions reported in ≥2% of patients were diarrhea, pyrexia, pneumonia, pneumonitis, hypophysitis, acute kidney injury, dyspnea, adrenal insufficiency, and colitis.

In Checkmate 9ER, serious adverse reactions occurred in 48% of patients receiving intravenous nivolumab and cabozantinib (n=320). The most frequent serious adverse reactions reported in ≥2% of patients were diarrhea, pneumonia, pneumonitis, pulmonary embolism, urinary tract infection, and hyponatremia. Fatal intestinal perforations occurred in 3 (0.9%) patients.

In Checkmate 025, serious adverse reactions occurred in 47% of patients receiving intravenous nivolumab (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 141, serious adverse reactions occurred in 49% of patients receiving intravenous nivolumab (n=236). The most frequent serious adverse reactions reported in ≥2% of patients receiving intravenous nivolumab were pneumonia, dyspnea, respiratory failure, respiratory tract infection, and sepsis.

In Checkmate 275, serious adverse reactions occurred in 54% of patients receiving intravenous nivolumab (n=270). The most frequent serious adverse reactions reported in ≥ 2% of patients receiving intravenous nivolumab were urinary tract infection, sepsis, diarrhea, small intestine obstruction, and general physical health deterioration.

In Checkmate 274, serious adverse reactions occurred in 30% of patients receiving intravenous nivolumab (n=351). The most frequent serious adverse reaction reported in ≥ 2% of patients receiving intravenous nivolumab was urinary tract infection. Fatal adverse reactions occurred in 1% of patients; these included events of pneumonitis (0.6%).

In Checkmate 901, serious adverse reactions occurred in 48% of patients receiving intravenous nivolumab in combination with chemotherapy. The most frequent serious adverse reactions reported in ≥2% of patients who received intravenous nivolumab with chemotherapy were urinary tract infection (4.9%), acute kidney injury (4.3%), anemia (3%), pulmonary embolism (2.6%), sepsis (2.3%), and platelet count decreased (2.3%). Fatal adverse reactions occurred in 3.6% of patients who received intravenous nivolumab in combination with chemotherapy; these included sepsis (1%).

In Checkmate 142 in MSI-H/dMMR mCRC patients receiving intravenous nivolumab with intravenous ipilimumab (n=119), serious adverse reactions occurred in 47% of patients. The most frequent serious adverse reactions reported in ≥2% of patients were colitis/diarrhea, hepatic events, abdominal pain, acute kidney injury, pyrexia, and dehydration.

In Checkmate 040, serious adverse reactions occurred in 59% of patients receiving intravenous nivolumab with intravenous ipilimumab (n=49). Serious adverse reactions reported in ≥4% of patients were pyrexia, diarrhea, anemia, increased AST, adrenal insufficiency, ascites, esophageal varices hemorrhage, hyponatremia, increased blood bilirubin, and pneumonitis.

In Checkmate 238, serious adverse reactions occurred in 18% of patients receiving intravenous nivolumab (n=452). Grade 3 or 4 adverse reactions occurred in 25% of intravenous nivolumab-treated patients (n=452). The most frequent Grade 3 and 4 adverse reactions reported in ≥2% of intravenous nivolumab-treated patients were diarrhea and increased lipase and amylase.

In Attraction-3, serious adverse reactions occurred in 38% of patients receiving intravenous nivolumab (n=209). Serious adverse reactions reported in ≥2% of patients who received intravenous nivolumab were pneumonia, esophageal fistula, interstitial lung disease, and pyrexia. The following fatal adverse reactions occurred in patients who received intravenous nivolumab: interstitial lung disease or pneumonitis (1.4%), pneumonia (1.0%), septic shock (0.5%), esophageal fistula (0.5%), gastrointestinal hemorrhage (0.5%), pulmonary embolism (0.5%), and sudden death (0.5%).

In Checkmate 577, serious adverse reactions occurred in 33% of patients receiving intravenous nivolumab (n=532). A serious adverse reaction reported in ≥2% of patients who received intravenous nivolumab was pneumonitis. A fatal reaction of myocardial infarction occurred in one patient who received intravenous nivolumab.

In Checkmate 648, serious adverse reactions occurred in 62% of patients receiving intravenous nivolumab in combination with chemotherapy (n=310). The most frequent serious adverse reactions reported in ≥2% of patients who received intravenous nivolumab with chemotherapy were pneumonia (11%), dysphagia (7%), esophageal stenosis (2.9%), acute kidney injury (2.9%), and pyrexia (2.3%). Fatal adverse reactions occurred in 5 (1.6%) patients who received OPDIVO in combination with chemotherapy; these included pneumonitis, pneumatosis intestinalis, pneumonia, and acute kidney injury. In Checkmate 648, serious adverse reactions occurred in 69% of patients receiving intravenous nivolumab in combination with intravenous ipilimumab (n=322). The most frequent serious adverse reactions reported in ≥2% who received intravenous nivolumab in combination with intravenous ipilimumab were pneumonia (10%), pyrexia (4.3%), pneumonitis (4.0%), aspiration pneumonia (3.7%), dysphagia (3.7%), hepatic function abnormal (2.8%), decreased appetite (2.8%), adrenal insufficiency (2.5%), and dehydration (2.5%). Fatal adverse reactions occurred in 5 (1.6%) patients who received intravenous nivolumab in combination with intravenous ipilimumab; these included pneumonitis, interstitial lung disease, pulmonary embolism, and acute respiratory distress syndrome.

In Checkmate 649, serious adverse reactions occurred in 52% of patients treated with intravenous nivolumab in combination with chemotherapy (n=782). The most frequent serious adverse reactions reported in ≥2% of patients treated with intravenous nivolumab in combination with chemotherapy were vomiting (3.7%), pneumonia (3.6%), anemia, (3.6%), pyrexia (2.8%), diarrhea (2.7%), febrile neutropenia (2.6%), and pneumonitis (2.4%). Fatal adverse reactions occurred in 16 (2.0%) patients who were treated with intravenous nivolumab in combination with chemotherapy; these included pneumonitis (4 patients), febrile neutropenia (2 patients), stroke (2 patients), gastrointestinal toxicity, intestinal mucositis, septic shock, pneumonia, infection, gastrointestinal bleeding, mesenteric vessel thrombosis, and disseminated intravascular coagulation.

In Checkmate 76K, serious adverse reactions occurred in 18% of patients receiving intravenous nivolumab (n=524). Adverse reactions which resulted in permanent discontinuation of intravenous nivolumab in >1% of patients included arthralgia (1.7%), rash (1.7%), and diarrhea (1.1%). A fatal adverse reaction occurred in 1 (0.2%) patient (heart failure and acute kidney injury). The most frequent Grade 3-4 lab abnormalities reported in ≥1% of intravenous nivolumab-treated patients were increased lipase (2.9%), increased AST (2.2%), increased ALT (2.1%), lymphopenia (1.1%), and decreased potassium (1.0%).

Common Adverse Reactions

In Checkmate 67T, the most common adverse reactions (≥10%) in patients treated with OPDIVO QVANTIG (n=247) were musculoskeletal pain (31%), fatigue (20%), pruritus (16%), rash (15%), hypothyroidism (12%), diarrhea (11%), cough (11%), and abdominal pain (10%).

In Checkmate 037, the most common adverse reaction (≥20%) reported with intravenous nivolumab (n=268) was rash (21%). In Checkmate 066, the most common adverse reactions (≥20%) reported with intravenous nivolumab (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 intravenous nivolumab arm (n=313) were fatigue (59%), rash (40%), musculoskeletal pain (42%), diarrhea (36%), nausea (30%), cough (28%), pruritus (27%), upper respiratory tract infection (22%), decreased appetite (22%), headache (22%), constipation (21%), arthralgia (21%), and vomiting (20%). In Checkmate 067, the most common (≥20%) adverse reactions in the intravenous nivolumab plus intravenous ipilimumab arm (n=313) were fatigue (62%), diarrhea (54%), rash (53%), nausea (44%), pyrexia (40%), pruritus (39%), musculoskeletal pain (32%), vomiting (31%), decreased appetite (29%), cough (27%), headache (26%), dyspnea (24%), upper respiratory tract infection (23%), arthralgia (21%), and increased transaminases (25%).

In Checkmate 816, the most common (>20%) adverse reactions in the intravenous nivolumab plus chemotherapy arm (n=176) were nausea (38%), constipation (34%), fatigue (26%), decreased appetite (20%), and rash (20%).

In Checkmate 77T, the most common adverse reactions (reported in ≥20%) in patients receiving intravenous nivolumab in combination with chemotherapy (n= 228) were anemia (39.5%), constipation (32.0%), nausea (28.9%), fatigue (28.1%), alopecia (25.9%), and cough (21.9%).

In Checkmate 017 and 057, the most common adverse reactions (≥20%) in patients receiving intravenous nivolumab (n=418) were fatigue, musculoskeletal pain, cough, dyspnea, and decreased appetite.

In Checkmate 214, the most common adverse reactions (≥20%) reported in patients treated with intravenous nivolumab plus intravenous ipilimumab (n=547) were fatigue (58%), rash (39%), diarrhea (38%), musculoskeletal pain (37%), pruritus (33%), nausea (30%), cough (28%), pyrexia (25%), arthralgia (23%), decreased appetite (21%), dyspnea (20%), and vomiting (20%).

In Checkmate 9ER, the most common adverse reactions (≥20%) in patients receiving intravenous nivolumab and cabozantinib (n=320) were diarrhea (64%), fatigue (51%), hepatotoxicity (44%), palmar-plantar erythrodysaesthesia syndrome (40%), stomatitis (37%), rash (36%), hypertension (36%), hypothyroidism (34%), musculoskeletal pain (33%), decreased appetite (28%), nausea (27%), dysgeusia (24%), abdominal pain (22%), cough (20%) and upper respiratory tract infection (20%).

In Checkmate 025, the most common adverse reactions (≥20%) reported in patients receiving intravenous nivolumab (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 141, the most common adverse reactions (≥10%) in patients receiving intravenous nivolumab (n=236) were cough (14%) and dyspnea (14%) at a higher incidence than investigator’s choice.

In Checkmate 275, the most common adverse reactions (≥ 20%) reported in patients receiving intravenous nivolumab (n=270) were fatigue (46%), musculoskeletal pain (30%), nausea (22%), and decreased appetite (22%).

In Checkmate 274, the most common adverse reactions (20%) reported in patients receiving intravenous nivolumab (n=351) were rash (36%), fatigue (36%), diarrhea (30%), pruritus (30%), musculoskeletal pain (28%), and urinary tract infection (22%).

In Checkmate 901, the most common adverse reactions (reported in ≥20% of patients) were nausea (52%), fatigue (48%), musculoskeletal pain (33%), constipation (30%), decreased appetite (30%), rash (25%), vomiting (23%), and peripheral neuropathy (20%).

In Checkmate 142 in MSI-H/dMMR mCRC patients receiving intravenous nivolumab as a single agent (n=74), the most common adverse reactions (≥20%) were fatigue (54%), diarrhea (43%), abdominal pain (34%), nausea (34%), vomiting (28%), musculoskeletal pain (28%), cough (26%), pyrexia (24%), rash (23%), constipation (20%), and upper respiratory tract infection (20%).

In Checkmate 142 in MSI-H/dMMR mCRC patients receiving intravenous nivolumab with intravenous ipilimumab (n=119), the most common adverse reactions (≥20%) were fatigue (49%), diarrhea (45%), pyrexia (36%), musculoskeletal pain (36%), abdominal pain (30%), pruritus (28%), nausea (26%), rash (25%), decreased appetite (20%), and vomiting (20%).

In Checkmate 040, the most common adverse reactions (≥20%) in patients receiving intravenous nivolumab with intravenous ipilimumab (n=49), were rash (53%), pruritus (53%), musculoskeletal pain (41%), diarrhea (39%), cough (37%), decreased appetite (35%), fatigue (27%), pyrexia (27%), abdominal pain (22%), headache (22%), nausea (20%), dizziness (20%), hypothyroidism (20%), and weight decreased (20%).

In Checkmate 238, the most common adverse reactions (≥20%) reported in intravenous nivolumab-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%).

In Attraction-3, the most common adverse reactions (≥20%) in intravenous nivolumab-treated patients (n=209) were rash (22%) and decreased appetite (21%).

In Checkmate 577, the most common adverse reactions (≥20%) in patients receiving intravenous nivolumab (n=532) were fatigue (34%), diarrhea (29%), nausea (23%), rash (21%), musculoskeletal pain (21%), and cough (20%).

In Checkmate 648, the most common adverse reactions (≥20%) in patients treated with intravenous nivolumab in combination with chemotherapy (n=310) were nausea (65%), decreased appetite (51%), fatigue (47%), constipation (44%), stomatitis (44%), fatigue (32%), diarrhea (29%), and vomiting (23%). In Checkmate 648, the most common adverse reactions reported in ≥20% of patients treated with intravenous nivolumab in combination with intravenous ipilimumab were rash (31%), fatigue (28 %), pyrexia (23%), nausea (22%), diarrhea (22%), fatigue (21%), and constipation (20%).

In Checkmate 649, the most common adverse reactions (≥20%) in patients treated with intravenous nivolumab in combination with chemotherapy (n=782) were peripheral neuropathy (53%), nausea (48%), fatigue (44%), diarrhea (39%), vomiting (31%), decreased appetite (29%), abdominal pain (27%), constipation (25%), and musculoskeletal pain (20%).

In Checkmate 76K, the most common adverse reactions (≥20%) reported with intravenous nivolumab (n=524) were fatigue (36%), musculoskeletal pain (30%), rash (28%), diarrhea (23%) and pruritus (20%).

Surgery Related Adverse Reactions

In Checkmate 77T, 5.3% (n=12) of the intravenous nivolumab-treated patients who received neoadjuvant treatment, did not receive surgery due to adverse reactions. The adverse reactions that led to cancellation of surgery in intravenous nivolumab-treated patients were cerebrovascular accident, pneumonia, and colitis/diarrhea (2 patients each) and acute coronary syndrome, myocarditis, hemoptysis, pneumonitis, COVID-19, and myositis (1 patient each).

Please see U.S. Full Prescribing Information for OPDIVO QVANTIG.

Clinical Trials and Patient Populations

Checkmate 649–previously untreated advanced or metastatic gastric cancer, gastroesophageal junction and esophageal adenocarcinoma; Checkmate 577–adjuvant treatment of esophageal or gastroesophageal junction cancer; Checkmate 238–adjuvant treatment of patients with completely resected Stage III or Stage IV melanoma; Checkmate 76K–adjuvant treatment of patients 12 years of age and older with completely resected Stage IIB or Stage IIC melanoma; Checkmate 274–adjuvant treatment of urothelial carcinoma; Checkmate 275–previously treated advanced or metastatic urothelial carcinoma; Checkmate 142–MSI-H or dMMR metastatic colorectal cancer, as a single agent or in combination with YERVOY; Checkmate 142–MSI-H or dMMR metastatic colorectal cancer, as a single agent or in combination with YERVOY; Attraction-3–esophageal squamous cell carcinoma; Checkmate 648–previously untreated, unresectable advanced recurrent or metastatic esophageal squamous cell carcinoma in combination with chemotherapy; Checkmate 040–hepatocellular carcinoma, in combination with YERVOY; Checkmate 037–previously treated metastatic melanoma; Checkmate 066–previously untreated metastatic melanoma; Checkmate 067–previously untreated metastatic melanoma, as a single agent or in combination with YERVOY; Checkmate 017–second-line treatment of metastatic squamous non-small cell lung cancer; Checkmate 057–second-line treatment of metastatic non-squamous non-small cell lung cancer; Checkmate 816–neoadjuvant non-small cell lung cancer, in combination with platinum-doublet chemotherapy; Checkmate 77T–Neoadjuvant treatment with platinum-doublet chemotherapy for non-small cell lung cancer followed by single-agent OPDIVO as adjuvant treatment after surgery; Checkmate 901–Adult patients with unresectable or metastatic urothelial carcinoma; Checkmate 141–recurrent or metastatic squamous cell carcinoma of the head and neck; Checkmate 025–previously treated renal cell carcinoma; Checkmate 214–previously untreated renal cell carcinoma, in combination with YERVOY; Checkmate 9ER–previously untreated renal cell carcinoma, in combination with cabozantinib

Please see U.S. Full Prescribing Information for OPDIVO and YERVOY.

Bristol Myers Squibb: Creating a Better Future for People with Cancer

Bristol Myers Squibb is inspired by a single vision — transforming patients’ lives through science. The goal of the company’s cancer research is to deliver medicines that offer each patient a better, healthier life and to make cure a possibility. Building on a legacy across a broad range of cancers that have changed survival expectations for many, Bristol Myers Squibb researchers are exploring new frontiers in personalized medicine and, through innovative digital platforms, are turning data into insights that sharpen their focus. Deep understanding of causal human biology, cutting-edge capabilities and differentiated research programs uniquely position the company to approach cancer from every angle.

Cancer can have a relentless grasp on many parts of a patient’s life, and Bristol Myers Squibb is committed to taking actions to address all aspects of care, from diagnosis to survivorship. As a leader in cancer care, Bristol Myers Squibb is working to empower all people with cancer to have a better future.

About the Bristol Myers Squibb and Ono Pharmaceutical Collaboration

In 2011, through a collaboration agreement with Ono Pharmaceutical Co., 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, Ono and Bristol Myers Squibb 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, X, YouTube, Facebook and Instagram.

Cautionary Statement Regarding Forward-Looking Statements

This press release contains “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995 regarding, among other things, the research, development and commercialization of pharmaceutical products. All statements that are not statements of historical facts are, or may be deemed to be, forward-looking statements. Such forward-looking statements are based on current expectations and projections about our future financial results, goals, plans and objectives and involve inherent risks, assumptions and uncertainties, including internal or external factors that could delay, divert or change any of them in the next several years, that are difficult to predict, may be beyond our control and could cause our future financial results, goals, plans and objectives to differ materially from those expressed in, or implied by, the statements. These risks, assumptions, uncertainties and other factors include, among others, that the outcome of pricing and reimbursement negotiations in individual countries in Europe may delay or limit the commercial potential of Opdivo SC for the additional indication described in this release, any marketing approvals, if granted, may have significant limitations on their use, that continued approval of such treatment for such indication may be contingent upon verification and description of clinical benefit in confirmatory trials, and whether such combination treatment for such indication will be commercially successful. No forward-looking statement can be guaranteed. Forward-looking statements in this press release should be evaluated together with the many risks and uncertainties that affect Bristol Myers Squibb’s business and market, particularly those identified in the cautionary statement and risk factors discussion in Bristol Myers Squibb’s Annual Report on Form 10-K for the year ended December 31, 2024, as updated by our subsequent Quarterly Reports on Form 10-Q, Current Reports on Form 8-K and other filings with the Securities and Exchange Commission. The forward-looking statements included in this document are made only as of the date of this document and except as otherwise required by applicable law, Bristol Myers Squibb undertakes no obligation to publicly update or revise any forward-looking statement, whether as a result of new information, future events, changed circumstances or otherwise.

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