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 Cavgd28 and Cminss, 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)--$BMY #CheckMate--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, Cavgd28 (time-averaged Opdivo serum concentration over 28 days) and Cminss (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 Cavgd28 was 2.10 (90% CI: 2.00-2.20) and the GMR for Cminss 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 QvantigTM, 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 (Cavgd28) and minimum concentration at steady state (Cminss). 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.
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