U.S. Food and Drug Administration approves OPDIVO® (nivolumab) in combination with CABOMETYX® (cabozantinib) as first-line treatment for patients with advanced renal cell carcinoma
In CheckMate -9ER, OPDIVO in combination with CABOMETYX doubled median progression-free survival and objective response rate and showed superior overall survival vs. sunitinib1
Approved across all International Metastatic Renal Cell Carcinoma Database Consortium risk categories1,2
Approval expands Company’s presence in first-line advanced renal cell carcinoma, which includes OPDIVO + YERVOY as a standard of care for intermediate- or poor-risk patients3
PRINCETON, N.J. — (BUSINESS WIRE) — $BMY #BMS—Bristol Myers Squibb (NYSE: BMY) today announced that OPDIVO® (nivolumab) 240 mg (injection for intravenous use) every two weeks or 480 mg every four weeks in combination with CABOMETYX® (cabozantinib) 40 mg once daily tablets was approved by the U.S. Food and Drug Administration (FDA) for the first-line treatment of patients with advanced renal cell carcinoma (RCC).1 The approval is based on the Phase 3 CheckMate -9ER trial, which compared OPDIVO in combination with CABOMETYX (n=323) versus sunitinib (n=328) in patients with advanced RCC.1 This application was reviewed under the FDA’s Real-Time Oncology Review (RTOR) pilot program, which aims to ensure that safe and effective treatments are available to patients as early as possible. 4 Please see below for additional CheckMate -9ER data context.
“At Bristol Myers Squibb, we are focused on developing transformative medicines that may improve survival for people living with cancer. The role of OPDIVO + YERVOY is well established for intermediate/poor-risk patients with advanced RCC, and today’s achievement extends the potential of an OPDIVO-based combination to even more patients,” says Adam Lenkowsky, general manager and head, U.S., Oncology, Immunology, Cardiovascular, Bristol Myers Squibb.1 “OPDIVO in combination with CABOMETYX brings together the strong heritage of both medicines to now provide physicians a new combination in advanced RCC that may offer improved outcomes to patients for whom an immunotherapy plus tyrosine kinase inhibitor regimen is appropriate.”1
OPDIVO and YERVOY are associated with the following Warnings and Precautions: severe and fatal immune-mediated adverse reactions including pneumonitis, colitis, hepatitis and hepatotoxicity, endocrinopathies, nephritis with renal dysfunction, dermatologic adverse reactions, other immune-mediated adverse reactions; infusion-related reactions; complications of allogeneic hematopoietic stem cell transplantation (HSCT); embryo-fetal toxicity; and increased mortality in patients with multiple myeloma when OPDIVO is added to a thalidomide analogue and dexamethasone, which is not recommended outside of controlled clinical trials.1 Please see the Important Safety Information section below.
“This combination of cabozantinib and nivolumab significantly improved key efficacy measures compared to sunitinib – progression-free survival, overall survival and objective response rate – while showing a low rate of treatment discontinuations due to side effects. The therapeutic benefit demonstrated in CheckMate -9ER and quality of life measures explored emphasize the role of this combination for patients with advanced kidney cancer,” said Toni Choueiri, M.D., director, Lank Center for Genitourinary Oncology at Dana-Farber Cancer Institute and the Jerome and Nancy Kohlberg Professor of Medicine at Harvard Medical School.1,2 “With this important FDA approval, the combination is poised to become a standard in newly diagnosed metastatic kidney cancer.”
In the CheckMate -9ER trial, the primary endpoint was progression-free survival (PFS) assessed by Blinded Independent Central Review (BICR), and the secondary endpoints included overall survival (OS) and BICR-assessed objective response rate (ORR).1 In the trial, patients treated with OPDIVO in combination with CABOMETYX lived twice as long without their tumors progressing as patients who were treated with sunitinib (median PFS was 16.6 months [95% Confidence Interval [CI]: 12.5-24.9] versus median PFS of 8.3 months [95% CI: 7.0-9.7]; [Hazard Ratio [HR]: 0.51 [95% CI: 0.41–0.64], P<0.0001; median follow-up of 18.1 months]; range: 10.6-30.6 months).1,2 OPDIVO in combination with CABOMETYX also reduced the risk of death by 40% compared to sunitinib (HR: 0.60 [98.89% CI 0.40–0.89]; P=0.0010; median OS was not reached for OPDIVO in combination with CABOMETYX and not available for sunitinib [range: 22.6-NR months]).1
Additionally, more patients responded to OPDIVO in combination with CABOMETYX than sunitinib, with an ORR of 55.7% (n=180/323) (95% CI: 50.1 to 61.2) versus 27.1% (n=89/328) (95% CI: 22.4 to 32.3); P<0.0001, respectively.1 In the combination arm, 8.0% (n=26/323) of patients experienced a complete response and 47.7% (n=154/323) experienced a partial response versus 4.6% (n=15/328) and 22.6% (n=74/328) of those treated with sunitinib.1,2 Among patients who responded, the median duration of response was 20.2 months for OPDIVO in combination with CABOMETYX (95% CI: 17.3 to NA) and 11.5 months for sunitinib (95% CI: 8.3 to 18.4).1 Consistent results for PFS were observed across pre-specified subgroups of International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk categories and PD-L1 tumor expression status.1
Adverse reactions greater than Grade 3 in the trial were similar with OPDIVO in combination with CABOMETYX versus sunitinib (75% versus 71%).2 All-cause adverse reactions leading to discontinuation of either OPDIVO or CABOMETYX occurred in 19.7% of patients; 6.6% of OPDIVO only, 7.5% of CABOMETYX only and 5.6% of the combination due to same adverse reaction at the same time.1,5
“While significant progress has been made in the treatment landscape for advanced kidney cancer over the last several years, patients still need more therapeutic options to treat this disease as we search for a possible cure,” said Bryan Lewis, president and co-founder of KidneyCAN.6,7 “As patients are living longer with advanced kidney cancer, focusing on the safety and effectiveness of new treatments has become even more important. The findings for the combination of OPDIVO and CABOMETYX in the CheckMate -9ER trial make the FDA approval of this combination a notable development for the patient community.”1
About CheckMate -9ER
CheckMate -9ER is an open-label, randomized, Phase 3 trial evaluating patients with previously untreated advanced renal cell carcinoma (RCC).1 A total of 651 patients (22% favorable risk, 58% intermediate risk, 20% poor risk) were randomized to OPDIVO in combination with CABOMETYX (n=323) versus sunitinib (n=328).1 Patients were randomized to receive 240 mg of OPDIVO every two weeks intravenously and 40 mg of CABOMETYX orally daily or sunitinib 50 mg orally daily for the first four weeks of a six-week cycle.1 Treatment with OPDIVO continued until disease progression per Response Evaluation version 1.1 (RECIST v1.1) or unacceptable toxicity.1 The recommended dosing for OPDIVO and CABOMETYX is 240 mg of OPDIVO every two weeks or 480 mg every four weeks in combination with 40 mg of CABOMETYX once daily administered orally without food.1 The recommended treatment for OPDIVO is until disease progression, unacceptable toxicity or up to two years.1 Treatment with CABOMETYX is until disease progression or unacceptable toxicity.1 The primary endpoint was progression-free survival (PFS) assessed by Blinded Independent Central Review (BICR), using RECIST v1.1.1 Secondary endpoints included overall survival (OS) and objective response rate (ORR), the latter of which was assessed by BICR using RECIST v1.1.1 The trial is sponsored by Bristol Myers Squibb and Ono Pharmaceutical Co and co-funded by Exelixis, Ipsen and Takeda Pharmaceutical Company Limited.
Select Safety Profile from CheckMate -9ER Study
Adverse reactions leading to discontinuation of either OPDIVO or CABOMETYX occurred in 19.7% of patients: 6.6% OPDIVO only, 7.5% CABOMETYX only and 5.6% both drugs due to the same adverse reaction at the same time.1,5 Adverse reactions leading to dose interruption or reduction of either OPDIVO or CABOMETYX occurred in 83% of patients: 3% OPDIVO only, 46% CABOMETYX only, 21% both drugs due to same adverse reaction at the same time and 6% both drugs, sequentially.1 Serious adverse reactions occurred in 48% of patients receiving OPDIVO in combination with CABOMETYX (n=320).1 The most frequent (≥2%) serious adverse reactions in those patients were diarrhea, pneumonia, pneumonitis, pulmonary embolism, urinary tract infection and hyponatremia.1 Fatal intestinal perforations occurred in 3 (0.9%) patients.1 The most common (≥20%) adverse reactions of any grade in patients receiving OPDIVO and CABOMETYX 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%).1
About Renal Cell Carcinoma
Renal cell carcinoma (RCC) is the most common type of kidney cancer in adults, accounting for approximately 15,000 deaths in the United States each year.8,9 RCC is approximately twice as common in men as in women.10 In the United States, the five-year survival rate, based on data from 2010 to 2016, for those diagnosed with metastatic (or advanced) kidney and renal pelvis cancer is 13%.9
INDICATIONS
OPDIVO® (nivolumab), in combination with YERVOY® (ipilimumab), is indicated for the first-line treatment of patients with intermediate or poor risk advanced renal cell carcinoma (RCC).
OPDIVO® (nivolumab), in combination with cabozantinib, is indicated for the first-line treatment of patients with advanced renal cell carcinoma (RCC).
IMPORTANT SAFETY INFORMATION
Severe and Fatal Immune-Mediated Adverse Reactions
Immune-mediated adverse reactions listed herein may not include all possible 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 or YERVOY. Early identification and management are essential to ensure safe use of OPDIVO and YERVOY. Monitor for signs and symptoms that may be clinical manifestations of underlying immune-mediated adverse reactions. Evaluate clinical chemistries including liver enzymes, creatinine, adrenocorticotropic hormone (ACTH) level, and thyroid function at baseline and periodically during treatment with OPDIVO and before each dose of YERVOY. 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 and YERVOY depending on severity (please see section 2 Dosage and Administration in the accompanying Full Prescribing Information). In general, if OPDIVO or YERVOY 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 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 and YERVOY can cause immune-mediated pneumonitis. The incidence of pneumonitis is higher in patients who have received prior thoracic radiation. In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, immune-mediated pneumonitis occurred in 3.9% (26/666) of patients, including Grade 3 (1.4%) and Grade 2 (2.6%).
Immune-Mediated Colitis
OPDIVO and YERVOY can cause immune-mediated colitis, which may be fatal. 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. In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, immune-mediated colitis occurred in 9% (60/666) of patients, including Grade 3 (4.4%) and Grade 2 (3.7%).
Immune-Mediated Hepatitis and Hepatotoxicity
OPDIVO and YERVOY can cause immune-mediated hepatitis. In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, immune-mediated hepatitis occurred in 7% (48/666) of patients, including Grade 4 (1.2%), Grade 3 (4.9%), and Grade 2 (0.4%).
OPDIVO in combination with cabozantinib can cause hepatic toxicity with higher frequencies of Grade 3 and 4 ALT and AST elevations compared to OPDIVO alone. Consider more frequent monitoring of liver enzymes as compared to when the drugs are administered as single agents. In patients receiving OPDIVO and cabozantinib, Grades 3 and 4 increased ALT or AST were seen in 11% of patients.
Immune-Mediated Endocrinopathies
OPDIVO and YERVOY 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 and YERVOY 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.
In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, adrenal insufficiency occurred in 7% (48/666) of patients, including Grade 4 (0.3%), Grade 3 (2.5%), and Grade 2 (4.1%). In patients receiving OPDIVO and cabozantinib, adrenal insufficiency occurred in 4.7% (15/320) of patients, including Grade 3 (2.2%) and Grade 2 (1.9%).
In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, hypophysitis occurred in 4.4% (29/666) of patients, including Grade 4 (0.3%), Grade 3 (2.4%), and Grade 2 (0.9%).
In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, thyroiditis occurred in 2.7% (22/666) of patients, including Grade 3 (4.5%) and Grade 2 (2.2%).
In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, hyperthyroidism occurred in 12% (80/666) of patients, including Grade 3 (0.6%), and Grade 2 (4.5%).
In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, hypothyroidism occurred in 18% (122/666) of patients, including Grade 3 (0.6%) and Grade 2 (11%).
In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, diabetes occurred in 2.7% (15/666) of patients, including Grade 4 (0.6%), Grade 3 (0.3%), and Grade 2 (0.9%).
Immune-Mediated Nephritis with Renal Dysfunction
OPDIVO and YERVOY can cause immune-mediated nephritis. In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, immune-mediated nephritis with renal dysfunction occurred in 4.1% (27/666) of patients, including Grade 4 (0.6%), Grade 3 (1.1%), and Grade 2 (2.2%).
Immune-Mediated Dermatologic Adverse Reactions
OPDIVO can cause immune-mediated rash or dermatitis. Exfoliative dermatitis, including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug rash with eosinophilia and systemic symptoms (DRESS) has occurred with PD-1/PD-L1 blocking antibodies. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate nonexfoliative rashes.
YERVOY can cause immune-mediated rash or dermatitis, including bullous and exfoliative dermatitis, SJS, TEN, and DRESS. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate non-bullous/ exfoliative rashes.
Withhold or permanently discontinue OPDIVO and YERVOY depending on severity (please see section 2 Dosage and Administration in the accompanying Full Prescribing Information).
In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, immune-mediated rash occurred in 16% (108/666) of patients, including Grade 3 (3.5%) and Grade 2 (4.2%).
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 monotherapy or OPDIVO in combination with YERVOY 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.
In addition to the immune-mediated adverse reactions listed above, across clinical trials of YERVOY monotherapy or in combination with OPDIVO, the following clinically significant immune-mediated adverse reactions, some with fatal outcome, occurred in <1% of patients unless otherwise specified: nervous system: autoimmune neuropathy (2%), myasthenic syndrome/myasthenia gravis, motor dysfunction; cardiovascular: angiopathy, temporal arteritis; ocular: blepharitis, episcleritis, orbital myositis, scleritis; gastrointestinal: pancreatitis (1.3%); other (hematologic/immune): conjunctivitis, cytopenias (2.5%), eosinophilia (2.1%), erythema multiforme, hypersensitivity vasculitis, neurosensory hypoacusis, psoriasis.
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, which has been observed in patients receiving OPDIVO and YERVOY, as this may require treatment with systemic corticosteroids to reduce the risk of permanent vision loss.
Infusion-Related Reactions
OPDIVO and YERVOY can cause severe infusion-related reactions. Discontinue OPDIVO and YERVOY in patients with severe (Grade 3) or life-threatening (Grade 4) infusion-related reactions. Interrupt or slow the rate of infusion in patients with mild (Grade 1) or moderate (Grade 2) infusion-related reactions. In RCC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, infusion-related reactions occurred in 5.1% (28/547) of patients.
Complications of Allogeneic 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 or YERVOY. 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 or YERVOY and allogeneic HSCT.
Follow patients closely for evidence of transplant-related complications and intervene promptly. Consider the benefit versus risks of treatment with OPDIVO and YERVOY prior to or after an allogeneic HSCT.
Embryo-Fetal Toxicity
Based on its mechanism of action and findings from animal studies, OPDIVO and YERVOY can cause fetal harm when administered to a pregnant woman. The effects of YERVOY are likely to be greater during the second and third trimesters of pregnancy. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with OPDIVO and YERVOY and for at least 5 months after the last dose.
Increased Mortality in Patients with Multiple Myeloma when OPDIVO is Added to a Thalidomide Analogue and Dexamethasone
In randomized clinical trials in patients with multiple myeloma, the addition of OPDIVO to a thalidomide analogue plus dexamethasone 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 OPDIVO or YERVOY in human milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment and for 5 months after the last dose.
Serious Adverse Reactions
In Checkmate 214, serious adverse reactions occurred in 59% of patients receiving OPDIVO plus YERVOY (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 OPDIVO 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.
Common Adverse Reactions
In Checkmate 214, the most common adverse reactions (≥20%) reported in patients treated with OPDIVO plus YERVOY (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 OPDIVO 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%).
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