The progression of ongoing clinical research in the first-line treatment of advanced renal cell carcinoma has remained critical, particularly with a focus on long-term efficacy in this setting (2)
When faced with an advanced renal cell carcinoma (RCC) cancer, finding an effective treatment option that may offer long term survival is critical to healthcare professionals, patients and their loved ones alike – as these patients can have a challenging road ahead.3,4 Historically the prognosis has been poor, with recent data pointing to a five-year relative survival rate of 17.4% for metastatic disease.2,3
However, clinical advances have brought to fruition the availability of additional options to consider, along with new hope for this community.5 And, as the target of long-term survival has remained a key driver in treatment-related decisions, ongoing research has included longer-term follow-up data further examining efficacy and safety of different approaches.
At the American Society of Clinical Oncology (ASCO®) 2024 Genitourinary Cancers Symposium held in January, eight-year extended follow-up data from a Phase 3 trial for a dual immunotherapy in certain patients with intermediate- or poor-risk advanced RCC was presented for the first time, highlighting the potential of this option.1 At eight years, the timeframe covered by this follow-up data is unprecedented in the evaluation of dual immunotherapy for this patient population.1
“Time is perhaps one of the most meaningful things that can be given to people impacted by an advanced RCC diagnosis,” says Lee James, MD, PhD, vice president of U.S. Medical Oncology at Bristol Myers Squibb. “This is why significant research has been focused on longer-term survival, which may translate into the potential for certain patients to have more years.”
This dual immunotherapy, Opdivo® (nivolumab) in combination with Yervoy® (ipilimumab), was approved by the U.S. FDA in 2018 for the first-line treatment of adult patients with intermediate- or poor-risk advanced RCC.5,6 The approval was supported by data from the Phase 3 CheckMate -214 trial at the primary analysis with a median follow-up of 25.2 months.5,6 Please see below for data from the primary analysis.
“As the longest dual immunotherapy clinical follow-up to-date in this particularly difficult to treat setting, it’s incredibly exciting to now have these eight-year findings from the CheckMate -214 trial,” explains James.1,3,4 “These data include several key measures that are critical when assessing therapeutic approaches in the treatment of a patient with advanced RCC, and both overall survival and duration of response may be of particular interest to healthcare professionals focused on RCC.”1 Please see eight-year extended follow up data below.
Opdivo and Yervoy are associated with the following Warnings and Precautions: Opdivo is associated with the following Warnings & Precautions: severe and fatal immune-mediated adverse reactions, including pneumonitis, colitis, hepatitis and hepatotoxicity, endocrinopathies, dermatologic adverse reactions, nephritis with renal dysfunction, 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.5 Please see Important Safety Information below.
CheckMate -214 primary analysis and eight-year extended follow-up data
The CheckMate -214 trial is a Phase 3, randomized, open-label study evaluating the combination of Opdivo + Yervoy versus sunitinib in patients with previously untreated, intermediate- and poor-risk advanced RCC. 5 Patients in the combination group (n=425) received Opdivo 3 mg/kg IV plus Yervoy 1 mg/kg IV every three weeks for four doses followed by Opdivo 3 mg/kg every two weeks. Patients in the comparator group (n=422) received sunitinib 50 mg orally once daily for four weeks, followed by two weeks off every cycle.5 For the approved dosing of Opdivo + Yervoy in this setting, please see full Prescribing Information. Patients were stratified by International Metastatic RCC Database Consortium (IMDC) prognostic score and region and were all treated until progression or unacceptable toxicity.5 The primary endpoints of the trial are overall survival (OS), progression-free survival (PFS) and objective response rate (ORR). ORR and PFS were assessed by independent radiology review committee (IRRC).5
In the primary analysis, the pre-specified 12-month OS rate was 80% (95% CI: 76-84) with Opdivo + Yervoy versus 75% (95% CI: 67-76) with sunitinib.6,7 The median follow-up time was 25.2 months.6 Opdivo + Yervoy reduced the risk of death by 37% versus sunitinib (hazard ratio [HR] 0.63; 99.8% confidence interval [CI]: 0.44 to 0.89; P<0.0001), with median OS not reached for the combination (95% CI: 28.2 to not estimable [NE]) and 25.9 months for sunitinib (95% CI: 22.1 to NE).5,6 The confirmed ORR was 41.6% (177/425) for Opdivo + Yervoy (95% CI: 36.9-46.5) versus 26.5% (112/422) for sunitinib (95% CI: 22.4-31.0) (P<0.0001).5 The complete response (CR) rate was 9.4% for Opdivo + Yervoy (n=40/425) and 1.2% for sunitinib (n=5/422), and the partial response (PR) rate was 32.2% (n=137/425) and 25.4% (n=107/422), respectively.5 The median duration of response (mDOR) for patients treated with Opdivo + Yervoy was not reached (95% CI: 21.8 -NR) and 18.2 months for patients treated with sunitinib (95% CI: 14.8 – NR).5 Median PFS was 11.6 months (95% CI: 8.7 to 15.5) for the Opdivo + Yervoy combination, compared to 8.4 months (95% CI: 7.0 to 10.8) for sunitinib (HR 0.82; 99.1% CI: 0.64 to 1.05; P=not significant).5,6 Per a pre-specified analysis, PFS did not reach statistical significance.
The most common adverse reactions (reported in at least 20% of Opdivo + Yervoy treated patients) were fatigue (58%), rash (39%), diarrhea (38%), musculoskeletal pain (37%), pruritis (33%), nausea (30%), cough (28%), pyrexia (25%), arthralgia (23%), decreased appetite (21%), dyspnea (20%), and vomiting (20%).5,6 Serious adverse reactions occurred in 59% of patients receiving Opdivo + Yervoy.5 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.5,6
OS, PFS and ORR, the trial’s three primary endpoints, were shown during a follow-up analysis at eight years (99.1 months median follow-up [range: 91.0 – 107.3]) in intermediate- and poor-risk patients.1 The Opdivo + Yervoy 90-month OS rate was 32.9% compared to 22.0% with sunitinib, and median OS of 46.7 months (95% CI: 35.0-55.7) versus 26.0 months (95% CI: 21.8-32.6), respectively [HR 0.69 (95% CI: 0.59-0.81)] (Figure 1).1
Figure 1 -CheckMate -214 eight-year median follow-up: Overall survival1
OS rates at follow-up analyses were not pre-specified within the study protocol and analyses were not powered to detect differences between treatment arms.7
In the eight-year analysis, the Opdivo + Yervoy 90-month PFS rate was 25.4% compared to 8.5% with sunitinib, and median PFS of 12.4 months (95% CI: 8.7 to 16.8) and 8.5 months (95% CI: 7.0 to 11.1), respectively (HR 0.73; 95% CI: 0.61 to 0.87) (Figure 2).1
Figure 2 - CheckMate -214 eight-year median follow-up: Progression-free survival1
†Performance status is based on IMDC prognostic score (0=favorable, 1-2=intermediate, 3+=poor).1,6
PFS rates at follow-up analyses were not pre-specified within the study protocol and analyses were not powered to detect differences between treatment arms.7
At eight years, the ORR for patients treated with Opdivo + Yervoy was 42% (n=180/425 [95% CI: 38-47]; CR: 12% [n=50], PR: 31% [n=130]) versus 27% with sunitinib (n=116/422 [95% CI: 23-32]; CR: 3% [n=11], PR: 25% [n=105]). The mDOR for patients treated with Opdivo + Yervoy was 82.8 months (95% CI: 54.1-NE) versus 19.8 months (95% CI: 16.4-26.4) with sunitinib (HR = 0.48 (95% CI: 0.33-0.69).1 And, Opdivo + Yervoy showed a 50% chance for responses to last up to 90 months, compared to 23% with sunitinib (Figure 3).1
Of those who had a complete response, 84% (n=42/50) of patients treated with Opdivo + Yervoy had an ongoing complete response at eight years of follow-up versus 91% for sunitinib (n=10/11).1
Figure 3 – CheckMate -214 eight-year median follow-up: Duration of response1
DOR rates at follow-up analyses were not pre-specified within the study protocol and analyses were not powered to detect differences between treatment arms.7
“With these latest findings, we continue to see the potential for long term overall survival with Opdivo + Yervoy compared to sunitinib alone through eight years for certain patients, adding to the growing body of evidence for this treatment approach as an important option for certain patients with advanced RCC,” said James. “Contributing to expanded investigation into the long-term potential of dual immunotherapy is an area of research that BMS has proudly led in partnership with the community for years and continues to help drive forward.”
For more information about Opdivo + Yervoy, please visit www.Opdivo.com.
INDICATION
OPDIVO® (nivolumab), in combination with YERVOY® (ipilimumab), is indicated for the first-line treatment of adult patients with intermediate or poor risk advanced renal cell carcinoma (RCC).
OPDIVO (10 mg/mL) and YERVOY (5 mg/mL) are injections for intravenous (IV) use.
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%).
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 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, other transplant (including corneal graft) 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 every 3 weeks, 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.
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%).
Please see US Full Prescribing Information for OPDIVO and YERVOY.
© 2024 Bristol-Myers Squibb Company.
OPDIVO® and YERVOY® are registered trademarks of Bristol-Myers Squibb Company. All other trademarks are the property of their respective owners.
7356-US-2300531 05/24
References
- Tannir NM, Escudier B, McDermott DF, et al. Nivolumab plus ipilimumab versus sunitinib for first-line treatment of advanced renal cell carcinoma: long-term follow-up data from the phase 3 CheckMate 214 trial (Abstract 363). Oral presentation at: ASCO® Genitourinary Cancers Symposium; January 25-27, 2024; San Francisco, CA.
- Khanna A, Crane A, Yerram N, et al. Contemporary management of advanced renal cell carcinoma. Clin Adv Hematol Oncol. 2018;16(6):438-446.
- SEER. Cancer Stat Facts: Kidney and Renal Pelvis Cancer. Available at https://seer.cancer.gov/statfacts/html/kidrp.html. Accessed March 04, 2024.
- American Cancer Society. Kidney Cancer Treatment. Available at https://www.cancer.org/cancer/types/kidney-cancer/treating/by-stage.html. Accessed March 04, 2024.
- Opdivo Prescribing Information. Opdivo U.S. Product Information. Last updated: March 2024. Princeton, NJ: Bristol Myers Squibb Company.
- Motzer RJ, Tannir NM, McDermott DF, et al. Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma. N Engl J Med. 2018; 378:1277-1290.
- Motzer RJ, Tannir NM, McDermott DF, et al. Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma. N Engl J Med. 2018; 378:1277-1290. [Protocol]