Hope With the Help of Dual I-O

July 8, 2024

INDICATIONS

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® (nivolumab), in combination with YERVOY® (ipilimumab), is indicated for the first-line treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) whose tumors express PD-L1 (≥1%) as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations.

OPDIVO® (nivolumab), in combination with YERVOY® (ipilimumab), is indicated for the treatment of adult and pediatric patients 12 years and older with unresectable or metastatic melanoma.

When asked how they hope to spend their remaining time, most patients with cancer agree: their greatest wish is simply to spend more time with loved ones. Even if that time is spent cleaning up after their grandson’s latest, misplaced masterpiece.

While patients yearn to slow down, their doctors may feel pressure to act quickly. Every day there is new data to peruse and novel treatments to discover within oncology, making it all the more difficult to decide on a particular treatment to help meet each patient's needs. Oncologists have struggled with this paradox for years. However, years of follow-up data in multiple tumors show that Bristol Myers Squibb (BMS) dual immuno-oncology (I-O) treatment has the potential to help meet the needs of both patients and doctors.

To celebrate the patient impact of dual I-O, BMS is shining a spotlight on real patients and the moments they thought they may never see after their diagnosis. BMS expanded the possibilities of I-O in 2015 with OPDIVO + YERVOY, the first immune checkpoint inhibitor combination to receive FDA approval for first-line treatment of metastatic melanoma (mMelanoma) in certain patients.^1,2 Read the full Important Safety Information below and click to read the full Prescribing Information.

The dual I-O agent has since gained additional first-line approvals, including for the treatment of patients with intermediate- or poor-risk advanced renal cell carcinoma (aRCC) and metastatic non-small cell lung cancer (mNSCLC) whose tumors express PD-L1 ≥1%.^1,3,4Many patients’ lives have been impacted across various tumor types with the help of dual I-O.

Today, BMS dual I-O continues to transform patient outcomes among some of the deadliest and most aggressive cancers, providing patients with the hope of more time.¹ Here are some real stories of patients who are thankful for dual I-O.

OPDIVO® (nivolumab) and YERVOY® (ipilimumab) are associated with the following Warnings and Precautions: severe and fatal 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.

When Carol was diagnosed with advanced RCC (aRCC) years ago, her life became very different. A doctor recommended she begin dual I-O treatment with OPDIVO + YERVOY and, after some time on treatment, she was hopeful she would feel better. BMS dual I-O helped Carol spend more time on her favorite hobby: creating custom, refurbished furniture for her family and other loved ones.

Carol represents one patient story for treatment of 1L aRCC with OPDIVO + YERVOY. Individual results may vary, and these results are not guaranteed for all patients. The 90-month OS rate for OPDIVO + YERVOY was 32.9% vs 22.0% for sunitinib. In the eight-year follow-up analysis of the Checkmate 214 study (99.1-month median follow-up), median OS was 46.7 months (95% CI: 35.0–55.7) with OPDIVO + YERVOY vs 26.0 months (95% CI: 21.8–32.6) with sunitinib; HR=0.69 (95% CI: 0.59–0.81). In the primary analysis (median follow-up of 25.2 months), median OS was not reached for OPDIVO + YERVOY (n=425, 95% CI: 28.2–NE) vs 25.9 months with sunitinib (n=422, 95% CI: 22.1–NE); HR=0.63 (99.8% CI: 0.44–0.89); P<0.0001.^1,5,6 The confirmed overall response rate was 41.6% (n=177/425 [95% CI: 36.9–46.5]); complete response (CR): 9.4% (n=40); partial response (PR): 32.2% (n=137) for OPDIVO + YERVOY vs 26.5% (n=112/422 [95% CI: 22.4–31.0]); CR: 1.2% (n=5); PR: 25.4% (n=107) for sunitinib (P<0.0001). Among the responders, median duration of response was not reached (95% CI: 21.8–NR) for OPDIVO + YERVOY vs 18.2 months (95% CI: 14.8–NR) for sunitinib. Median progression-free survival (PFS) for OPDIVO + YERVOY and sunitinib was 11.6 months (95% CI: 8.7–15.5) vs 8.4 months (95% CI: 7.0–10.8), respectively; HR=0.82 (99.1% CI: 0.64–1.05). Per a pre-specified analysis, PFS did not meet statistical significance.^1,6 See study design.

SELECT IMPORTANT SAFETY INFORMATION

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 additional Important Safety Information below.

The durable survival of OPDIVO + YERVOY is not limited to advanced RCC.^5,7,8 John—a Navy veteran, travel enthusiast, and father of four—was told he had six months to live when he was diagnosed with mNSCLC. That was years ago. Now, he particularly enjoys spending time with his family and his dogs, whether that means taking them for a leisurely walk through the park or catching them in the act of ransacking the living room. Individual results may vary, and these results are not guaranteed for all patients.

John’s story is just one of many inspiring cases of treatment with OPDIVO + YERVOY for 1L mNSCLC (PD-L1 ≥1%). As shown in the extended follow-up analysis of the Checkmate 227 trial, 22% of patients are still alive at six years on this treatment vs 13% for chemotherapy [Minimum follow-up of 73.5 months: HR=0.78 (95% CI: 0.67–0.91); Primary analysis: HR=0.79 (95% CI: 0.67–0.94; P=0.0066), median overall survival (OS) was 17.1 months (95% CI: 15.0–20.1) for OPDIVO + YERVOY (n=396) vs 14.9 months (95% CI: 12.7–16.7) for chemotherapy (n=397)].^1,7 See study design.

SELECT IMPORTANT SAFETY INFORMATION

Serious Adverse Reactions
In Checkmate 227, serious adverse reactions occurred in 58% of patients (n=576). The most frequent (≥2%) serious adverse reactions were pneumonia, diarrhea/colitis, pneumonitis, hepatitis, pulmonary embolism, adrenal insufficiency, and hypophysitis. Fatal adverse reactions occurred in 1.7% of patients; these included events of pneumonitis (4 patients), myocarditis, acute kidney injury, shock, hyperglycemia, multi-system organ failure, and renal failure.

Common Adverse Reactions
In Checkmate 227, the most common (≥20%) adverse reactions were fatigue (44%), rash (34%), decreased appetite (31%), musculoskeletal pain (27%), diarrhea/colitis (26%), dyspnea (26%), cough (23%), hepatitis (21%), nausea (21%), and pruritus (21%).

Please see additional Important Safety Information below.

OPDIVO + YERVOY has demonstrated long-term survival durability across multiple tumor types,^5,7,8 offering the hope of time and memories to patients while supporting care teams in their treatment decisions. Dave is a restaurant owner and father of four whose life was flipped upside down when he was diagnosed with metastatic melanoma. In his typical fashion, he faced the issue head-on and pursued treatment immediately. To be extra certain he was making an informed decision, he sought second and third opinions on his treatment options. All the doctors he spoke with agreed that he was an ideal candidate for OPDIVO + YERVOY. His results proved them right—he was able to resume his passions: feeding his community and spending time with family. Individual results may vary, and these results are not guaranteed for all patients.

OPDIVO + YERVOY has shown to extend survival of patients with metastatic melanoma in the primary and follow-up analyses of the Checkmate 067 trial. At 7.5 years, 48% of patients treated with OPDIVO + YERVOY were alive, compared with 22% of patients treated with YERVOY alone. Median OS was 72.1 months for OPDIVO + YERVOY and 19.9 months with YERVOY. Primary analysis at 28 months: HR=0.55 (95% CI: 0.44–0.69); P<0.0001.^1,8 At the primary analysis of nine months, mPFS was 11.5 months (95% CI: 8.9–16.7) for OPDIVO + YERVOY, 6.9 months (95% CI: 4.3–9.5) for OPDIVO, and 2.9 months (95% CI: 2.8–3.4) for YERVOY.¹See study design.

SELECT IMPORTANT SAFETY INFORMATION

Please see additional Important Safety Information below.

These real stories couldn’t have happened without the clinical dedication of oncologists across the country who believed in the power of a dual I-O approach and their patients who trusted that dual I-O was the right treatment option for them.

Learn more about dual I-O treatment for your appropriate patients here.

1L=first-line; CI=confidence interval; HR=hazard ratio; NE=not evaluable; NR=not reached; PD-L1=programmed death-ligand 1.

STUDY INFORMATION

1L Intermediate- or Poor-Risk aRCC
Checkmate 214: Checkmate 214 was a phase 3, randomized (1:1), open-label study of OPDIVO 3 mg/kg IV and YERVOY 1 mg/kg IV (n=425) every 3 weeks for 4 doses, followed by OPDIVO 3 mg/kg IV every 2 weeks* vs sunitinib (n=422) 50 mg administered orally once daily for 4 weeks, followed by 2 weeks off every cycle, in patients with previously untreated intermediate-/poor-risk aRCC. Patients were stratified by IMDC prognostic score and region, and treatment was continued until disease progression or unacceptable toxicity. The co-primary endpoints in IMDC intermediate-/poor-risk patients were OS, ORR,† and PFS.^1,6†

*The recommended dose of OPDIVO in combination with YERVOY is 3 mg/kg administered as an IV infusion over 30 minutes, followed by YERVOY 1 mg/kg administered as an IV infusion over 30 minutes on the same day, q3w for 4 doses. The recommended subsequent dose of OPDIVO as a single agent is either 240 mg or 480 mg administered as an IV infusion over 30 minutes q2w or q4w, respectively, until disease progression or unacceptable toxicity.¹†In the primary analysis at a median follow-up of 25.2 months, ORR and PFS were assessed by an independent radiographic review committee.^1,6IV=intravenous; q2w=every 2 weeks; q3w=every 3 weeks; q4w=every 4 weeks.

mNSCLC (PD-L1≥1%)
Checkmate 227: Checkmate 227 was a randomized, open-label, phase 3 trial in patients with metastatic or recurrent NSCLC. Key eligibility criteria included patients 18 years or older, stage IV or recurrent NSCLC, ECOG PS 0/1, and no prior systemic anticancer therapy. Patients with known EGFR mutations or ALK translocations sensitive to available targeted inhibitor therapy, untreated brain metastases, carcinomatous meningitis, active autoimmune disease, or medical conditions requiring systemic immunosuppression were excluded from the study. Treatment continued until disease progression, unacceptable toxicity, or for up to 24 months. Tumor specimens were evaluated prospectively using the PD-L1 IHC 28-8 pharmDx assay at a central laboratory. In Part 1a (n=793), patients with PD-L1 ≥1% were randomized to either OPDIVO 3 mg/kg q2w* + YERVOY 1 mg/kg q6w (n=396) or platinum-doublet chemotherapy^† (n=397). The primary endpoint in Part 1a was OS in patients with PD-L1 ≥1%. Pre-specified descriptive efficacy outcome measures included PFS, ORR, and DOR.^1,7

*The recommended PI dose of OPDIVO is 360 mg q3w with YERVOY 1 mg/kg q6w.^1,10
†In Checkmate 227, patients in the comparator arm received up to 4 cycles of platinum-doublet chemo q3w; NSQ: pemetrexed + carboplatin or cisplatin, with optional pemetrexed maintenance following chemo; SQ: gemcitabine + carboplatin or cisplatin.^1,10
ALK=anaplastic lymphoma kinase; ECOG=Eastern Cooperative Oncology Group; EGFR=epidermal growth factor receptor; IHC=immunohistochemistry.

Metastatic Melanoma
OPDIVO + YERVOY was evaluated in a double-blind, randomized study of previously untreated, unresectable, or metastatic melanoma. Adult patients were randomized (1:1:1) to receive OPDIVO + YERVOY (OPDIVO 1 mg/kg and YERVOY 3 mg/kg q3w for 4 doses, followed by OPDIVO monotherapy 3 mg/kg q2w*), OPDIVO 3 mg/kg q2w, or YERVOY 3 mg/kg q3w for 4 doses, followed by placebo q2w. Major efficacy outcome measures were investigator-assessed PFS per RECIST v1.1 and OS. Additional efficacy outcome measures were confirmed ORR and DOR.¹

*The recommended dose of OPDIVO is 1 mg/kg administered as an IV infusion over 30 minutes, followed by YERVOY 3 mg/kg administered as an IV infusion over 30 minutes on the same day, q3w for a maximum of 4 doses or until unacceptable toxicity, whichever occurs earlier. After completing 4 doses of the combination, administer OPDIVO as a single agent, either 240 mg q2w or 480 mg q4w, as an IV infusion over 30 minutes until disease progression or unacceptable toxicity.¹

INDICATIONS

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® (nivolumab), in combination with YERVOY® (ipilimumab), is indicated for the treatment of adult and pediatric patients 12 years and older with unresectable or metastatic melanoma.

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 monotherapy, immune-mediated pneumonitis occurred in 3.1% (61/1994) of patients, including Grade 4 (<0.1%), Grade 3 (0.9%), and Grade 2 (2.1%). In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, immune-mediated pneumonitis occurred in 7% (31/456) of patients, including Grade 4 (0.2%), Grade 3 (2.0%), and Grade 2 (4.4%). 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%). In NSCLC patients receiving OPDIVO 3 mg/kg every 2 weeks with YERVOY 1 mg/kg every 6 weeks, immune-mediated pneumonitis occurred in 9% (50/576) of patients, including Grade 4 (0.5%), Grade 3 (3.5%), and Grade 2 (4.0%). Four patients (0.7%) died due to pneumonitis.

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 monotherapy, immune-mediated colitis occurred in 2.9% (58/1994) of patients, including Grade 3 (1.7%) and Grade 2 (1%). In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, immune-mediated colitis occurred in 25% (115/456) of patients, including Grade 4 (0.4%), Grade 3 (14%) and Grade 2 (8%). 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 monotherapy, immune-mediated hepatitis occurred in 1.8% (35/1994) of patients, including Grade 4 (0.2%), Grade 3 (1.3%), and Grade 2 (0.4%). In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, immune-mediated hepatitis occurred in 15% (70/456) of patients, including Grade 4 (2.4%), Grade 3 (11%), and Grade 2 (1.8%). 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 monotherapy, adrenal insufficiency occurred in 1% (20/1994), including Grade 3 (0.4%) and Grade 2 (0.6%). In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, adrenal insufficiency occurred in 8% (35/456), including Grade 4 (0.2%), Grade 3 (2.4%), and Grade 2 (4.2%). 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 monotherapy, hypophysitis occurred in 0.6% (12/1994) of patients, including Grade 3 (0.2%) and Grade 2 (0.3%).

In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, hypophysitis occurred in 9% (42/456), including Grade 3 (2.4%) and Grade 2 (6%). 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 monotherapy, thyroiditis occurred in 0.6% (12/1994) of patients, including Grade 2 (0.2%). 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 monotherapy, hyperthyroidism occurred in 2.7% (54/1994) of patients, including Grade 3 (<0.1%) and Grade 2 (1.2%). In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, hyperthyroidism occurred in 9% (42/456) of patients, including Grade 3 (0.9%) and Grade 2 (4.2%). 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 monotherapy, hypothyroidism occurred in 8% (163/1994) of patients, including Grade 3 (0.2%) and Grade 2 (4.8%). In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, hypothyroidism occurred in 20% (91/456) of patients, including Grade 3 (0.4%) and Grade 2 (11%). 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 monotherapy, diabetes occurred in 0.9% (17/1994) of patients, including Grade 3 (0.4%) and Grade 2 (0.3%), and 2 cases of diabetic ketoacidosis. 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 monotherapy, immune-mediated nephritis and renal dysfunction occurred in 1.2% (23/1994) of patients, including Grade 4 (<0.1%), Grade 3 (0.5%), and Grade 2 (0.6%). 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 monotherapy, immune-mediated rash occurred in 9% (171/1994) of patients, including Grade 3 (1.1%) and Grade 2 (2.2%). In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, immune-mediated rash occurred in 28% (127/456) of patients, including Grade 3 (4.8%) and Grade 2 (10%). 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 patients receiving OPDIVO monotherapy as a 60-minute infusion, infusion-related reactions occurred in 6.4% (127/1994) of patients. In a separate trial in which patients received OPDIVO monotherapy as a 60-minute infusion or a 30-minute infusion, infusion-related reactions occurred in 2.2% (8/368) and 2.7% (10/369) of patients, respectively. Additionally, 0.5% (2/368) and 1.4% (5/369) of patients, respectively, experienced adverse reactions within 48 hours of infusion that led to dose delay, permanent discontinuation or withholding of OPDIVO. In melanoma patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, infusion-related reactions occurred in 2.5% (10/407) of patients. 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 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 OPDIVO plus YERVOY arm (n=313) relative to the OPDIVO arm (n=313). The most frequent (≥10%) serious adverse reactions in the OPDIVO plus YERVOY arm and the OPDIVO arm, respectively, were diarrhea (13% and 2.2%), colitis (10% and 1.9%), and pyrexia (10% and 1.0%). In Checkmate 227, serious adverse reactions occurred in 58% of patients (n=576). The most frequent (≥2%) serious adverse reactions were pneumonia, diarrhea/colitis, pneumonitis, hepatitis, pulmonary embolism, adrenal insufficiency, and hypophysitis. Fatal adverse reactions occurred in 1.7% of patients; these included events of pneumonitis (4 patients), myocarditis, acute kidney injury, shock, hyperglycemia, multi-system organ failure, and renal failure. 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 067, the most common (≥20%) adverse reactions in the OPDIVO plus YERVOY 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 067, the most common (≥20%) adverse reactions in the OPDIVO 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 227, the most common (≥20%) adverse reactions were fatigue (44%), rash (34%), decreased appetite (31%), musculoskeletal pain (27%), diarrhea/colitis (26%), dyspnea (26%), cough (23%), hepatitis (21%), nausea (21%), and pruritus (21%). 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.

Clinical Trials and Patient Populations
Checkmate 227—previously untreated metastatic non-small cell lung cancer, in combination with YERVOY; Checkmate 067–previously untreated metastatic melanoma, as a single agent or in combination with YERVOY; Checkmate 214–previously untreated renal cell carcinoma, in combination with YERVOY

References:

OPDIVO [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; 2024.
Bristol-Myers Squibb Receives Approval from the U.S. Food and Drug Administration for the Opdivo (nivolumab) + Yervoy (ipilimumab) Regimen in BRAF V600 Wild-Type Unresectable or Metastatic Melanoma. Press release. Bristol-Myers Squibb. October 1, 2015. Accessed April 17, 2024. https://news.bms.com/news/details/2015/Bristol-Myers-Squibb-Receives-Approval-from-the-US-Food-and-Drug-Administration-for-the-Opdivo-nivolumab--Yervoy-ipilimumab-Regimen-in-BRAF-V600-Wild-Type-Unresectable-or-Metastatic-Melanoma/default.aspx
U.S. Food and Drug Administration. FDA approves nivolumab plus ipilimumab combination for intermediate or poor-risk advanced renal cell carcinoma. FDA website. April 16, 2018. Accessed April 3, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-nivolumab-plus-ipilimumab-combination-intermediate-or-poor-risk-advanced-renal-cell
U.S. Food and Drug Administration. FDA approves nivolumab plus ipilimumab for first-line mNSCLC (PD-L1 tumor expression ≥1%). FDA website. May 15, 2020. Accessed April 3, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-nivolumab-plus-ipilimumab-first-line-mnsclc-pd-l1-tumor-expression-1
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. Oral presentation at ASCO GU 2024. Abstract 363.
Motzer RJ, Tannir NM, McDermott DF, et al; for the Checkmate 214 Investigators. Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. N Engl J Med. 2018;378(14):1277-1290.
Ramalingam SS, Ciuleanu TE, Caro RB, et al. Six-year survival and health-related quality of life outcomes with first-line nivolumab plus ipilimumab in patients with metastatic NSCLC from CheckMate 227. Oral presentation at WCLC 2023. Abstract 0A14.03.
Hodi FS, Chiarion-Sileni V, Lewis KD, et al. Long-term survival in advanced melanoma for patients treated with nivolumab plus ipilimumab in CheckMate 067. Poster presented at ASCO 2022. Abstract 9522.
Hellmann MD, Paz-Ares L, Bernabe Caro R, et al. Nivolumab plus ipilimumab in advanced non-small-cell lung cancer. N Engl J Med. 2019;381(21):2020-2031.
Hellmann MD, Paz-Ares L, Bernabe Caro R, et al. Nivolumab plus ipilimumab in advanced non-small-cell lung cancer. N Engl J Med. 2019;381(21):2020-2031 [supplementary appendix].

OPDIVO®, YERVOY® and the related logos are registered trademarks of Bristol-Myers Squibb Company.

7356-US-2400256 07/24