For patients with mNSCLC (PD-L1 ≥1%)

OPDIVO® + YERVOY® was assessed in a landmark phase 3 study that included patients regardless of histology1

Part 1a study design1,2

OPDIVO® (nivolumab) + YERVOY® (ipilimumab) combination therapy checkmate 227 part 1 clinical trial design with key eligibility criteria, stratification, dosing, treatment, and primary and secondary endpoints.

OPDIVO® (nivolumab) + YERVOY® (ipilimumab) combination therapy checkmate 227 part 1 clinical trial design with key eligibility criteria, stratification, dosing, treatment, and primary and secondary endpoints.

  • Patients with untreated brain metastases, carcinomatous meningitis, active autoimmune disease, or medical conditions requiring systemic immunosuppression were excluded1
  • Tumor specimens were evaluated prospectively using the PD-L1 IHC 28-8 pharmDx assay at a central laboratory.1

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.1,2,4

ALK=anaplastic lymphoma kinase; DOR=duration of response; ECOG PS=Eastern Cooperative Oncology Group Performance Status; EGFR=epidermal growth factor receptor; IHC=immunohistochemistry; I-O=immuno-oncology; mNSCLC=metastatic non-small cell lung cancer;
NSCLC=non-small cell lung cancer; NSQ=non-squamous; ORR=overall response rate; OS=overall response;
PD-L1=programmed death-ligand 1; PFS=progression-free survival; q2w=every 2 weeks; q3w=every 3 weeks;
q6w=every 6 weeks; SQ=squamous.


For patients with mNSCLC
(PD-L1 ≥1%)

OPDIVO + YERVOY offers dual I-O durability and long-term survival, regardless of histology1

OS in patients with tumor PD-L1 expression ≥1% (primary analysis)1,2

OPDIVO® (nivolumab) + YERVOY® (ipilimumab) Combination Therapy - Primary Analysis OS in patients with PD-L1≥1%

OPDIVO® (nivolumab) + YERVOY® (ipilimumab) Combination Therapy - Primary Analysis OS in patients with PD-L1≥1%

  • Median PFS: 5.1 months (95% CI: 4.1–6.3) with OPDIVO + YERVOY and 5.6 months
    (95% CI: 4.6–5.8) with chemo alone; HR=0.82; 95% CI: 0.69–0.971‡
  • 29% of patients enrolled had SQ disease; 71% had NSQ disease1
  • With median follow-up of 43.1 months, the 3-year OS rate for OPDIVO + YERVOY was 33% vs 22% for chemotherapy3

CI=confidence interval; HR=hazard ratio; mo=month.

In Checkmate 227 (PD-L1 ≥1%),
the 2-year landmark OS was

40%with
OPDIVO + YERVOY


VS

33%with
chemotherapy


vs chemo. 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.1,2,4

In Checkmate 227 Part 1a, PFS, ORR, and DOR were pre-specified descriptive analyses. The primary efficacy outcome measure was OS.1,4

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%).

For patients with mNSCLC
(PD-L1 ≥1%)

mDOR of 23.2 months among OPDIVO + YERVOY responders1

  • ORR was 36% (142/396) with OPDIVO + YERVOY and 30% (119/397) with chemo1,2
  • 5.8% CR with OPDIVO + YERVOY and 1.8% with chemo2

DOR in patients with tumor PD-L1 expression ≥1% (among responders)1,4

OPDIVO® (nivolumab) + YERVOY® (ipilimumab) Combination Therapy - DOR in patients with PD-L1≥1%

OPDIVO® (nivolumab) + YERVOY® (ipilimumab) Combination Therapy - DOR in patients with PD-L1≥1%

  • In Checkmate 227 Part 1a, PFS, ORR, and DOR were pre-specified descriptive analyses. The primary efficacy outcome measure was OS1,4
  • ORR: 36% (142/396, 95% CI: 31–41) CR=5.8%, PR=30.1% with OPDIVO + YERVOY and 30% (119/397, 95% CI: 26–35) CR=1.8%, PR=28.2% with chemo1,2,4
  • Median TTR was 2.0 months with OPDIVO + YERVOY and 1.6 months with chemo4

CR=complete response; mDOR=median duration of response; PR=partial response; TTR=time to response.


SELECT IMPORTANT SAFETY INFORMATION

WARNING: IMMUNE-MEDIATED ADVERSE REACTIONS

YERVOY can result in severe and fatal immune-mediated adverse reactions. These immune-mediated reactions may involve any organ system; however, the most common severe immune-mediated adverse reactions are enterocolitis, hepatitis, dermatitis (including toxic epidermal necrolysis), neuropathy, and endocrinopathy. The majority of these immune-mediated reactions initially manifested during treatment; however, a minority occurred weeks to months after discontinuation of YERVOY.

Assess patients for signs and symptoms of enterocolitis, dermatitis, neuropathy, and endocrinopathy, and evaluate clinical chemistries including liver function tests (LFTs), adrenocorticotropic hormone (ACTH) level, and thyroid function tests, at baseline and before each dose.

Permanently discontinue YERVOY and initiate systemic high-dose corticosteroid therapy for severe immune-mediated reactions.

Immune-Mediated Pneumonitis

  • OPDIVO can cause immune-mediated pneumonitis. Fatal cases have been reported. Monitor patients for signs with radiographic imaging and for symptoms of pneumonitis. Administer corticosteroids for Grade 2 or more severe pneumonitis. Permanently discontinue for Grade 3 or 4 and withhold until resolution for Grade 2. In NSCLC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, immune-mediated pneumonitis occurred in 9% (50/576) of patients, including Grade 4 (0.5%), Grade 3 (3.5%), and Grade 2 (4.0%) immune-mediated pneumonitis. Four patients (0.7%) died due to pneumonitis.

Immune-Mediated Colitis

  • OPDIVO can cause immune-mediated colitis. Monitor patients for signs and symptoms of colitis. Administer corticosteroids for Grade 2 (of more than 5 days duration), 3, or 4 colitis. Withhold OPDIVO monotherapy for Grade 2 or 3 and permanently discontinue for Grade 4 or recurrent colitis upon re-initiation of OPDIVO. When administered with YERVOY, withhold OPDIVO and YERVOY for Grade 2 and permanently discontinue for Grade 3 or 4 or recurrent colitis.
  • 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. Addition of an alternative immunosuppressive agent to the corticosteroid therapy, or replacement of the corticosteroid therapy, should be considered in corticosteroid-refractory immune-mediated colitis if other causes are excluded.

Immune-Mediated Hepatitis

  • OPDIVO can cause immune-mediated hepatitis. Monitor patients for abnormal liver tests prior to and periodically during treatment. Administer corticosteroids for Grade 2 or greater transaminase elevations. Withhold OPDIVO for Grade 2 and permanently discontinue OPDIVO for Grade 3 or 4.

Immune-Mediated Endocrinopathies

  • OPDIVO can cause immune-mediated hypophysitis, immune-mediated adrenal insufficiency, autoimmune thyroid disorders, and Type 1 diabetes mellitus. Monitor patients for signs and symptoms of hypophysitis, signs and symptoms of adrenal insufficiency, thyroid function prior to and periodically during treatment, and hyperglycemia. Administer hormone replacement as clinically indicated and corticosteroids for Grade 2 or greater hypophysitis. Withhold for Grade 2 or 3 and permanently discontinue for Grade 4 hypophysitis. Administer corticosteroids for Grade 3 or 4 adrenal insufficiency. Withhold for Grade 2 and permanently discontinue for Grade 3 or 4 adrenal insufficiency. Administer hormone-replacement therapy for hypothyroidism. Initiate medical management for control of hyperthyroidism. Withhold OPDIVO for Grade 3 and permanently discontinue for Grade 4 hyperglycemia.

Immune-Mediated Nephritis and Renal Dysfunction

  • OPDIVO can cause immune-mediated nephritis. Monitor patients for elevated serum creatinine prior to and periodically during treatment. Administer corticosteroids for Grades 2-4 increased serum creatinine. Withhold OPDIVO for Grade 2 or 3 and permanently discontinue for Grade 4 increased serum creatinine.

Immune-Mediated Skin Adverse Reactions

  • OPDIVO can cause immune-mediated rash, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), some cases with fatal outcome. Administer corticosteroids for Grade 3 or 4 rash. Withhold for Grade 3 and permanently discontinue for Grade 4 rash. For symptoms or signs of SJS or TEN, withhold OPDIVO and refer the patient for specialized care for assessment and treatment; if confirmed, permanently discontinue.

Immune-Mediated Encephalitis

  • OPDIVO can cause immune-mediated encephalitis. Evaluation of patients with neurologic symptoms may include, but not be limited to, consultation with a neurologist, brain MRI, and lumbar puncture. Withhold OPDIVO in patients with new-onset moderate to severe neurologic signs or symptoms and evaluate to rule out other causes. If other etiologies are ruled out, administer corticosteroids and permanently discontinue OPDIVO for immune-mediated encephalitis.

Other Immune-Mediated Adverse Reactions

  • Based on the severity of the adverse reaction, permanently discontinue or withhold OPDIVO, administer high-dose corticosteroids, and, if appropriate, initiate hormone-replacement therapy. Across clinical trials of OPDIVO in combination with YERVOY, the following clinically significant immune-mediated adverse reactions, some with fatal outcome, occurred in <1.0% of patients receiving OPDIVO: myocarditis, rhabdomyolysis, myositis, uveitis, iritis, pancreatitis, facial and abducens nerve paresis, demyelination, polymyalgia rheumatica, autoimmune neuropathy, Guillain-Barré syndrome, hypopituitarism, systemic inflammatory response syndrome, gastritis, duodenitis, sarcoidosis, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), motor dysfunction, vasculitis, aplastic anemia, pericarditis, and myasthenic syndrome.
  • 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 may require treatment with systemic steroids to reduce the risk of permanent vision loss.

Infusion-Related Reactions

  • OPDIVO can cause severe infusion-related reactions, which have been reported in <1.0% of patients in clinical trials. Discontinue OPDIVO in patients with Grade 3 or 4 infusion-related reactions. Interrupt or slow the rate of infusion in patients with Grade 1 or 2. 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.

Embryo-Fetal Toxicity

  • Based on mechanism of action, OPDIVO and YERVOY can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with OPDIVO or 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 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

  • It is not known whether OPDIVO or YERVOY is present in human milk. Because many drugs, including antibodies, are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from OPDIVO or YERVOY, advise women not to breastfeed during treatment and for at least 5 months after the last dose.

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 U.S. Full Prescribing Information for OPDIVO and YERVOY, including Boxed WARNING regarding immune-mediated adverse reactions for YERVOY.


References:

  • 1. OPDIVO [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; 2020.
  • 2. 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.
  • 3. Ramalingam SS, Ciuleanu TE, Pluzanski A, et al. Nivolumab + ipilimumab versus platinum-doublet chemotherapy as first-line treatment for advanced non-small cell lung cancer: Three-year update from CheckMate 227 Part 1. Oral presentation at ASCO 2020. Abstract 9500.
  • 4. 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].
  • 5. YERVOY [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; 2020.