An option following progression with fluoropyrimidine, oxaliplatin, and irinotecan
An option following progression with fluoropyrimidine, oxaliplatin, and irinotecan
Developed under the direction and sponsorship of Bristol-Myers Squibb Company
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OPDIVO® (nivolumab) + YERVOY® (ipilimumab) - Injection for Intravenous Use
For appropriate patients with MSI-H/dMMR mCRC that has progressed
following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan
OPDIVO® + Yervoy®
delivered an ORR of 46%
(95% CI: 35–58) AND mDOR WAS
not reached1,2
Please see additional data below.
Colorectal cancer
Indication1
OPDIVO® (nivolumab), in combination with YERVOY® (ipilimumab), is indicated for the treatment of adults and pediatric patients 12 years and older with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer (CRC) that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan. This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.
OPDIVO (10 mg/mL) and YERVOY (5 mg/mL) are injections for intravenous use.1,3
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.
OPDIVO is associated with the following Warnings and Precautions including immune‑mediated: pneumonitis, colitis, hepatitis, endocrinopathies, nephritis and renal dysfunction, skin adverse reactions, encephalitis, other adverse reactions; infusion-related reactions; embryo‑fetal toxicity; and increased mortality in patients with multiple myeloma when OPDIVO is added to thalidomide analogue and dexamethasone, which is not recommended outside of controlled clinical trials.
Please see additional Important Safety Information below.
OPDIVO + YERVOY delivered an ORR of 46%
(95% CI: 35–58), and mDOR was not reached1,2*
OPDIVO + YERVOY ORR + DOR
‘+’ Indicates censored value.
* In patients who had disease progression following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan.1 The median time to response (TTR) was 3.3 months (range: 1.3 to 11.1 months).4
This study is ongoing.5
In the entire combination cohort in Checkmate 142, OPDIVO + YERVOY demonstrated an ORR of 49% (95% CI: 39-58; 58/119), a CR of 4.2% (5/119), and a PR of 45% (53/119). Median DOR was not reached (range: 1.9 to 23.2+ months). The proportion with ≥6 months response duration was 83%. The proportion with ≥12 months response duration was 19%1,2,4
In the combination cohort, 78% of the 51 patients with ongoing responses were followed <12 months from the date of onset of response1
Select Important Safety Information
OPDIVO was discontinued in 13% of patients and delayed in 45% of patients because of adverse reactions.
Serious adverse reactions occurred in 47% of patients. The most frequent serious adverse reactions reported in at least 2% of patients were colitis/diarrhea, hepatic events, abdominal pain, acute kidney injury, pyrexia, and dehydration.
The most common adverse reactions (reported in ≥20% of patients) in the OPDIVO with YERVOY cohort were fatigue (49%), diarrhea (45%), pyrexia (36%), musculoskeletal pain (36%), abdominal pain (30%), pruritus (28%), nausea (26%), rash (25%), decreased appetite (20%), and vomiting (20%).
Checkmate 142 Study Information1
A multicenter, non‑randomized, multiple parallel‑cohort, open‑label study, which included a single‑arm cohort investigating OPDIVO in combination with YERVOY in patients with locally determined MSI‑H/dMMR mCRC who had disease progression during or after prior treatment with fluoropyrimidine‑, oxaliplatin‑, or irinotecan‑based chemotherapy. Select key eligibility criteria included at least 1 prior line of treatment for metastatic disease, ECOG PS 0 or 1, and absence of the following: active brain metastases, active autoimmune disease, or medical conditions requiring systemic immunosuppression. Across 119 patients, 69% had received prior treatment with a fluoropyrimidine, oxaliplatin, and irinotecan. Patients enrolled in the OPDIVO + YERVOY MSI-H/dMMR mCRC cohort received OPDIVO 3 mg/kg and YERVOY 1 mg/kg IV every 3 weeks for 4 doses, followed by OPDIVO 3 mg/kg IV as a single agent every 2 weeks. Treatment was continued until unacceptable toxicity or radiographic progression. Efficacy outcome measures included ORR and DOR, as assessed by independent radiographic review committee (IRRC) using Response Evaluation Criteria In Solid Tumors (RECIST v1.1).
The recommended dose of OPDIVO for adult patients and for pediatric patients age 12 years and older and weighing 40 kg or more is 3 mg/kg administered as an intravenous infusion over 30 minutes, followed by YERVOY 1 mg/kg administered as an intravenous infusion over 30 minutes on the same day, every 3 weeks for 4 doses. After completing 4 doses of the combination, administer OPDIVO as a single agent, either 240 mg every 2 weeks or 480 mg every 4 weeks as an intravenous infusion over 30 minutes until disease progression or unacceptable toxicity. The recommended dose of OPDIVO for pediatric patients age 12 years and older and weighing less than 40 kg is 3 mg/kg administered as an intravenous infusion over 30 minutes, followed by YERVOY 1 mg/kg administered as an intravenous infusion over 30 minutes on the same day, every 3 weeks for 4 doses. After completing 4 doses of the combination, administer OPDIVO 3 mg/kg as a single agent every 2 weeks as an intravenous infusion over 30 minutes until disease progression or unacceptable toxicity.1
86% (102/119) of patients received all 4 doses of OPDIVO + YERVOY in the combination cohort6
OPDIVO + YERVOY and OPDIVO monotherapy dosing schedule
During the induction phase, OPDIVO 3 mg/kg is 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, every 3 weeks for 4 doses1
Based on exploratory dose exposure–response relationships for efficacy and safety, OPDIVO q2w 240 mg and q4w 480 mg are predicted to be similar7
The first dose of OPDIVO monotherapy should be administered after completing 4 doses of the OPDIVO and YERVOY combination1
No premedications required1
Review the Full Prescribing Information for OPDIVO and YERVOY, including the Boxed WARNING, prior to initiation
CI=confidence interval; CR=complete response; DOR=duration of response; ECOG PS=Eastern Cooperative Oncology Group Performance Status; IV=intravenous; mCRC=metastatic CRC; mDOR=median DOR; ORR=objective response rate; PR=partial response; q2w=every 2 weeks; q4w=every 4 weeks.
IMPORTANT SAFETY INFORMATION
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 MSI-H/dMMR mCRC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, immune-mediated pneumonitis occurred in 1.7% (2/119) of patients.
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. In MSI-H/dMMR mCRC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, immune-mediated colitis occurred in 7% (8/119) of patients.
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. In MSI-H/dMMR mCRC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, immune-mediated hepatitis occurred in 8% (10/119) of patients.
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.
In MSI-H/dMMR mCRC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, immune-mediated hypophysitis occurred in 3.4% (4/119) of patients. In MSI-H/dMMR mCRC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, adrenal insufficiency occurred in 5.9% (7/119) of patients. In MSI-H/dMMR mCRC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, hypothyroidism or thyroiditis resulting in hypothyroidism occurred in 15% (18/119) of patients. Hyperthyroidism occurred in 12% (14/119) of patients.
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. In MSI-H/dMMR mCRC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, immune-mediated nephritis and renal dysfunction occurred in 1.7% (2/119) of patients.
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. In MSI-H/dMMR mCRC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, immune-mediated rash occurred in 14% (17/119) of patients.
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. Encephalitis occurred in one MSI-H/dMMR mCRC patient (0.8%) receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg after 15 days of exposure
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 monotherapy or 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.
In MSI-H/dMMR mCRC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, infusion-related reactions occurred in 4.2% (5/119) of patients.
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 142 in MSI-H/dMMR mCRC patients receiving OPDIVO with YERVOY, serious adverse reactions occurred in 47% of patients. The most frequent serious adverse reactions reported in ≥2% of patients were colitis/diarrhea, hepatic events, abdominal pain, acute kidney injury, pyrexia, and dehydration.
Common Adverse Reactions
In Checkmate 142 in MSI-H/dMMR mCRC patients receiving OPDIVO with YERVOY, the most common adverse reactions (≥20%) were fatigue (49%), diarrhea (45%), pyrexia (36%), musculoskeletal pain (36%), abdominal pain (30%), pruritus (28%), nausea (26%), rash (25%), decreased appetite (20%), and vomiting (20%).
Please see U.S. Full Prescribing Information for OPDIVO and YERVOY, including Boxed WARNING regarding immune‑mediated adverse reactions for YERVOY.
To learn more about the OPDIVO + YERVOY combination treatment for appropriate mCRC patients, call
1-85​5-OP​DIVO-1 (1-85​5-67​3-48​61)
Sincerely,
Your OPDIVO + YERVOY Team
References:
1. OPDIVO [package insert]. Princeton, NJ: Bristol‑Myers Squibb Company; 2019.
2. Overman MJ, Lonardi S, Wong KYM, et al. J Clin Oncol. 2018;36(8):773‑779.
3. YERVOY [package insert]. Princeton, NJ: Bristol‑Myers Squibb Company; 2019.
4. Data on file. NIVO 391. Princeton, NJ: Bristol‑Myers Squibb Company; 2017.
5. Clinicaltrials.gov. NCT02060188. Accessed July 9, 2019.
6. Data on file. NIVO 377. Princeton, NJ: Bristol‑Myers Squibb Company; 2018.
7. Long GV, Tykodi SS, Schneider JG, et al. Assessment of nivolumab exposure and clinical safety of 480 mg every 4 weeks flat‑dosing schedule in patients with cancer. Annals of Oncology. 2018;1‑6.
Bristol-Myers Squibb
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© 20​19 Bristol‑Myers Squibb Company. All rights reserved.
OPDIVO®, YERVOY®, and the related logos are trademarks of Bristol‑Myers Squibb Company.
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