The Role of Immunotherapy in Advancing Overall Survival for Metastatic Melanoma

December 17, 2020
Sponsored by Bristol Myers Squibb

The melanoma treatment landscape has been marked by incredible progress, particularly when reflecting on the prognosis that was historically associated with metastatic disease. “For many, many decades, treatment options were very limited for patients with advanced melanoma, and median survival for most patients was measured in months,” said Sunandana Chandra, M.D., Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL.1 “It’s this unmet need and a desire to do better for patients – coupled with deepening our understanding of the highly immunogenic nature of melanoma – that spurred much of the research we see coming to fruition today.”2,3,4

“Since then, the research and treatment landscape has become increasingly promising, with outcomes-driven advances that may offer more patients the chance for longer-term survival,” Dr. Chandra explained.1

Advances in Immunotherapy and Combination Approaches

As immunotherapy agents became an increasingly important area of focus in the treatment of melanoma, research began to look at targeting the immune system with immune-checkpoint inhibitors that work in different but complementary ways.

A deepening commitment to changing the melanoma landscape ultimately led to the expanded approval of Opdivo® (nivolumab) + Yervoy® (ipilimumab) in 2016 as the first and only dual immunotherapy indicated for the treatment of unresectable or metastatic melanoma.

Opdivo (10 mg/mL) and Yervoy (5 mg/mL) are injections for intravenous use.5,6 Opdivo and Yervoy are associated with the following Warnings and Precautions: severe and fatal immune-mediated adverse reactions including pneumonitis, colitis, hepatitis, 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.5 Please see additional Important Safety Information section below.

The Critical Roles of Programmed Death Receptor-1 (PD-1) and Cytotoxic T-Lymphocyte Antigen-4 (CTLA-4) in Tumor Activity

Researchers have come to understand the critical roles PD-1 and CTLA-4 play in tumor activity as negative regulators of T-cell activation and proliferation, and discovered how they can be suppressed in an effort to enhance the immune system’s anti-tumor response.5,7 The combination of Opdivo + Yervoy functions with different but complementary inhibition of PD-1 (Opdivo) and CTLA-4 (Yervoy).5 Yervoy blocks CTLA-4, helping to activate and stimulate T-cell proliferation, while also reducing the immune-suppressing activity of regulatory T-cells.6 Opdivo blocks PD-1 on the T cell to help restore the immune response by uncovering previously hidden tumor cells.5 The combined use of Opdivo and Yervoy results in enhanced anti-tumor immune response, which may help target and attack the tumor cells while reinforcing active immunosurveillance to help defend against the tumor.5 As these therapies work together to augment immune pathways, they may also result in the immune system attacking healthy cells.5 Please see Important Safety Information below.

Phase 3 Study: Initial Analysis & Follow-up at Five Years, Focusing on Survival Outcomes

The combination of Opdivo + Yervoy or Opdivo monotherapy versus Yervoy monotherapy was evaluated in CheckMate -067, a Phase 3, double-blind, randomized trial of 945 patients with previously untreated advanced melanoma.5 Overall survival (OS) and progression-free survival (PFS) were co-primary endpoints of the trial, and additional efficacy outcome measures were confirmed overall response rates (ORR) and duration of response (DOR).5 CheckMate -067 did not compare treatment with Opdivo + Yervoy versus Opdivo monotherapy.5

Patients in the combination group (n=314) received Opdivo 1 mg/kg plus Yervoy 3 mg/kg every three weeks (Q3W) for four doses, followed by Opdivo 3 mg/kg every two weeks (Q2W).5 Patients in the Opdivo group (n=316) received Opdivo 3 mg/kg plus placebo Q2W.5 Patients in the Yervoy group (n=315) received Yervoy 3 mg/kg Q3W for four doses plus placebo Q2W.5 Patients were treated until progression or unacceptable toxicity.1 The recommended dose of Opdivo is 1 mg/kg administered as an intravenous infusion over 30 minutes, followed by Yervoy 3 mg/kg administered as an intravenous infusion over 90 minutes on the same day, every three weeks for a maximum of four doses or until unacceptable toxicity, whichever occurs earlier.5 After completing four doses of the combination, administer Opdivo as a single agent, either 240 mg every two weeks or 480 mg every four weeks as an intravenous infusion over 30 minutes until disease progression or unacceptable toxicity.5

Results from the primary analysis at 28 months of the CheckMate -067 trial showed Opdivo + Yervoy and Opdivo alone reduced the risk of death by 45% (hazard ratio [HR] 0.55; 95% confidence interval [CI]: 0.44-0.69; P<0.0001) and 37% (HR 0.63; 95% CI: 0.50-0.78; P<0.0001) compared to Yervoy alone.5 Outcomes from CheckMate -067 with Opdivo + Yervoy cannot be compared to Opdivo monotherapy.5

“This pivotal trial’s endpoints observed with Opdivo + Yervoy in metastatic melanoma marked an important milestone that began to change how we think about the disease and our options for treating it,” said Dr. Chandra. “As more follow-up analyses and survival outcomes in CheckMate -067 are published, we have more data that support the potential of Opdivo + Yervoy as one immunotherapy combination option that may deliver a chance for long-term survival for patients, regardless of factors like BRAF mutation status.”

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 + Yervoy arm (n=313) relative to the Opdivo arm (n=313).5 The most frequent (≥10%) serious adverse reactions in the Opdivo + Yervoy arm and the Opdivo arm, respectively, were diarrhea (13% and 2.2%), colitis (10% and 1.9%), and pyrexia (10% and 1.0%).5

A follow-up analysis of CheckMate -067 at five years examined related outcomes in the treatment of metastatic melanoma with Opdivo + Yervoy or Opdivo monotherapy versus Yervoy alone.8

With a minimum follow-up of 60 months (five years), OS rates were (see Figure 1):8

Overall Survival

Median OS was more than 60 months (median not reached [NR] (95% CI, 38.2 to NR)) for patients receiving Opdivo + Yervoy, 36.9 months (95% CI, 28.2 to 58.7) for Opdivo alone and 19.9 months (95% CI, 16.8 to 24.6) for Yervoy alone.8

In the primary analysis, median progression-free survival (mPFS) was 11.5 months (95% CI, 8.9 to 16.7) for patients receiving Opdivo + Yervoy, 6.9 months (95% CI, 4.3 to 9.5) with Opdivo monotherapy and 2.9 months (95% CI, 2.8 to 3.4) with Yervoy.5 Results from the primary analysis also showed the risk of disease progression was reduced by 58% (HR, 0.42; 95% CI, 0.34 to 0.51; P<0.0001) for patients receiving Opdivo + Yervoy and 43% (HR, 0.57; 95% CI, 0.47 to 0.69; P<0.0001) with Opdivo monotherapy.5 At five years, mPFS was 11.5 months (95% CI, 8.7 to 19.3) for patients receiving Opdivo + Yervoy, 6.9 months (95% CI, 5.1 to 10.2) with Opdivo monotherapy and 2.9 months (95% CI, 2.8 to 3.2) with Yervoy.8

The primary analysis at nine months showed ORR of 50% for Opdivo + Yervoy, 40% for Opdivo alone, and 14% for Yervoy, and complete response rates of 8.9%, 8.5% and 1.9%, respectively.5 At five years, ORR were observed at 50% for Opdivo + Yervoy, 42% for Opdivo alone and 15% for Yervoy – while the percentage of patients experiencing a complete response continued to increase, with rates of 18% for Opdivo + Yervoy, 16% for Opdivo alone, and 5% for Yervoy alone.9

"Some oncologists may opt to treat melanoma in BRAF MT patients with targeted therapy; in my practice, whether I choose combination immunotherapy or targeted therapy really depends on the individual patient’s characteristics,” said Dr. Chandra. “For the appropriate patient, I have chosen combination immunotherapy at times, a choice that is reinforced in the five-year CheckMate -067 data, which showed a continuation of long-term durable survival for metastatic melanoma patients treated with Opdivo + Yervoy, regardless of BRAF status.”8

A separate analysis of OS at five years among patients with BRAF-mutant (MT) or wild-type (WT) tumors showed (see Figures 2 and 3):8

Overall Survival Among Patients with BRAF Mutations

Overall Survival Among BRAF WT Patients

“In the analysis at 60 months, 60% survival in BRAF-mutant patients was observed,” said Dr. Chandra.8 “These aren’t just numbers – these are results that can have a real impact on, and be deeply meaningful for, our patients.”

Select Safety Profile & Adverse Events Observed

“We know that the nature of immunotherapy is such that there is a chance both cancerous and healthy cells can be affected,” said Dr. Chandra.5 “As with any course of treatment, we as physicians can best identify and manage any potential immune-mediated or other adverse reactions in our patients by maintaining regular and open lines of communication with them.”

In CheckMate -067, the most common (≥20%) adverse reactions in the Opdivo + 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%).5 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%).5

In a separate Phase 3 study of Yervoy 3 mg/kg, the most common adverse reactions (≥5%) in patients who received Yervoy at 3 mg/kg (n=131) were fatigue (41%), diarrhea (32%), pruritus (31%), rash (29%), and colitis (8%).6 Please see additional Important Safety Information below.

In the five-year follow-up, the safety profile for Opdivo + Yervoy was consistent with prior findings, with no new safety signals.10 Grade 3/4 adverse events occurred in 186 (59%), 73 (23%) and 86 (28%) patients, respectively.10

Continuing to Elevate Possibilities for Patients

The goal of longer-term survival remains a top priority in the treatment of metastatic melanoma for all patients, regardless of BRAF status. The five-year follow-up data from the CheckMate -067 trial represents the longest registrational clinical study of Opdivo + Yervoy to date, and the findings may offer important insights and evidence for physicians to consider when determining a treatment plan for their patients.

“While there’s still more progress to be made for our patients, it’s encouraging to consider how far we’ve come in treating metastatic melanoma,” said Dr. Chandra. “The combination of Opdivo + Yervoy has changed the outlook for many patients, and the overall survival and durable response observed with the combination point to its potential to deliver longer-lasting results across BRAF MT and WT patients, which amounts to a broader cross-section of patients.”8

For more information about Opdivo + Yervoy, please visit www.opdivohcp.com.

INDICATION

OPDIVO® (nivolumab), in combination with YERVOY® (ipilimumab), is indicated for the treatment of patients with unresectable or metastatic melanoma.

IMPORTANT SAFETY INFORMATION

Severe and Fatal Immune-Mediated Adverse Reactions

Immune-mediated adverse reactions listed herein may not be inclusive of 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%).

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 a separate Phase 3 trial of YERVOY 3 mg/kg monotherapy, immune-mediated colitis occurred in 12% (62/511) of patients, including Grade 3-5 (7%) and Grade 2 (5%).

Immune-Mediated Hepatitis

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 a separate Phase 3 trial of YERVOY 3 mg/kg monotherapy, immune-mediated hepatitis occurred in 4.1% (21/511) of patients, including Grade 3-5 (1.6%) and Grade 2 (2.5%).

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 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% (4/456), including Grade 3 (2.4%) and Grade 2 (6%).

In patients receiving OPDIVO monotherapy, thyroiditis occurred in 0.6% (12/1994) of patients, including Grade 2 (0.2%).

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 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 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 a separate Phase 3 trial of YERVOY 3 mg/kg monotherapy, Grade 2-5 immune-mediated endocrinopathies occurred in 4% (21/511) of patients. Severe to life-threatening (Grade 3-4) endocrinopathies occurred in 9 (1.8%) patients. All 9 patients had hypopituitarism, and some had additional concomitant endocrinopathies such as adrenal insufficiency, hypogonadism, and hypothyroidism. Six of the 9 patients were hospitalized for severe endocrinopathies. Moderate (Grade 2) endocrinopathy occurred in 12 patients (2.3%), including hypothyroidism, adrenal insufficiency, hypopituitarism, hyperthyroidism and Cushing’s syndrome.

Immune-Mediated Nephritis and 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%).

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-LA 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 a separate Phase 3 trial of YERVOY 3 mg/kg monotherapy, immune-mediated rash occurred in 15% (76/511) of patients, including Grade 3-5 (2.5%) and Grade 2 (12%).

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 (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 separate Phase 3 trials of YERVOY 3 mg/kg and 10 mg/kg, infusion-related reactions occurred in 2.9% (28/982).

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 mechanism of action, 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 at least 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%).

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 a separate Phase 3 trial of YERVOY 3 mg/kg, the most common adverse reactions (≥5%) in patients who received YERVOY at 3 mg/kg were fatigue (41%), diarrhea (32%), pruritus (31%), rash (29%), and colitis (8%).

Please see U.S. Full Prescribing Information for OPDIVO and YERVOY.

Opdivo® and Yervoy® are registered trademarks of Bristol-Myers Squibb Company.

© 2020 Bristol-Myers Squibb Company. All Rights Reserved.

7356US2002346-01 12/20

References

  1. Hodi, F. S., Chiarion-Sileni, V., Gonzalez, R., et al. Nivolumab plus ipilimumab or nivolumab alone versus ipilimumab alone in advanced melanoma (CheckMate 067): 4-year outcomes of a multicentre, randomised, phase 3 trial. The Lancet Oncology. 2018;19(11):1480–1492.
  2. Faramarzi S, Ghafouri-Fard S. Melanoma: a prototype of cancer-testis antigen-expressing malignancies. Immunotherapy. 2017;9(13):1103-1113.
  3. Linnemann, C., van Buuren, M. M., Bies, et al. High-throughput epitope discovery reveals frequent recognition of neo-antigens by CD4+ T cells in human melanoma. Nature medicine. 2015;21(1):81–85.
  4. Passarelli, A., Mannavola, F., Stucci, L. S., et al. Immune system and melanoma biology: a balance between immunosurveillance and immune escape. Oncotarget. 2017;8(62):106132–106142.
  5. Opdivo Prescribing Information. Opdivo U.S. Product Information. Last updated: June 2020. Princeton, NJ: Bristol Myers Squibb Company.
  6. Yervoy Prescribing Information. Yervoy U.S. Product Information. Last updated: May 2020. Princeton, NJ: Bristol Myers Squibb Company.
  7. Buchbinder EI, Desai A. CTLA-4 and PD-1 Pathways: Similarities, Differences, and Implications of Their Inhibition. Am J Clin Oncol. 2016;39(1):98-106.
  8. Larkin J, Chiarion-Sileni V, Gonzalez R, et. al. Five-Year Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma. N Engl J Med. 2019;381(16):1535-1546.
  9. Data on file. NIVO 488. Princeton, NJ. Bristol Myers Squibb
  10. Larkin J, Sileni V, Gonzalez R, et. al. “Five-Year Survival Outcomes of the CheckMate 067 Phase 3 Trial of Nivolumab Plus Ipilimumab Combination Therapy in Advanced Melanoma.” European Society for Medical Oncology. September 2019, Barcelona, Spain. Conference Presentation.

Related Content:

Sponsored

x