FDA Approves TECVAYLI® for Relapsed or Refractory Multiple Myeloma

SUMMARY: The FDA on October 25, 2022, granted accelerated approval to TECVAYLI® (Teclistamab-cqyv), the first bispecific B-Cell Maturation Antigen (BCMA)-directed CD3 T-cell engager, for adult patients with Relapsed or Refractory multiple myeloma who have received at least four prior lines of therapy, including a Proteasome Inhibitor, an Immunomodulatory agent, and an anti-CD38 monoclonal antibody. Multiple Myeloma is a clonal disorder of plasma cells in the bone marrow and the American Cancer Society estimates that in the United States, 34,470 new cases will be diagnosed in 2022 and 12,640 patients will die of the disease. Multiple Myeloma is a disease of the elderly, with a median age at diagnosis of 69 years and characterized by intrinsic clonal heterogeneity. Almost all patients eventually will relapse, and patients with a high-risk cytogenetic profile, extramedullary disease or refractory disease have the worst outcomes. The introduction of Proteasome Inhibitors, Immunomodulatory agents and CD 38 targeted therapies has resulted in higher Response Rates, as well as longer Progression Free Survival (PFS) and Overall Survival (OS), with the median survival for patients with myeloma approaching 10 years or more. Nonetheless, multiple myeloma in 2022 remains an incurable disease.

B-Cell Maturation Antigen (BCMA) is a member of the Tumor Necrosis Factor superfamily of proteins. It is a transmembrane signaling protein primarily expressed by malignant and normal plasma cells and some mature B cells. BCMA is involved in JNK and NF-kB signaling pathways that induce B-cell development and autoimmune responses. BCMA has been implicated in autoimmune disorders, as well as B-lymphocyte malignancies, Leukemia, Lymphomas, and Multiple Myeloma. At the time of writing, there are three BCMA-targeted therapies approved by the FDAfor patients with Relapsed or Refractory multiple myeloma with triple-class exposure. They include CARVYKTI® (Ciltacabtageneautoleucel) and ABECMA® (Idecabtagenevicleucel),which are B-Cell Maturation Antigen (BCMA)-directed genetically modified autologous T cell immunotherapies (CART-Cell therapies), and BLENREP® (Belantamabmafodotin-blmf), which is a B-Cell Maturation Antigen (BCMA)-directed antibody and microtubule inhibitor drug conjugate (Antibody Drug Conjugate). Even though CAR T-cell therapies have resulted in remarkable clinical responses, logistic challenges include at least 2 weeks of hospital stay, long manufacturing times, need for bridging therapy, and high cost of treatment.

TECVAYLI® is a bispecific antibody with dual binding sites, that targets both CD3 expressed on the surface of T cells and BCMA expressed on the surface of myeloma cells, and thereby mediates T-cell activation and lysis of BCMA-expressing myeloma cells. This effect occurs regardless of T-cell–receptor specificity or Major Histocompatibility Complex class I molecules on the surface of myeloma cells. This mechanism of action of TECVAYLI® is distinct from that of other available therapies for this patient group.

The present FDA approval was based on the efficacy and safety results from the pivotal, single-arm, multi-cohort, open-label, multi-center Phase 1/2 portion of MajesTEC-1 study, which enrolled 165 patients, who had Relapsed or Refractory myeloma after at least three therapy lines, including triple-class exposure to an Immunomodulatory drug, a Proteasome Inhibitor, and an anti-CD38 antibody. Patients received TECVAYLI® 1.5 mg/kg subcutaneously once weekly, after receiving step-up doses of 0.06 and 0.3 mg/kg separated by 2- 4 days and completed 2-4 days before the administration of the first full TECVAYLI® dose. Patients were hospitalized and premedicated with Dexamethasone, Acetaminophen, and Diphenhydramine for each step-up dose and for the first full dose of TECVAYLI®. Treatment was continued until disease progression, unacceptable toxicity, or the end of the study. The median age was 64 years, the median time between diagnosis and the first treatment dose was 6 years, 26% had at least one high-risk cytogenetic abnormality defined as del(17p), t(4;14), or t(14;16) among those with available cytogenetic data (N=148), 77.6% had triple-class refractory disease, and patients had received a median of 5 previous lines of therapy. The Primary end point was the Overall Response Rate (ORR), which was defined as a Partial Response or better according to the International Myeloma Working Group criteria, as assessed by an Independent Review Committee. Secondary end points included Duration of Response, Very Good Partial Response (VGPR) or better, Progression Free and Overall Survival, Minimal Residual Disease (MRD) status and Safety.

At a median follow-up of 14.1 months, the Overall Response Rate was 63%, with 39.4% having a Complete Response or better. Close to 60% of patients had a Very Good Partial Response or better. Approximately, 27% of patients had negative results for Minimal Residual Disease in bone marrow (<1 myeloma cell in 100,000 cells), and the MRD-negativity rate among the patients with a Complete Response or better was 46%. The median Duration of Response was 18.4 months, and the median duration of Progression Free Survival was 11.3 months. Common adverse events included Cytokine Release Syndrome (CRS) noted in 72% and were mostly Grade 1 or 2 and fully resolved. None of the patients discontinued TECVAYLI® due to CRS. Other common adverse events included neutropenia, anemia, and thrombocytopenia, as well as immune effector cell–associated neurotoxicity syndrome, but none of the patients discontinued therapy because of neurotoxic events.

It was concluded from this study that TECVAYLI® had substantial clinical activity, with a high rate of deep and durable response in patients with triple-class-exposed Relapsed or Refractory multiple myeloma. Toxic effects were common but were mainly of low grade and reversible. The researchers added that the efficacy of TECVAYLI® compared favorably with other FDA approved treatments that are currently available for later lines in multiple myeloma, including BLENREP® (Belantamabmafodotin-blmf), XPOVIO® (Selinexor), and CAR T-cell therapies.

Teclistamab in Relapsed or Refractory Multiple Myeloma. Moreau P, Garfall AL,van de DonkNW,et al. N Engl J Med 2022; 387:495-505

FDA Approves IMJUDO® plus IMFINZI® for Patients with Advanced Hepatocellular Carcinoma

SUMMARY: The FDA on October 21, 2022, approved IMJUDO® (Tremelimumab) in combination with IMFINZI® (Durvalumab), for adult patients with unresectable HepatoCellular Carcinoma (HCC). The American Cancer Society estimates that for 2022, about 41,260 new cases of primary liver cancer and intrahepatic bile duct cancer will be diagnosed in the US and 30,520 patients will die of their disease. Liver cancer is seen more often in men than in women and the incidence has more than tripled since 1980. This increase has been attributed to the higher rate of Hepatitis C Virus (HCV) infection among baby boomers (born between 1945 through 1965). Obesity and Type II diabetes have also likely contributed to the increasing trend. Other risk factors include alcohol, which increases liver cancer risk by about 10% per drink per day, and tobacco use, which increases liver cancer risk by approximately 50%. HepatoCellular Carcinoma (HCC) is also a leading cause of cancer deaths worldwide, accounting for more than 700,000 deaths each year, and majority of patients typically present at an advanced stage. The prognosis for unresectable HCC remains poor and one year survival rate is less than 50% following diagnosis and only 7% of patients with advanced disease survive five years. NEXAVAR® was approved by the FDA in 2007 for the first line treatment of unresectable HepatoCellular Carcinoma (HCC) and the median Overall Survival was 10.7 months in the NEXAVAR® group and 7.9 months in the placebo group.

Immune checkpoints are cell surface inhibitory proteins/receptors that are expressed on activated T cells. They harness the immune system and prevent uncontrolled immune reactions by switching off the T cells of the immune system. Immune checkpoint proteins/receptors include CTLA-4 (Cytotoxic T-Lymphocyte Antigen 4, also known as CD152) and PD-1(Programmed cell Death 1). Checkpoint inhibitors unleash the T cells resulting in T cell proliferation, activation, and a therapeutic response.

IMFINZI® (Durvalumab) is a human monoclonal antibody that binds to the PD-L1 protein and blocks the interaction of PD-L1 with the PD-1 and CD80 proteins, countering the tumor’s immune-evading tactics and unleashes the T cells. IMJUDO® is a human monoclonal antibody that targets and blocks the activity of CTLA-4, contributing to T-cell activation, priming the immune response to cancer and fostering cancer cell death. In a Phase II study, a single priming dose of IMJUDO® added to IMFINZI® (STRIDE regimen), showed encouraging clinical activity and limited toxicity in patients with unresectable HepatoCellular Carcinoma (HCC), suggesting that a single exposure to IMJUDO® may be sufficient to improve upon activity of IMFINZI®.

HIMALAYA trial is a randomized, open-label, multicenter, global, Phase III study conducted in 190 centres across 16 countries, including in the US, Canada, Europe, South America and Asia. In this study, 1,171 patients with Stage III or IV unresectable HepatoCellular Carcinoma who had received no prior systemic therapy and were not eligible for locoregional therapy (treatment localized to the liver and surrounding tissue), were randomly assigned to receive either the STRIDE regimen which consisted of a single priming dose of IMJUDO® 300 mg IV added to IMFINZI® (Durvalumab) 1500 mg IV, followed IMFINZI® 1500 mg IV by every 4 weeks (N= 393), IMFINZI® monotherapy given at the same dose and schedule (N = 389) or NEXAVAR® (Sorafenib) 400 mg orally BID (N=389). Enrolled patients had ECOG performance status of 0 or 1 and Child-Pugh A disease and could not have main portal vein thrombosis. Patients were stratified based on macrovascular invasion (Yes versus No), etiology of liver disease (Hepatitis B virus versus Hepatitis C virus versus others), and ECOG Performance Status (0 versus 1). The Primary endpoint was Overall Survival (OS) for STRIDE regimen versus NEXAVAR® and key Secondary endpoints included OS for IMFINZI® monotherapy versus NEXAVAR®, Objective Response Rate and Progression Free Survival (PFS) for STRIDE and IMFINZI® monotherapy. The present FDA approval was based on a comparison of the 782 patients randomized to IMJUDO® plus IMFINZI® (STRIDE regimen) to NEXAVAR®.

The Primary objective of this study was met at the time of data cutoff. At a median follow up of 16.1 months of treatment with the STRIDE regimen, there was a 22% reduction in the risk of death for patients who received the STRIDE regimen compared to NEXAVAR® alone (HR=0.78; P=0.0035). The median OS with the STRIDE regimen was 16.4 months, compared with 13.8 months with NEXAVAR®, and the 3 year OS rate was 30.7% versus 20.2 % respectively. The Overall Response Rate for the combination STRIDE regimen was 20.1% compared to 5.1% for NEXAVAR®.

IMFINZI® monotherapy met the objective of OS non-Inferiority to NEXAVAR® (HR=0.86), and the median OS after 16.5 months of median follow up was 16.6 months with IMFINZI® monotherapy versus 13.8 months with NEXAVAR®, and the 3 year OS rate was 24.7% versus 20.2 % respectively. The Overall Response Rate with IMFINZI® monotherapy was 17% compared to 5.1% for NEXAVAR®. The Secondary endpoint of PFS was not superior in either investigational study group relative to the NEXAVAR® control arm. The most common adverse reactions occurring in patients were rash, diarrhea, fatigue, pruritis, musculoskeletal pain and abdominal pain.

It was concluded that HIMALAYA is the first large Phase III trial to add a novel single priming dose of an anti-CTLA4 antibody IMJUDO®, to another checkpoint inhibitor, IMFINZI®. This combination regimen (STRIDE) demonstrated superior efficacy and a favorable benefit-risk profile when compared with NEXAVAR® and should be considered a novel , first-line standard of care systemic therapy, for patients with unresectable Hepatocellular Carcinoma.

Tremelimumab plus Durvalumab in Unresectable Hepatocellular Carcinoma. Abou-Alfa GK, Lau G, Kudo M, et al. Published June 6, 2022. NEJM Evid 2022; 1 (8) DOI:https://doi.org/10.1056/EVIDoa2100070.

OPDIVO® (nivolumab) for the Adjuvant Treatment of High-Risk Urothelial Carcinoma*

*Urothelial carcinoma at high risk of recurrence after undergoing radical resection.
Written by: Terence Friedlander, MD
Professor of Medicine, Division of Hematology/Oncology, Zuckerberg San Francisco General Hospital, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco

Content sponsored by: Bristol Myers Squibb
Dr Friedlander is a paid consultant for BMS and was compensated for his contribution in drafting this content.

Overview of High-Risk Urothelial Carcinoma*
Currently, radical resection with or without perioperative therapy is the standard of care for treating high-risk urothelial carcinoma (UC).1* However, there is still a high chance of recurrence within 2 years of radical resection, with less favorable survival rates for the high-risk patient population.1 While neoadjuvant therapy has an established role in treating high-risk UC,* data are less clear regarding the role of adjuvant therapy.2 In a retrospective observational cohort study of patients 65 years or older with UC at high risk of recurrence after radical resection, including patients who received neoadjuvant chemotherapy, median disease-free survival (mDFS) was determined to be 13.5 months.1 Cisplatin-based chemotherapy is the neoadjuvant standard of care, but prior to 2021 there were no FDA-approved adjuvant therapy options.1-3 Studies have shown that adjuvant chemotherapy may delay recurrence and improve overall survival (OS), but these studies have not definitively shown a survival benefit, largely due to inadequate sample sizes.2 Additionally, approximately 50% of patients are ineligible for cisplatin-based treatment.1 As a result, there is a high unmet need for this difficult-to-treat population, and it is important for the urologist, oncologist, and patient to discuss and align on perioperative treatments at the time of diagnosis and early in the patient journey.1,2,4 Entering the adjuvant treatment landscape, immune checkpoint inhibitors may be an additional treatment option for HCPs to consider for their patients with high-risk UC.1,2*

Adjuvant OPDIVO in High-Risk Urothelial Carcinoma*
OPDIVO is approved and indicated for the adjuvant treatment of adult patients with UC who are at high risk of recurrence after undergoing radical resection, regardless of prior neoadjuvant chemotherapy, nodal involvement, or PD-L1 status.5 The approval is based on Checkmate 274, a phase 3, multicenter, double-blind, randomized trial of adjuvant OPDIVO versus placebo.6 More information on the study design can be found in the images below. Baseline characteristics were balanced across treatment arms.6
Checkmate 274Important Safety Information
Select Important Safety Information
In Checkmate 274, serious adverse reactions occurred in 30% of OPDIVO patients. The most frequent serious adverse reaction reported in ≥2% of patients was urinary tract infection. Fatal adverse reactions occurred in 1% of patients; these included events of pneumonitis (0.6%). The most-common adverse reactions reported in ≥20% of patients were rash, fatigue, diarrhea, pruritus, musculoskeletal pain, and UTI. OPDIVO was discontinued or delayed due to adverse reactions in 18% and 33% of patients, respectively.5

OPDIVO is associated with the following Warnings and Precautions: severe and fatal immune-mediated adverse reactions including pneumonitis, colitis, hepatitis and hepatotoxicity, endocrinopathies, nephritis with renal dysfunction, dermatologic adverse reactions, other immune-mediated adverse reactions; infusion-related reactions; complications of allogeneic hematopoietic stem cell transplantation; 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.

OPDIVO may cause severe infusion-related reactions. In patients who received OPDIVO as a 60-minute intravenous infusion, infusion-related reactions occurred in 6.4% (127/1994) of patients.5 For additional information regarding infusion-related reactions, please see Important Safety Information for OPDIVO.
Checkmate-274-Defined-High-Risk-PatientsDouble-median-DFS-with-OPDIVO
Checkmate 274 was not powered to detect differences in the treatment effect at extended follow-up analysis; therefore, results from this exploratory analysis should be interpreted with caution.

Adjuvant OPDIVO demonstrated superior disease-free survival (DFS) compared with placebo at the primary analysis (minimum follow-up of 5.9 months).5,6 Median DFS was 20.8 months with OPDIVO versus 10.8 months with placebo (HR=0.70 [95% CI: 0.57–0.86];P=0.0008).5 OS was also evaluated as a secondary endpoint, but at the time of the planned interim analysis, these data were immature with 33% of deaths in the ITT population; in the UTUC subpopulation, 37 deaths occurred, 20 of which occurred with OPDIVO versus 17 with placebo.5 Although the subgroup analyses were not statistically powered, for patients with prior neoadjuvant cisplatin therapy (n=308), the DFS hazard ratio was 0.52 [95% CI: 0.38–0.71] and for patients without prior neoadjuvant cisplatin therapy (n=401), the DFS hazard ratio was 0.92 [95% CI: 0.69–1.21].6 In additional exploratory subgroup analyses, no improvement in DFS was observed with nivolumab compared to placebo in patients with UTUC (n=149) the unstratified DFS hazard ratio was 1.15 (95% CI: 0.74–1.80); in patients with PD-L1 expression of <1% (n=414), the unstratified DFS hazard ratio was 0.83 (95% CI: 0.64–1.08).5

At the extended follow-up analysis (minimum follow-up of 11.0 months), mDFS was doubled with adjuvant OPDIVO compared with placebo. Median DFS was 22.0 months with OPDIVO versus 10.9 months with placebo (HR=0.70 [95% CI: 0.57–0.85]).12

Summary/conclusions
Given the high unmet need in this difficult-to-treat population, the call for approved adjuvant treatment options continues to rise.1,2 Adjuvant OPDIVO offers a chance to change the future for patients with high-risk UC as the only FDA-approved adjuvant option for adult patients with UC at high risk of recurrence after radical resection regardless of prior neoadjuvant chemotherapy, nodal involvement, or PD-L1 status.5,6,12 In Checkmate 274, OPDIVO significantly extended mDFS at the time of primary analysis and doubled mDFS at the time of extended follow-up analysis.5,6,12 Further data will be generated for the secondary endpoint of OS, which may provide greater insight into the efficacy of OPDIVO in this context.6,8 Given the clinical profile of Checkmate 274 and subsequent FDA approval, OPDIVO may help extend DFS for appropriate patients in need of treatment in the adjuvant UC setting.5,6,12

*Urothelial carcinoma at high risk of recurrence after undergoing radical resection.

Additional Definitions
CI=confidence interval; HCP=healthcare provider; HR=hazard ratio; ITT=intent to treat; PD-L1=programmed death ligand 1; UTUC=upper tract urothelial carcinoma.

Indication
OPDIVO® (nivolumab), as a single agent, is indicated for the adjuvant treatment of adult patients with urothelial carcinoma (UC) who are at high risk of recurrence after undergoing radical resection of UC.

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. Early identification and management are essential to ensure safe use of OPDIVO. Monitor for signs and symptoms that may be clinical manifestations of underlying immune-mediated adverse reactions. Evaluate clinical chemistries including liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment with OPDIVO. 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 depending on severity (please see section 2 Dosage and Administration in the accompanying Full Prescribing Information). In general, if OPDIVO 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 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 can cause immune-mediated colitis. 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%).

Immune-Mediated Hepatitis and Hepatotoxicity
OPDIVO 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%).

Immune-Mediated Endocrinopathies
OPDIVO 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 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 monotherapy, hypophysitis occurred in 0.6% (12/1994) of patients, including Grade 3 (0.2%) and Grade 2 (0.3%).

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 monotherapy, hypothyroidism occurred in 8% (163/1994) of patients, including Grade 3 (0.2%) and Grade 2 (4.8%).

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.

Immune-Mediated Nephritis with Renal Dysfunction
OPDIVO 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-L1 blocking antibodies. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate nonexfoliative rashes.

Withhold or permanently discontinue OPDIVO 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%).

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 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.

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, as this may require treatment with systemic corticosteroids to reduce the risk of permanent vision loss.

Infusion-Related Reactions
OPDIVO can cause severe infusion-related reactions. Discontinue OPDIVO 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.

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. 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 and allogeneic HSCT.

Follow patients closely for evidence of transplant-related complications and intervene promptly. Consider the benefit versus risks of treatment with OPDIVO prior to or after an allogeneic HSCT.

Embryo-Fetal Toxicity
Based on its mechanism of action and findings from animal studies, OPDIVO 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 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 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 274, serious adverse reactions occurred in 30% of patients receiving OPDIVO (n=351). The most frequent serious adverse reaction reported in ≥2% of patients receiving OPDIVO was urinary tract infection. Fatal adverse reactions occurred in 1% of patients; these included events of pneumonitis (0.6%).

Common Adverse Reactions
In Checkmate 274, the most common adverse reactions (≥20%) reported in patients receiving OPDIVO (n=351) were rash (36%), fatigue (36%), diarrhea (30%), pruritus (30%), musculoskeletal pain (28%), and urinary tract infection (22%).

Please see US Full Prescribing Information for OPDIVO.

References
1. Drakaki A, Pantuck A, Mhatre SK, et al. “Real-world” outcomes and prognostic indicators among patients with high-risk muscle-invasive urothelial carcinoma. Urol Oncol. 2021;39:76.e15-76.e22.
2. Referenced without permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Bladder Cancer V.2.2022. © National Comprehensive Cancer Network, Inc. 2022. All rights reserved. Accessed August 4, 2022. To view the most recent and complete version of the guidelines, go online to NCCN.org. NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way.
3. Apolo AB, Msaouel P, Niglio S, et al. Evolving Role of Adjuvant Systemic Therapy for Kidney and Urothelial Cancers. Am Soc Clin Oncol Educ Book. 2022;42:1-16. doi:10.1200/EDBK_350829.
4. Nayan M, Bhindi B, Yu JL, et al. The initiation of a multidisciplinary bladder cancer clinic and the uptake of neoadjuvant chemotherapy: A time-series analysis. Can Urol Assoc J. 2016;10(1-2):25-30.
5. OPDIVO [package insert]. Princeton, NJ: Bristol-Myers Squibb Company.
6. Bajorin DF, Witjes JA, Gschwend JE, et al. Adjuvant nivolumab versus placebo in muscle-invasive urothelial carcinoma. N Engl J Med. 2021;384(22):2102-2114.
7. Bajorin DF, Witjes JA, Gschwend JE, et al. First results from the phase 3 CheckMate 274 trial of adjuvant nivolumab versus placebo in patients who underwent radical surgery for high-risk muscle-invasive urothelial carcinoma. Oral presentation at ASCO GU 2021. Abstract 391.
8. Bajorin DF, Witjes JA, Gschwend JE, et al. Adjuvant nivolumab versus placebo in muscle-invasive urothelial carcinoma. N Engl J Med. 2021;384(22):2102-2114 [supplementary appendix].
9. American Cancer Society. Bladder cancer early detection, diagnosis, and staging. Accessed August 5, 2022. https://www.cancer.org/content/dam/CRC/PDF/Public/8559.00.pdf.
10. Data on file. NIVO 639. Princeton, NJ: Bristol-Myers Squibb Company; 2021.
11. Witjes JA, Bajorin DF, Galsky MD, et al. Results for patients with muscle-invasive bladder cancer in the CheckMate 274 trial. Poster presentation at ASCO 2022. Abstract 4585.
12. Galsky MD, Witjes JA, Gschwend JE, et al. Disease-free survival with longer follow-up from the phase 3 CheckMate 274 trial of adjuvant nivolumab in patients who underwent surgery for high-risk muscle-invasive urothelial carcinoma. Oral presentation at the American Urological Association (AUA) Annual Meeting 2022. Abstract 22-3807.

© 2022 Bristol-Myers Squibb Company. OPDIVO® and the related logos are trademarks of Bristol-Myers Squibb Company. 1506-US-2200368 8/22

Late Breaking Abstract – ESMO 2022: PADCEV® plus KEYTRUDA® in Previously Untreated Cisplatin-Ineligible Patients with Locally Advanced or Metastatic Urothelial Cancer

SUMMARY: The American Cancer Society estimates that in the United States for 2022, about 81,180 new cases of bladder cancer will be diagnosed and approximately 17,100 patients will die of the disease. Bladder cancer is the fourth most common cancer in men, but it is less common in women. A third of the patients initially present with locally invasive or metastatic disease. Patients with urothelial carcinoma are currently treated in the first line setting with a Platinum based chemotherapy regimen, and a checkpoint Inhibitor (PD-1 or PD-L1 inhibitor) in the second line setting. Approximately 50% of patients with advanced urothelial carcinoma are ineligible for Cisplatin-based chemotherapy. There is therefore a critical need for effective and tolerable first line treatment options in locally advanced or metastatic Urothelial Carcinoma.

Enfortumab vedotin-ejfv (PADCEV®) is an Antibody-Drug Conjugate (ADC) that targets Nectin-4, a cell adhesion molecule highly expressed in urothelial cancers and other solid tumors. Nectin-4 has been implicated in tumor cell growth and proliferation. Following binding to Nectin-4 on the cell surface, Enfortumab vedotin becomes internalized and is processed by lysosomes, with the liberation of its cytotoxic payload, Monomethyl auristatin E, which in turn disrupts microtubule assembly, leading to cell cycle arrest and apoptosis. Enfortumab vedotin resulted in significantly longer Overall Survival, Progression Free Survival, and a higher Overall Response Rate, than standard chemotherapy, in patients with locally advanced or metastatic urothelial carcinoma, who had previously received Platinum-based treatment and a PD-1 or PD-L1 inhibitor. Preclinical studies with Enfortumab vedotin have shown hallmarks of immune cell death potentially augmented by PD-1/PD-L1 inhibitors, and the rationale for this clinical trial was based on results from a previous cohort study.

Pembrolizumab (KEYTRUDA®) is a fully humanized, Immunoglobulin G4, anti-PD-1, monoclonal antibody, that binds to the PD-1 receptor and blocks its interaction with ligands PD-L1 and PD-L2. By doing so, it unleashes the tumor-specific effector T cells, and is thereby able to undo PD-1 pathway-mediated inhibition of the immune response. Pembrolizumab is the first agent to improve Overall Survival over chemotherapy, in the second line setting, for patients with recurrent, advanced urothelial carcinoma, and a significant proportion of patients who respond, have very durable responses.

EV-103 is a clinical trial conducted to examine the safety and efficacy of Enfortumab vedotin given as monotherapy, and in combination with other anticancer therapies, as first line and second line treatment, for patients with urothelial cancer. This study was conducted in multiple parts for both locally advanced or metastatic urothelial cancer and muscle invasive bladder cancer.

EV-103/KEYNOTE-869 Cohort K is a randomized cohort investigating Enfortumab vedotin alone or in combination with Pembrolizumab as first line treatment in patients with unresectable locally advanced or metastatic urothelial cancer, who are ineligible to receive Cisplatin-based chemotherapy. In this Phase Ib/II randomized study, 149 eligible patients (N=149) were randomly assigned to receive a combination of Enfortumab vedotin 1.25 mg/kg given intravenously on days 1 and 8, and Pembrolizumab 200 mg given intravenously on day 1, every 21 days (N=76) or Enfortumab vedotin monotherapy given on the same schedule (N=73). Ineligibility for Cisplatin-based chemotherapy could be due to at least one of the following: Glomerular filtration rate (GFR) less than 60 mL/min, ECOG Performance Status of 2, Grade 2 or more hearing loss, or New York Heart Association Class III heart failure. No prior systemic treatment for locally advanced or metastatic disease, and adjuvant/neoadjuvant Platinum-based therapy within 12 months prior to randomization, were allowed. The Primary endpoint was confirmed Objective Response Rate (ORR) by BICR (Blinded Independent Central Review). Secondary endpoints included Duration of Response (DOR), Safety, Progression Free Survival (PFS) and Overall Survival (OS).

At a median follow up of 14.2 months, the confirmed Objective Response Rate was 64.5% with the Enfortumab vedotin and Pembrolizumab combination, with 10.5% of patients experiencing a Complete Response and 53.9% of patients experiencing a Partial Response. The median Duration of Response was not reached. The most common Treatment-Related Adverse Events (TRAEs) were peripheral sensory neuropathy (55.6%), fatigue (51.1%), and alopecia (48.9%).

It was concluded that in Cisplatin-ineligible patients with unresectable locally advanced or metastatic urothelial cancer, treatment with Enfortumab vedotin and Pembrolizumab combination in chemo naïve patients, resulted in high Overall Response Rate, along with a safety profile that was tolerable. The authors added that Antibody-Drug Conjugates have the potential to make a greater impact in treating bladder cancer, especially in combination with checkpoint inhibitors, as shown in this trial and these data support ongoing investigations of first line Enfortumab vedotin and Pembrolizumab in patients with locally advanced or metastatic urothelial cancer.

Study EV-103 Cohort K: Antitumor activity of enfortumab vedotin (EV) monotherapy or in combination with pembrolizumab (P) in previously untreated cisplatin-ineligible patients (pts) with locally advanced or metastatic urothelial cancer (la/mUC). Rosenberg JE, Milowsky M, Ramamurthy C, et al. Annals of Oncology (2022) 33 (suppl_7): S808-S869. 10.1016/annonc/annonc1089. LBA73

Late Breaking Abstract – ESMO 2022: Neoadjuvant KEYTRUDA® with Chemoradiation in Locally Advanced Head and Neck Squamous Cell Carcinoma

SUMMARY: The American Cancer Society estimates that in the US for 2022, about 54,000 new cases of oral cavity or oropharyngeal cancer will be diagnosed and about 11,230 patients will die of the disease. Patients with Squamous Cell Carcinoma of the head and neck, frequently present with locoregionally advanced disease.

The treatment paradigm for Head and Neck cancer has been rapidly evolving with the recognition and better understanding of immune evasion and the role of immune checkpoints or gate keepers in suppressing antitumor immunity. Blocking the immune checkpoints unleashes the T cells, resulting in T cell proliferation, activation, and a therapeutic response. Checkpoint inhibitors administered in a neoadjuvant setting activates both the priming phase of immunity within tumor tissue, and the effector phase within the tumor microenvironment. It has been shown that neoadjuvant immunotherapy expands more T-cell clones than adjuvant treatment. Preclinical models have also demonstrated that both radiation therapy and Cisplatin chemotherapy increase the PD-L1 expression on the tumor, suggesting that combining radiotherapy with anti-PD-1 therapy could improve the outcomes.

Pembrolizumab (KEYTRUDA®) is a fully humanized, Immunoglobulin G4, monoclonal antibody and checkpoint inhibitor, that binds to the PD-1 receptor and blocks its interaction with ligands PD-L1 and PD-L2, thereby undoing PD-1 pathway-mediated inhibition of the immune response and unleashing the tumor-specific effector T cells. Pembrolizumab has been shown to improve Overall Survival in patients with Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma

KEYNOTE-412 is a randomized, double-blind, Phase III trial, conducted to evaluate the efficacy and safety of Pembrolizumab in combination with chemoradiation versus placebo in combination with chemoradiation, in treatment naïve patients with locally advanced Head and Neck Squamous Cell carcinoma. In this study, 804 patients were randomly assigned 1:1 to receive Pembrolizumab 200 mg IV every 3 weeks plus chemoradiation (70Gy in 35 fractions along with Cisplatin 100 mg/m2 IV every 3 weeks) followed by Pembrolizumab (N=402), or placebo every 3 weeks plus chemoradiation, followed by placebo (N=402). Patients received Pembrolizumab /placebo priming dose 1 week before chemoradiation, followed by 2 doses during chemoradiation and 14 doses of maintenance therapy after chemoradiation, for a total of 17 doses. Enrolled patients had newly diagnosed, pathologically proven, treatment naive locally advanced Head and Neck Squamous Cell carcinoma (T3-T4, N0-N3 or any N2a-3, T1-T4 larynx/hypopharynx/oral cavity/p16-negative oropharynx cancers, or T4 or N3 p16-positive oropharynx cancer). Both treatment groups were well balanced. The Primary endpoint was Event Free Survival (EFS). Secondary endpoints included Overall Survival (OS), and Safety.

At the time of data cutoff, with a median follow up of 47.7 months, there was a favorable trend toward improved Event Free Survival (EFS) with the addition of Pembrolizumab vs placebo to chemoradiation (HR 0.83, P=0.04), but the difference did not achieve statistical significance. The 2-year EFS was 63.2% in the Pembrolizumab group and 56.2% in the placebo group. In an exploratory analysis however, the 2-year EFS among patients with high expression of PD-L1 (CPS 20 or higher) was 71% in the Pembrolizumab group and 62% in the placebo group. A favorable of Overall Survival benefit was also observed among these patients, with a 3-year OS of 79% in Pembrolizumab group and 73% in the placebo group.

It was concluded that Pembrolizumab in combination with chemoradiation was associated with a favorable trend toward improved Event Free Survival, compared with placebo plus chemoradiation, in patients with locally advanced Head and Neck Squamous Cell carcinoma, but the difference did not reach statistical significance. The researchers added that perhaps patients with high CPS score on the tumor could benefit with this treatment approach.

Primary results of the phase III KEYNOTE-412 study: Pembrolizumab (pembro) with chemoradiation therapy (CRT) vs placebo plus CRT for locally advanced (LA) head and neck squamous cell carcinoma (HNSCC). Machiels J, Tao Y, Burtness B, et al. Annals of Oncology (2022) 33 (suppl_7): S808-S869. 10.1016/annonc/annonc1089. LBA5

Late Breaking Abstract – ESMO 2022: CABOMETYX®, OPDIVO® and YERVOY® in Previously Untreated Advanced Renal Cell Carcinoma

SUMMARY: The American Cancer Society estimates that 79,000 new cases of kidney cancers will be diagnosed in the United States in 2022 and about 13,920 people will die from this disease. Clear Cell Renal Cell Carcinoma (RCC) is by far the most common type of kidney cancer in adults. Modifiable risk factors include smoking, obesity, workplace exposure to certain substances and high blood pressure. The five-year survival of patients with advanced RCC is about 14% and there is a significant unmet need for improved therapies for this disease.

OPDIVO® (Nivolumab) is a fully human, immunoglobulin G4 monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, whereas YERVOY® (Ipilimumab) is a fully human immunoglobulin G1 monoclonal antibody that blocks Immune checkpoint protein/receptor CTLA-4 (Cytotoxic T-Lymphocyte Antigen 4, also known as CD152). Blocking the Immune checkpoint proteins unleashes the T cells, resulting in T cell proliferation, activation, and a therapeutic response. The FDA in 2018, granted approvals to OPDIVO® and YERVOY® in combination, for the treatment of Intermediate or Poor-risk, previously untreated advanced Renal Cell Carcinoma.

CABOMETYX® (Cabozantinib) is an oral, small-molecule Tyrosine Kinase Inhibitor (TKI), which targets Vascular Endothelial Growth Factor Receptors (VEGFR), as well as tyrosine kinases MET and AXL. Both MET and AXL are upregulated in Renal Cell Carcinoma as a consequence of VHL inactivation, and increased expression of MET and AXL is associated with tumor progression and development of resistance to VEGFR inhibitors. Further, CABOMETYX® promotes an immune-permissive environment, which may enhance response to checkpoint inhibitors. CABOMETYX® was approved by the FDA in 2016 for the treatment of advanced Renal Cell Carcinoma.

COSMIC-313 is a global, multicenter, randomized, double-blinded, controlled, ongoing Phase III pivotal trial, conducted to evaluate the triplet combination of Cabozantinib, Nivolumab and Ipilimumab versus the doublet combination of Nivolumab and Ipilimumab, in patients with previously untreated advanced Intermediate or Poor-risk Renal Cell Carcinoma. COSMIC-313 was designed to answer whether adding Cabozantinib to dual checkpoint inhibition can improve outcomes among patients with Intermediate and Poor-risk advanced Renal Cell Carcinoma.

In this trial, 855 treatment naïve, advanced clear cell Renal Cell Carcinoma patients of IMDC (International Metastatic RCC Database Consortium) Intermediate or Poor risk were randomized 1:1 to receive Cabozantinib plus Nivolumab and Ipilimumab (N=428) or placebo plus Nivolumab and Ipilimumab (N=427). Patients in the study group received Cabozantinib 40 mg, orally once daily in combination with Nivolumab 3 mg/kg IV and Ipilimumab 1 mg/kg IV once every 3 weeks for 4 doses total followed by Cabozantinib 40 mg orally once daily and Nivolumab 480 mg/kg flat dose IV, once every 4 weeks for up to 2 years. Patients in the control group received the same regimen, but instead of Cabozantinib, received a matched placebo. Both treatment groups were well balanced. The median patient age was 60 years, 75% were men, 63% had PD-L1 expression of less than 1%, 75% had Intermediate-risk disease, 25% were Poor risk, and 65% had prior nephrectomy. The Primary endpoint was Progression Free Survival (PFS), as assessed by Blinded Independent Radiology Committee (BIRC). Secondary endpoints included Overall Survival (OS), Objective Response Rate (ORR) and Safety. The median follow up was 20.2 months.

The study met the Primary endpoint and the median PFS was not reached in the Cabozantinib group and was 11.3 months in the placebo group (HR=0.73; P=0.013). Patients treated with the Cabozantinib three-drug combination had a 27% lower risk of disease progression or death compared to those on the two drug immunotherapy combination. This PFS benefit was predominantly noted in the Intermediate-risk group. The Objective Response Rate was 43% with the Cabozantinib combination versus 36% in the placebo plus dual immunotherapy group, with 3% of patients achieving a Complete Response in both treatment groups. The Disease Control Rate was 86% and 72%, respectively. The median Duration of Response was not reached in either treatment group. Grade 3/4 adverse events occurred in 73% of patients treated with the combination of Cabozantinib, Nivolumab and Ipilimumab, and in 41% of patients treated with the Nivolumab and Ipilimumab combination. Discontinuation of all treatment agents due to adverse events occurred in 12% and 5% of patients, respectively.

The authors concluded that this is the first study to show that a TKI added to dual checkpoint inhibition significantly improved Progression Free Survival, in patients with untreated, Intermediate or Poor risk advanced kidney cancer, compared to doublet immunotherapy. Follow-up for Overall Survival is ongoing.

Phase III study of cabozantinib (C) in combination with nivolumab (N) and ipilimumab (I) in previously untreated advanced renal cell carcinoma (aRCC) of IMDC intermediate or poor risk (COSMIC-313). Choueiri TK, Powles TB, Albiges L, et al. Annals of Oncology (2022) 33 (suppl_7): S808-S869. 10.1016/annonc/annonc1089. LBA8

FDA Approves IMFINZI® in Combination with Chemotherapy for Advanced Biliary Tract Cancer

SUMMARY: The FDA on September 2, 2022, approved IMFINZI® (Durvalumab) in combination with Gemcitabine and Cisplatin for adult patients with locally advanced or metastatic Biliary Tract cancer. Bile Tract cancer (Cholangiocarcinoma) is a rare, heterogenous cancer, and comprises about 30% of all primary liver tumors and includes both intrahepatic and extrahepatic bile duct cancers. Klatskin tumor is a type of Cholangiocarcinoma that begins in the hilum, at the junction of the left and right bile ducts. It is the most common type of Cholangiocarcinoma, accounting for more than half of all cases. About 8,000 people in the US are diagnosed with Cholangiocarcinoma each year and approximately 20% of the cases are suitable for surgical resection. The 5-year survival among those with advanced stage disease is less than 10%, with limited progress made over the past two decades. There is therefore an unmet need for new effective therapies.

Patients with advanced Biliary Tract cancers often receive chemotherapy in the first and second line settings, with limited benefit. Gemcitabine and Cisplatin combination is currently the first line standard-of-care treatment. With the recognition of immunogenic features displayed by Biliary Tract cancers, the role of immune checkpoint inhibitors for improving disease control and prolonging survival, has been increasingly explored.

IMFINZI® (Durvalumab) is a human monoclonal antibody that binds to the PD-L1 protein and blocks the interaction of PD-L1 with the PD-1 and CD80 proteins, countering the tumor’s immune-evading tactics and unleashes the T cells. IMFINZI® in combination with Gemcitabine and Cisplatin showed encouraging antitumor activity in a Phase II study, among patients with advanced Biliary Tract cancers.

TOPAZ-1 is a double-blind, multicenter, global, Phase III trial conducted to evaluate the efficacy of first line immunotherapy given along with Gemcitabine and Cisplatin in patients with advanced metastatic Biliary Tract cancer. In this study, a total of 685 previously untreated patients with unresectable, locally advanced, recurrent or metastatic Biliary Tract cancer were randomized 1:1 to receive IMFINZI® (Durvalumab) 1500 mg IV every 3 weeks (N=341) or placebo (N=344), along with Gemcitabine 1000 mg/m2 IV and Cisplatin 25 mg/m2 IV given on Days 1 and 8, every 3 weeks for up to 8 cycles, followed by IMFINZI® 1500 mg IV every 4 weeks or placebo, until disease progression or unacceptable toxicity. Patients with recurrent disease more than 6 months following curative surgery or adjuvant therapy were also included. The median patient age was 64 years and approximately 50% of patients had an ECOG Performance Status of 0. Randomization was stratified by disease status (initially unresectable, recurrent) and primary tumor location (intrahepatic cholangiocarcinoma versus extrahepatic cholangiocarcinoma versus gallbladder cancer). Approximately 56% had intrahepatic cholangiocarcinoma, followed by gallbladder cancer (25%) and extrahepatic cholangiocarcinoma (19%). Tumor assessments were conducted every 6 weeks for the first 24 weeks, and then every 8 weeks until confirmed objective disease progression. The Primary endpoint was Overall Survival (OS) and Secondary endpoints included Progression Free Survival (PFS), Objective Response Rate (ORR), and Safety.

IMFINZI® plus Gemcitabine and Cisplatin significantly improved Overall Survival compared with placebo plus chemotherapy, with a 20% reduction in the risk of death. The median OS was 12.8 months and 11.5 months in the IMFINZI® and placebo groups, respectively (HR=0.80; P=0.021). The median PFS was 7.2 months and 5.7 months in the IMFINZI® and placebo arms, respectively (HR=0.75; P=0.001). The Objective Response Rate was 26.7% in the IMFINZI® plus chemotherapy group and 18.7% in the placebo plus chemotherapy group. Grade 3 or 4 treatment-related adverse events were almost similar in both treatment groups (62.7% versus 64.9%), and treatment discontinuation due to adverse events was 8.9% in the IMFINZI® plus chemotherapy group and 11.4% in the placebo plus chemotherapy group.

It was concluded that in patients with advanced Biliary Tract cancers, IMFINZI® in combination with Gemcitabine and Cisplatin significantly improved Overall Survival and Progression Free Survival with manageable safety, when compared to chemotherapy alone, and should therefore be considered first line standard-of- care for this patient group.

A phase 3 randomized, double-blind, placebo-controlled study of durvalumab in combination with gemcitabine plus cisplatin (gemcis) in patients (pts) with advanced biliary tract cancer (BTC): TOPAZ-1. Oh D-Y, He AR, Qin S, et al. J Clin Oncol. 2022;40(suppl 4):378. DOI:10.1200/JCO.2022.40.4_suppl.378.

Opdualag™ (nivolumab and relatlimab-rmbw): A New Dual I-O Option in the 1L Treatment of Metastatic Melanoma

Written By: Leonel Fernando Hernandez Aya, MD. Division of Medical Oncology, Department of Medicine, University of Miami Miller School of Medicine, Sylvester Comprehensive Cancer Center

Content Sponsored by: Bristol Myers Squibb
Dr Hernandez Aya is a paid consultant for BMS and was compensated for his contribution in drafting this content.

See additional definitions of abbreviations used throughout the article at the bottom of this page.

Overview of Metastatic Melanoma
Since the approval of anti–CTLA-4 in 2011 for metastatic melanoma, immuno-oncology(I-O) has transformed treatment outcomes.1 There are now several approved I-O options, and of those approved for the treatment of metastatic melanoma, dual immunotherapy in particular has had long-term success.2 The first dual immunotherapy, approved in 2015, consisted of PD-1 and CTLA-4 checkpoint inhibitors for the 1L treatment of unresectable or metastatic melanoma, regardless of BRAF mutation status.1,3,4 This anti–PD-1 and anti–CTLA-4 combination showed benefit in overall survival (OS) compared with anti–CTLA-4 alone.5 In general, the safety profile was consistent with previous experience with anti–PD-1 or anti–CTLA-4 alone.4 Until March 2022, this dual anti–PD-1 and anti–CTLA-4 immunotherapy was the only option indicated for the 1L treatment of unresectable or metastatic melanoma.3,6 Opdualag, the second approved dual immunotherapy, has provided an additional treatment option for nivolumab-monotherapy–appropriate patients with unresectable or metastatic melanoma.6-8

Opdualag
Opdualag is a dual immunotherapy option combining an anti–PD-1, nivolumab, with the first-in-class anti–LAG-3, relatlimab, in a fixed-dose formulation.7,8 PD-1 and LAG-3 are two distinct inhibitory immune checkpoints.7 Combined PD-1 and LAG-3 inhibition results in increased T-cell activation compared to the activity of either antibody alone. This initiates an improved anti-tumor immune response.8

Opdualag is indicated for the treatment of adult and pediatric patients 12 years of age or older with unresectable or metastatic melanoma.8 The approval is based on RELATIVITY-047, a phase 3, randomized, double-blind, global study of Opdualag versus nivolumab monotherapy.7 Patients were stratified by AJCC v8 M stage, BRAF, PD-L1, and LAG-3 status.7 Key exclusion criteria include patients with active or untreated brain or leptomeningeal metastases, uveal melanoma, active autoimmune disease, or medical conditions requiring systemic treatment with moderate- or high-dose corticosteroids or immunosuppressive medications.8

RELATIVITY-047 enrolled 714 patients who were randomized 1:1 to receive Opdualag (480 mg nivolumab/160 mg relatlimab as a fixed-dose combination[FDC]) every 4 weeks (n=355) or nivolumab 480 mg every 4 weeks (n=359).8 The primary endpoint was progression-free survival(PFS), and secondary endpoints were OS and overall response rate(ORR). PFS was determined by BICR using RECIST v1.1. Baseline characteristics were balanced across both treatment arms.7

Study design8

Median duration of treatment for Opdualag at the 19.3-month median follow-up was 8.3 months.7,9 Treat until disease progression or unacceptable toxicity.8

*Patients were allowed to have received prior adjuvant and neoadjuvant melanoma therapy. Anti–PD-1, anti–CTLA-4, or BRAF-MEK therapy was allowed as long as there was at least 6 months between the last dose of therapy and date of recurrence; interferon therapy was allowed as long as the last dose was at least 6 weeks prior to randomization.8† PD-L1 expression (≥1% vs <1%) using PD-L1 IHC 28-8 pharmDx test.8‡ LAG-3 expression (≥1% vs <1%) using a clinical trial assay. The final analysis of OS was not statistically significant.8

Opdualag is associated with the following Warnings and Precautions: severe and fatal immune-mediated adverse reactions (IMARs) including pneumonitis, colitis, hepatitis, endocrinopathies, nephritis with renal dysfunction, dermatologic adverse reactions, myocarditis, and other immune-mediated adverse reactions; infusion-related reactions; complications of allogeneic hematopoietic stem cell transplantation (HSCT); and embryo-fetal toxicity.

Opdualag demonstrated superior PFS compared to nivolumab at the primary analysis(median of 13.2 months) with curve separation as early as 3 months and sustained over time.7,8 Median PFS (mPFS)was 10.1 months with Opdualag versus 4.6 months with nivolumab (HR=0.75; 95% CI: 0.62–0.92; P=0.0055).8 Similarly, patients who received Opdualag had longer PFS regardless of key prognostic indicators, such as the AJCC metastasis stage of the tumor, LDH level, and tumor burden.7

At the follow-up analysis (median of 19.3 months), mPFS was 10.22 months with Opdualag and 4.63 months with nivolumab (HR=0.78; 95% CI: 0.64-0.94).10 OS and ORR were also evaluated.8 The final analysis for the secondary endpoint of OS was not statistically significant (threshold for significance was P<0.04302), and median OS (mOS)was not reached with Opdualag compared with nivolumab, which resulted in a mOS of 34.1 months (HR=0.80; 95% CI: 0.64–1.01; P=0.0593). Additionally, the ORR was higher with Opdualag (43%) versus nivolumab (33%), with the median DOR not yet reached for both treatment arms.8,10 ORR was not formally tested based on the testing hierarchy.8

Progression-free survival at the 19.3-month median follow-up10*†‡

Symbols represent censored observations.
*Assessed by BICR.8† Final PFS analysis.8‡ Kaplan-Meier estimate. Based on stratified Cox proportional hazard model.8II Based on stratified log-rank test.8

Overall survival10*

*At the time of the final OS analysis, which was event-driven and occurred after the final PFS analysis.8† Based on stratified Cox proportional hazard model.8‡ Based on stratified log-rank test. Not significant at alpha level 0.04302.8

In RELATIVITY-047, Opdualag had no additional safety events and similar most common Grade 3/4 AEs versus nivolumab monotherapy.7,8 Adverse reactions occurring in ≥15% of patients receiving Opdualag were musculoskeletal pain (45%), fatigue (39%), rash (28%), pruritus (25%), diarrhea (24%), nausea (17%), headache (18%), hypothyroidism (17%), decreased appetite (15%), and cough (15%).8

Toxicity was graded per NCI CTCAE v5.
*Clinically relevant adverse reactions in <15% of patients who received Opdualag included vitiligo, adrenal insufficiency, myocarditis, and hepatitis.8† Includes multiple terms.8

Opdualag is a FDC administered as a 30-minute intravenous infusion every 4 weeks.8 A FDC is the co-formulation of 2 active ingredients in a single vial administered as a single infusion, which may help reduce preparation and infusion times and could help minimize potential risk of administration errors.7,8,11 Opdualag can cause severe infusion-related reactions. Discontinue Opdualag in patients with severe or life-threatening infusion-related reactions. Interrupt or slow the rate of infusion in patients with mild to moderate infusion-related reactions. In patients who received Opdualag as a 60-minute intravenous infusion, infusion-related reactions occurred in 7% (23/355) of patients.8

Summary/conclusions
Dual immunotherapy has changed the metastatic melanoma treatment landscape.2 Currently there are 2 dual immunotherapy options available for 1L treatment of adult patients with unresectable or metastatic melanoma.3,8 As the newest dual immunotherapy, Opdualag more than doubled mPFS with a similar safety profile compared with nivolumab.8 Opdualag can be used for the treatment of all nivolumab monotherapy-appropriate patients, providing the opportunity for more patients with unresectable or metastatic melanoma to receive a dual immunotherapy.8 From my clinical experience, “it is great to have another treatment option for patients with metastatic melanoma.”

Indication for Opdualag
Opdualag is indicated for the treatment of adult and pediatric patients 12 years of age or older with unresectable or metastatic melanoma.

Important Safety Information for Opdualag
Severe and Fatal Immune-Mediated Adverse Reactions
Immune-mediated adverse reactions (IMARs) listed herein may not include all possible severe and fatal immune-mediated adverse reactions.

IMARs which may be severe or fatal, can occur in any organ system or tissue. IMARs can occur at any time after starting treatment with a LAG-3 and PD-1/PD-L1 blocking antibodies. While IMARs usually manifest during treatment, they can also occur after discontinuation of Opdualag. Early identification and management of IMARs are essential to ensure safe use. Monitor patients closely for symptoms and signs that may be clinical manifestations of underlying IMARs. Evaluate clinical chemistries including liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. In cases of suspected IMARs, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate.

Withhold or permanently discontinue Opdualag depending on severity (please see section 2 Dosage and Administration in the accompanying Full Prescribing Information). In general, if Opdualag requires interruption or discontinuation, 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 IMARs 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
Opdualag can cause immune-mediated pneumonitis, which may be fatal. In patients treated with other PD-1/PD-L1 blocking antibodies, the incidence of pneumonitis is higher in patients who have received prior thoracic radiation. Immune-mediated pneumonitis occurred in 3.7% (13/355) of patients receiving Opdualag, including Grade 3 (0.6%), and Grade 2 (2.3%) adverse reactions. Pneumonitis led to permanent discontinuation of Opdualag in 0.8% and withholding of Opdualag in 1.4% of patients.

Immune-Mediated Colitis
Opdualag can cause immune-mediated colitis, defined as requiring use of corticosteroids and no clear alternate etiology. A common symptom included in the definition of colitis was diarrhea. Cytomegalovirus 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.

Immune-mediated diarrhea or colitis occurred in 7% (24/355) of patients receiving Opdualag, including Grade 3 (1.1%) and Grade 2 (4.5%) adverse reactions. Colitis led to permanent discontinuation of Opdualag in 2% and withholding of Opdualag in 2.8% of patients.

Immune-Mediated Hepatitis
Opdualag can cause immune-mediated hepatitis, defined as requiring the use of corticosteroids and no clear alternate etiology.

Immune-mediated hepatitis occurred in 6% (20/355) of patients receiving Opdualag, including Grade 4 (0.6%), Grade 3 (3.4%), and Grade 2 (1.4%) adverse reactions. Hepatitis led to permanent discontinuation of Opdualag in 1.7% and withholding of Opdualag in 2.3% of patients.

Immune-Mediated Endocrinopathies
Opdualag can cause primary or secondary adrenal insufficiency, hypophysitis, thyroid disorders, and Type 1 diabetes mellitus, which can be present with diabetic ketoacidosis. Withhold or permanently discontinue Opdualag 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. In patients receiving Opdualag, adrenal insufficiency occurred in 4.2% (15/355) of patients receiving Opdualag, including Grade 3 (1.4%) and Grade 2 (2.5%) adverse reactions. Adrenal insufficiency led to permanent discontinuation of Opdualag in 1.1% and withholding of Opdualag in 0.8% of patients.

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. Hypophysitis occurred in 2.5% (9/355) of patients receiving Opdualag, including Grade 3 (0.3%) and Grade 2 (1.4%) adverse reactions. Hypophysitis led to permanent discontinuation of Opdualag in 0.3% and withholding of Opdualag in 0.6% of patients.

Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism; initiate hormone replacement or medical management as clinically indicated. Thyroiditis occurred in 2.8% (10/355) of patients receiving Opdualag, including Grade 2 (1.1%) adverse reactions. Thyroiditis did not lead to permanent discontinuation of Opdualag. Thyroiditis led to withholding of Opdualag in 0.3% of patients. Hyperthyroidism occurred in 6% (22/355) of patients receiving Opdualag, including Grade 2 (1.4%) adverse reactions. Hyperthyroidism did not lead to permanent discontinuation of Opdualag. Hyperthyroidism led to withholding of Opdualag in 0.3% of patients. Hypothyroidism occurred in 17% (59/355) of patients receiving Opdualag, including Grade 2 (11%) adverse reactions. Hypothyroidism led to the permanent discontinuation of Opdualag in 0.3% and withholding of Opdualag in 2.5% of patients.

Monitor patients for hyperglycemia or other signs and symptoms of diabetes; initiate treatment with insulin as clinically indicated. Diabetes occurred in 0.3% (1/355) of patients receiving Opdualag, a Grade 3 (0.3%) adverse reaction, and no cases of diabetic ketoacidosis. Diabetes did not lead to the permanent discontinuation or withholding of Opdualag in any patient.

Immune-Mediated Nephritis with Renal Dysfunction
Opdualag can cause immune-mediated nephritis, which is defined as requiring use of steroids and no clear etiology. In patients receiving Opdualag, immune-mediated nephritis and renal dysfunction occurred in 2% (7/355) of patients, including Grade 3 (1.1%) and Grade 2 (0.8%) adverse reactions. Immune-mediated nephritis and renal dysfunction led to permanent discontinuation of Opdualag in 0.8% and withholding of Opdualag in 0.6% of patients.

Withhold or permanently discontinue Opdualag depending on severity (please see section 2 Dosage and Administration in the accompanying Full Prescribing Information).

Immune-Mediated Dermatologic Adverse Reactions
Opdualag can cause immune-mediated rash or dermatitis, defined as requiring use of steroids and no clear alternate etiology. Exfoliative dermatitis, including Stevens-Johnson syndrome, toxic epidermal necrolysis, and Drug Rash with eosinophilia and systemic symptoms has occurred with PD-1/L-1 blocking antibodies. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate non-exfoliative rashes.

Withhold or permanently discontinue Opdualag depending on severity (please see section 2 Dosage and Administration in the accompanying Full Prescribing Information).

Immune-mediated rash occurred in 9% (33/355) of patients, including Grade 3 (0.6%) and Grade 2 (3.4%) adverse reactions. Immune-mediated rash did not lead to permanent discontinuation of Opdualag. Immune-mediated rash led to withholding of Opdualag in 1.4% of patients.

Immune-Mediated Myocarditis
Opdualag can cause immune-mediated myocarditis, which is defined as requiring use of steroids and no clear alternate etiology. The diagnosis of immune-mediated myocarditis requires a high index of suspicion. Patients with cardiac or cardio-pulmonary symptoms should be assessed for potential myocarditis. If myocarditis is suspected, withhold dose, promptly initiate high dose steroids (prednisone or methylprednisolone 1 to 2 mg/kg/day) and promptly arrange cardiology consultation with diagnostic workup. If clinically confirmed, permanently discontinue Opdualag for Grade 2-4 myocarditis.

Myocarditis occurred in 1.7% (6/355) of patients receiving Opdualag, including Grade 3 (0.6%), and Grade 2 (1.1%) adverse reactions. Myocarditis led to permanent discontinuation of Opdualag in 1.7% of patients.

Other Immune-Mediated Adverse Reactions
The following clinically significant IMARs occurred at an incidence of <1% (unless otherwise noted) in patients who received Opdualag 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: 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. Some cases can be associated with retinal detachment. Various grades of visual impairment, including blindness, can occur. If uveitis occurs in combination with other IMARs, consider a Vogt-Koyanagi-Harada–like syndrome, as this may require treatment with systemic steroids to reduce the risk of permanent vision loss; Gastrointestinal: pancreatitis including 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, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, solid organ transplant rejection.

Infusion-Related Reactions
Opdualag can cause severe infusion-related reactions. Discontinue Opdualag in patients with severe or life-threatening infusion-related reactions. Interrupt or slow the rate of infusion in patients with mild to moderate infusion-related reactions. In patients who received Opdualag as a 60-minute intravenous infusion, infusion-related reactions occurred in 7% (23/355) of patients.

Complications of Allogeneic Hematopoietic Stem Cell Transplantation (HSCT)
Fatal and other serious complications can occur in patients who receive allogeneic hematopoietic stem cell transplantation (HSCT) before or after being treated with a PD-1/PD-L1 receptor blocking antibody. Transplant-related complications include hyperacute graft-versus-host disease (GVHD), acute GVHD, chronic GVHD, hepatic veno-occlusive disease after reduced intensity conditioning, and steroid-requiring febrile syndrome (without an identified infectious cause). These complications may occur despite intervening therapy between PD-1/PD-L1 blockade and allogeneic HSCT.

Follow patients closely for evidence of transplant-related complications and intervene promptly. Consider the benefit versus risks of treatment with a PD-1/PD-L1 receptor blocking antibody prior to or after an allogeneic HSCT.

Embryo-Fetal Toxicity
Based on its mechanism of action and data from animal studies, Opdualag 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 Opdualag for at least 5 months after the last dose of Opdualag.

Lactation
There are no data on the presence of Opdualag in human milk, the effects on the breastfed child, or the effect on milk production. Because nivolumab and relatlimab may be excreted in human milk and because of the potential for serious adverse reactions in a breastfed child, advise patients not to breastfeed during treatment with Opdualag and for at least 5 months after the last dose.

Serious Adverse Reactions
In Relativity-047, fatal adverse reaction occurred in 3 (0.8%) patients who were treated with Opdualag; these included hemophagocytic lymphohistiocytosis, acute edema of the lung, and pneumonitis. Serious adverse reactions occurred in 36% of patients treated with Opdualag. The most frequent serious adverse reactions reported in ≥1% of patients treated with Opdualag were adrenal insufficiency (1.4%), anemia (1.4%), colitis (1.4%), pneumonia (1.4%), acute myocardial infarction (1.1%), back pain (1.1%), diarrhea (1.1%), myocarditis (1.1%), and pneumonitis (1.1%).

Common Adverse Reactions and Laboratory Abnormalities
The most common adverse reactions reported in ≥20% of the patients treated with Opdualag were musculoskeletal pain (45%), fatigue (39%), rash (28%), pruritus (25%), and diarrhea (24%).

The most common laboratory abnormalities that occurred in ≥20% of patients treated with Opdualag were decreased hemoglobin (37%), decreased lymphocytes (32%), increased AST (30%), increased ALT (26%), and decreased sodium (24%).

Please see US Full Prescribing Information for Opdualag.

Indication for OPDIVO® (nivolumab) + YERVOY® (ipilimumab)
OPDIVO, in combination with YERVOY, is indicated for the treatment of adult patients 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%).

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%).

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%).

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% (42/456), 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.

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%).

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%).

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 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.

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%).

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%).

Please see US Full Prescribing Information for OPDIVO and YERVOY.

References
1. Michielin O, Atkins MB, Koon HB, Dummer R, Ascierto PA. Evolving impact of long-term survival results on metastatic melanoma treatment. J Immunother Cancer. 2020. doi:10.1136/jitc-2020-000948.
2. Curti BD, Faries MB. Recent advances in the treatment of melanoma. N Engl J Med. 2021;384(23):2229-2240.
3. OPDIVO [package insert]. Princeton, NJ: Bristol-Myers Squibb Company.
4. Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med. 2015;373(1):23-34.
5. 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.
6. Cancer Research Institute. FDA Approval Timeline of Active Immunotherapies. Updated June 27, 2022. Accessed July 11, 2022. https://www.cancerresearch.org/en-us/scientists/immuno-oncology-landscape/fda-approval-timeline-of-active-immunotherapies.
7. Tawbi HA, Schadendorf D, Lipson EJ, et al. Relatlimab and nivolumab versus nivolumab in untreated advanced melanoma. N Engl J Med. 2022;386(1):24-34.
8. Opdualag [package insert]. Princeton, NJ: Bristol-Myers Squibb Company.
9. PubD 00058298. Princeton, NJ: Bristol-Myers Squibb Company; 2022.
10. Long GV, Hodi FS, Lipson EJ, et al. Relatlimab and nivolumab vs nivolumab in previously untreated metastatic or unresectable melanoma: overall survival and response rates from RELATIVITY-047 (CA224-047). Oral presentation at ASCO Plenary Series 2022. Presentation number 9505.
11. US Food and Drug Administration. CFR–Code of Federal Regulations Title 21. Updated March 29, 2022. Accessed July 1, 2022.https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/cfrsearch.cfm?fr=300.50.

© 2022 Bristol-Myers Squibb Company. OPDIVO®, YERVOY®, Opdualag™, and the related logos are trademarks of Bristol-Myers Squibb Company.
7356-US-2200441 8/22

Additional Definitions
AJCC=American Joint Committee on Cancer; BICR=blinded independent central review; CI=confidence interval;CTLA-4=cytotoxic T-lymphocyte antigen 4; DOR=duration of response; ECOG PS=Eastern Cooperative Oncology Group Performance Status; HR=hazard ratio;IHC=immunohistochemistry; IV=intravenous;LAG-3=lymphocyte-activation gene 3; LDH=lactate dehydrogenase; M stage=metastasis stage; mo=month; no=number; NS=not significant; PD-1=programmed death receptor-1; PD-L1=programmed death ligand 1; q4w=every 4 weeks; RECIST=Response Evaluation Criteria In Solid Tumors.

Late Breaking Abstract – ASCO 2022: Landmark Five Year Overall Survival Rates for OPDIVO® and YERVOY® Combination in NSCLC

SUMMARY: The American Cancer Society estimates that for 2022, about 236,740 new cases of lung cancer will be diagnosed and 135,360 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. Non-Small Cell Lung Cancer (NSCLC) accounts for approximately 85% of all lung cancers. Of the three main subtypes of NSCLC, 30% are Squamous Cell Carcinomas (SCC), 40% are Adenocarcinomas and 10% are Large Cell Carcinomas. With changes in the cigarette composition and decline in tobacco consumption over the past several decades, Adenocarcinoma now is the most frequent histologic subtype of lung cancer.

Immune checkpoints are cell surface inhibitory proteins/receptors that are expressed on activated T cells. They harness the immune system and prevent uncontrolled immune reactions by switching off the immune system T cells. Immune checkpoint proteins/receptors include CTLA-4 (Cytotoxic T-Lymphocyte Antigen 4, also known as CD152) and PD-1(Programmed cell Death 1). Checkpoint inhibitors unleash the T cells resulting in T cell proliferation, activation, and a therapeutic response. OPDIVO® (Nivolumab) is a fully human, immunoglobulin G4 monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, thereby undoing PD-1 pathway-mediated inhibition of the immune response and unleashing the T cells. YERVOY® is a fully human immunoglobulin G1 monoclonal antibody that blocks Immune checkpoint protein/receptor CTLA-4.

CheckMate-227 is an open-label, multi-part, global, Phase III trial in which OPDIVO® based regimens were compared with Platinum-doublet chemotherapy in patients with first line advanced NSCLC, across non-squamous and squamous tumor histologies. This study consisted of Part 1a/Part 1b and Part 2. In Part 2 of this trial, OPDIVO® plus chemotherapy was compared with chemotherapy alone, regardless of PD-L1 expression. Part 2 did not meet its Primary endpoint for Overall Survival for OPDIVO® plus chemotherapy versus chemotherapy alone, in patients with non-squamous NSCLC, and is published elsewhere.

Part 1a: Patients received OPDIVO® 3 mg/kg IV every 2 weeks plus YERVOY® 1 mg/kg IV every 6 weeks (N=396), OPDIVO® monotherapy 240 mg IV every 2 weeks (N=396) or chemotherapy alone given every 3 weeks for up to four cycles (N=397), in patients whose tumors had PD-L1 expression of 1% or more.
Part 1b: Patients received OPDIVO® plus YERVOY® (N=187), OPDIVO® 360 mg IV every 3 weeks plus chemotherapy IV every 3 weeks for up to four cycles (N=177), or chemotherapy alone IV every 3 weeks for up to four cycles (N=186), in patients whose tumors did not express PD-L1 (less than 1%)

Patients were stratified by histology, and treatment was administered until disease progression, unacceptable toxicity, or administered for 2 years for immunotherapy. It should be noted that when this trial was launched, chemotherapy along with immunotherapy or immunotherapy alone was not approved for the front-line treatment of NSCLC. Therefore, dual immunotherapy combination was not compared with current standards of care such as chemotherapy plus immunotherapy.

There were two independent Primary endpoints in Part 1 for OPDIVO® plus YERVOY® versus chemotherapy: Overall survival (OS) in patients whose tumors express PD-L1 (assessed in patients enrolled in Part 1a) and Progression Free Survival (PFS) in patients with TMB of 10 mut/Mb or more, across the PD-L1 spectrum (assessed in patients enrolled across Part 1a and Part 1b). Other assessments included Objective Response Rate (ORR), Duration of Response (DOR), and treatment-free interval. Treatment-free interval was measured in patients who discontinued study therapy and was defined as the time from last study dose to start of subsequent systemic therapy.

The Overall Survival (OS) data was previously reported at a minimum follow up of 29 months, and the median OS was of 17.1 months for the OPDIVO® plus YERVOY® group, compared to 14.9 months in the chemotherapy group (HR=0.79; P=0.007), with a 2-year OS rate of 40.0% and 32.8%, respectively. The researchers here in presented data after a minimum follow up of 61.3 months (5 years).

Patients whose tumors had PD-L1 expression of 1% or more continued to have sustained long term OS benefit with OPDIVO® plus YERVOY® when compared to chemotherapy (HR=0.77), and the 5-year OS rates were 24% with OPDIVO® plus YERVOY® compared to 14% with chemotherapy alone.

Patients with a PD-L1 expression of less than 1% also demonstrated continued long term OS benefit with OPDIVO® plus YERVOY® when compared to chemotherapy (HR = 0.65), and the 5-year OS rates were 19% for OPDIVO® plus YERVOY&reg compared to 7% for chemotherapy alone.

Among patients who survived for 5 years, median PFS was 59.1 months for PD-L1–positive patients and 60.7 months for PD-L1–negative patients who received OPDIVO® plus YERVOY®, compared to 9.5 months and 24.9 months respectively, for those who received chemotherapy.

Among those who responded to treatment, more patients who received OPDIVO® plus YERVOY® remained in response at five years, compared to chemotherapy, in both PD-L1 expression of 1% or more group (28% versus 3%) and PD-L1 expression of less than 1% group (21% versus 0%), respectively.

Among patients treated with OPDIVO® plus YERVOY® who were alive at five years, approximately two-thirds of patients did not receive any subsequent therapy for more than three years after stopping treatment, regardless of PD-L1 expression.

It was concluded that in this longest reported follow up of a Phase III trial of first line, chemotherapy free, combination immunotherapy, in metastatic Non Small cell Lung Cancer, a combination of OPDIVO® plus YERVOY® continued to provide long term durable clinical benefit and increased 5-year survivorship, when compared to chemotherapy, in previously untreated patients with metastatic NSCLC, regardless of PD-L1 expression.

Five-year survival outcomes with nivolumab (NIVO) plus ipilimumab (IPI) versus chemotherapy (chemo) as first-line (1L) treatment for metastatic non–small cell lung cancer (NSCLC): Results from CheckMate 227. Brahmer JR, Lee J-S, Ciuleanu T-E, et al. J Clin Oncol. 2022;40(suppl 17):LBA9025. doi:10.1200/JCO.2022.40.17_suppl.LBA9025

FDA Approves OPDIVO® Combination for Advanced Esophageal Carcinoma

SUMMARY: The FDA on May 27, 2022, approved OPDIVO® (Nivolumab) in combination with Fluoropyrimidine and Platinum-based chemotherapy, as well as OPDIVO® in combination with YERVOY® (Ipilimumab) for the first-line treatment of patients with advanced or metastatic esophageal Squamous Cell Carcinoma. The American Cancer Society estimates that in 2022, about 20,640 new cases of esophageal cancer will be diagnosed in the US and about 16,410 individuals will die of the disease. It is the sixth most common cause of global cancer death. Squamous Cell Carcinoma is the most common type of cancer of the esophagus among African Americans, while Adenocarcinoma is more common in Caucasians. Squamous Cell Carcinoma accounts for approximately 85% of cases.

Majority of esophageal cancers are unresectable at diagnosis, and most patients treated with curative intent eventually will relapse, and only about 20% of patients will survive at least 5 years following diagnosis. Patients with advanced esophageal cancer have a median survival of less than a year when treated with the standard Fluoropyrimidine plus Platinum based chemotherapy. For those patients progressing on first line chemotherapy, treatment options are limited, with a 5-year relative survival rate of 8% or less.

OPDIVO® (Nivolumab) is a fully human, immunoglobulin G4 monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, thereby undoing PD-1 pathway-mediated inhibition of the immune response and unleashing the T cells. It has been noted that approximately 50% of patients with advanced esophageal Squamous Cell Carcinoma express tumor-cell Programmed Death Ligand 1 (PD-L1) greater than 1%. In the ATTRACTION-3 multicentre, Phase III trial, treatment with OPDIVO® was associated with a significant improvement in Overall Survival, compared with chemotherapy, in previously treated patients with advanced esophageal Squamous Cell Carcinoma, regardless of PD-L1 expression. In the CheckMate 649 Phase III trial involving patients with gastric, gastroesophageal junction, or esophageal adenocarcinoma, first-line treatment with OPDIVO® plus chemotherapy resulted in a significant Overall Survival (OS) and Progression Free Survival (PFS) benefit, as compared with chemotherapy alone, as well as durable Objective Response Rate (ORR), with an acceptable safety profile.

CheckMate 648 is a global, open-label, Phase III trial in which the efficacy and safety of both an Immune Checkpoint Inhibitor in combination with chemotherapy and a dual Immune Checkpoint Inhibitor combination was evaluated in previously untreated patients with advanced esophageal Squamous Cell Carcinoma. The researchers herein reported the results for OPDIVO® plus chemotherapy and for OPDIVO® plus YERVOY® (Ipilimumab) as compared with chemotherapy alone. In this study, 970 patients with previously untreated, unresectable, advanced, recurrent or metastatic esophageal Squamous Cell Carcinoma were randomly assigned 1:1:1 to receive OPDIVO® plus chemotherapy (N=321), OPDIVO® plus YERVOY® (N=325), or chemotherapy alone. Patients in the OPDIVO® plus chemotherapy group received OPDIVO® 240 mg IV every 2 weeks and chemotherapy consisted of Fluorouracil 800 mg/m2 IV Days 1-5 and Cisplatin 80 mg/m2 IV on Day 1, given every 4 weeks. The OPDIVO® plus YERVOY® group received OPDIVO® 3 mg/kg IV every 2 weeks plus YERVOY® 1 mg/kg IV every 6 weeks. Treatment was continued until disease progression or unacceptable toxicity. Patients could receive OPDIVO® or OPDIVO® plus YERVOY® for a maximum of 2 years. Demographic and baseline clinical characteristics were balanced across the treatment groups and in patients with tumor-cell PD-L1 expression of 1% or greater (49% of patients in each treatment group had tumor-cell PD-L1 expression of 1% or greater). The Primary end points were Overall Survival (OS) and Progression Free Survival (PFS), as determined by Blinded Independent Central Review (BICR), with hierarchical testing performed first in patients with tumor-cell PD-L1 expression of 1% or greater and then in the overall population. The Secondary end points included Objective Response Rate (ORR), which was also assessed by BICR.

After a minimum follow up period of 13 months, Overall Survival was significantly longer with OPDIVO® plus chemotherapy than with chemotherapy alone, both among patients with tumor-cell PD-L1 expression of 1% or greater (15.4 months versus 9.1 months; HR=0.54; P<0.001) and in the overall population (13.2 months versus 10.7 months; HR=0.74; P=0.002). These findings suggested a 46% and 26% lower risk of death respectively with OPDIVO® plus chemotherapy, than with chemotherapy alone. Overall Survival was also significantly longer with OPDIVO® plus YERVOY® than with chemotherapy among patients with tumor-cell PD-L1 expression of 1% or greater (13.7 months versus 9.1 months; HR=0.64; P=0.001) and in the overall population (12.7 months versus 10.7 months; HR=0.78; P=0.01).

There was a significant improvement in Progression Free Survival seen with OPDIVO® plus chemotherapy over chemotherapy alone, among patients with tumor-cell PD-L1 expression of 1% or greater (HR=0.65; P=0.002). This PFS benefit was not seen with OPDIVO® plus YERVOY®, as compared with chemotherapy. The incidence of Grade 3 or 4 treatment-related Adverse Events was 47% with OPDIVO® plus chemotherapy, 32% with OPDIVO® plus YERVOY® and 36% with chemotherapy alone.

Treatment with either OPDIVO®-based regimens resulted in a higher Complete Response rate, as well as in more durable responses, than chemotherapy alone. Of the three treatment regimens, OPDIVO® plus chemotherapy led to the highest Objective Response Rate and OPDIVO® plus YERVOY® resulted in the longest median Duration of Response.

It was concluded that first-line treatment of advanced esophageal Squamous Cell Carcinoma with either OPDIVO® plus chemotherapy or OPDIVO® plus YERVOY®, resulted in a significantly longer Overall Survival benefit and durable responses, than chemotherapy alone.

Nivolumab Combination Therapy in Advanced Esophageal Squamous-Cell Carcinoma. Doki Y, Ajani JA, Kato K, et al. N Engl J Med 2022;386:449-462