On May 20, 2021, nivolumab was approved for adjuvant treatment of patients with completely resected esophageal or gastroesophageal junction (GEJ) cancer with residual pathologic disease after neoadjuvant chemoradiotherapy.1,2
Supporting Efficacy Data
Approval was based on findings from the double-blind, phase III CheckMate 577 trial (ClinicalTrials.gov identifier NCT02743494).2,3 In the trial, 794 patients with completely resected esophageal or GEJ cancer who had residual pathologic disease following neoadjuvant concurrent chemoradiotherapy were randomly assigned 2:1 to receive nivolumab (n = 532) at 240 mg or placebo (n = 262) every 2 weeks for 16 weeks, followed by nivolumab at 480 mg or placebo every 4 weeks, beginning at week 17 for up to 1 year of treatment. The trial excluded patients who did not receive concurrent chemoradiotherapy prior to surgery and those who had stage IV resectable disease, autoimmune disease, or any condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone or equivalent) or other immunosuppressive medications.
Nivolumab has warnings/precautions for immune-mediated adverse reactions, including pneumonitis, colitis, hepatitis and hepatotoxicity, endocrinopathies, dermatologic adverse reactions, and nephritis and renal dysfunction; infusion-related reactions; complications of allogeneic hematopoietic stem cell transplantation; and embryofetal toxicity.
Among all patients, median age was 62 years (36% ≥ 65 years); 85% were male; 82% were White, 15% were Asian, and 1.1% were Black. Eastern Cooperative Oncology Group performance status was 0 (58%) or 1 in all patients; disease stage was II in 35% and III in 65%; 60% had esophageal cancer and 40% had GEJ cancer; and 58% had pathologic positive lymph node status. Histology was adenocarcinoma in 71% and squamous cell carcinoma in 29%. PD-L1 status was positive (≥ 1% expression) in 16%, negative in 72%, and indeterminate or could not be evaluated in 12%.
The main efficacy outcome measure was disease-free survival, defined as the time from date of randomization to the time of investigator-assessed first recurrence (local, regional, or distant) or death from any cause prior to subsequent anticancer therapy. Median disease-free survival was 22.4 months (95% confidence interval [CI] = 16.6–34.0 months) in the nivolumab group vs 11.0 months (95% CI = 8.3–14.3 months) in the placebo group (hazard ratio = 0.69, 95% CI = 0.56–0.85, P = .0003). The benefit of nivolumab was observed regardless of tumor PD-L1 expression or histology.
How It Works
Nivolumab is a human immunoglobulin G4 monoclonal antibody that binds the PD-1 receptor on T cells and blocks its interaction with the ligands PD-L1 and PD-L2, thereby releasing PD-1 pathway–mediated inhibition of immune response. Binding of PD-L1 and PD-L2 to the PD-1 receptor inhibits T-cell proliferation and cytokine production. Upregulation of PD-1 ligands occurs in some tumors, and signaling through this pathway can contribute to inhibition of active T-cell tumor immune surveillance. In syngeneic mouse tumor models, blocking PD-1 activity resulted in decreased tumor growth.
How It Is Used
The recommended dose of nivolumab for adjuvant treatment of resected esophageal or GEJ cancer is 240 mg every 2 weeks or 480 mg every 4 weeks, both via 30-minute intravenous infusion, for a total treatment duration of 1 year. Treatment should be continued until disease progression, unacceptable toxicity, or for up to 1 year.
Infusion should be interrupted or slowed for grade 1 or 2 infusion-related reactions, and treatment should be permanently discontinued for grade 3 or 4 reactions. No dose reductions for nivolumab are recommended. In general, nivolumab should be withheld for grade 3 immune-mediated adverse reactions and permanently discontinued for grade 4 immune-mediated adverse reactions, recurrent grade 3 immune-mediated reactions that require systemic immunosuppressive treatment, or an inability to reduce the corticosteroid dose to 10 mg or less of prednisone or equivalent per day within 12 weeks of initiating steroids.
Specific instructions are provided in the product labeling for nivolumab alone or in combination with other agents for management and dose modification, including withholding or discontinuing treatment for adverse reactions, covering infusion-related reactions and the following immune-mediated adverse reactions: pneumonitis, colitis, hepatitis with and without tumor involvement of the liver, endocrinopathies, nephritis with renal dysfunction, exfoliative dermatologic conditions, myocarditis, and neurologic toxicity.
Among patients receiving single-agent nivolumab in clinical trials, the most common adverse events of any grade (incidence ≥ 20%) have been fatigue, rash, musculoskeletal pain, pruritus, diarrhea, nausea, asthenia, cough, dyspnea, constipation, decreased appetite, back pain, arthralgia, upper respiratory tract infection, pyrexia, headache, abdominal pain, and vomiting.
Among patients receiving nivolumab in the CheckMate 577 trial, 61% were exposed to treatment for more than 6 months and 54% for more than 9 months. In the trial, the most common adverse events of any grade (incidence ≥ 20%) in patients receiving nivolumab were fatigue, diarrhea, nausea, rash, musculoskeletal pain, and cough. Grade 3 to 4 adverse events occurred in 34% vs 32% of patients; the most common in the nivolumab group included fatigue, diarrhea, rash, and decreased appetite. The most common grade 3 to 4 laboratory abnormalities were lymphopenia, increased amylase, and increased aspartate transaminase. Adverse events led to a dose delay in 28% of patients and treatment discontinuation in 12%. A fatal adverse event (myocardial infarction) occurred in one patient.
Nivolumab has warnings/precautions for immune-mediated adverse reactions, which may be severe or fatal and can occur in any organ system or tissue, including pneumonitis, colitis, hepatitis and hepatotoxicity, endocrinopathies, dermatologic adverse reactions, and nephritis and renal dysfunction; infusion-related reactions; complications of allogeneic hematopoietic stem cell transplantation; and embryofetal toxicity. Treatment of patients with multiple myeloma with a PD-1– or PD-L1–blocking antibody in combination with a thalidomide analog plus dexamethasone is not recommended outside of controlled clinical trials. Patients should be monitored for early identification and management of immune-mediated adverse reactions, including evaluation of liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. Patients should be advised not to breastfeed while receiving nivolumab.
1. U.S. Food and Drug Administration: FDA approves nivolumab for resected esophageal or GEJ cancer. Available at https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-nivolumab-resected-esophageal-or-gej-cancer. Accessed June 10, 2021.
2. Opdivo (nivolumab) injection prescribing information, Bristol Myers Squibb Company, May 2021. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/125554s092lbl.pdf. Accessed June 10, 2021.
3. Kelly RJ, Ajani JA, Kuzdzal J, et al: N Engl J Med 384:1191-1203, 2021.