On June 10, 2020, nivolumab was approved for treatment of patients with unresectable, advanced, recurrent, or metastatic esophageal squamous cell carcinoma after prior fluoropyrimidine- and platinum-based chemotherapy.1,2
Supporting Efficacy Data
Approval was based on findings from the open-label, phase III ATTRACTION-3 trial (ClinicalTrials.gov identifier NCT02569242).2,3 In the trial, 419 patients with unresectable, advanced, recurrent, or metastatic esophageal squamous cell carcinoma who were refractory to or intolerant of at least one fluoropyrimidine- and platinum‑based regimen were randomly assigned to receive nivolumab at 240 mg via 30-minute infusion over every 2 weeks (n = 210) or the investigator’s choice of taxane chemotherapy consisting of docetaxel at 75 mg/m2 every 3 weeks or paclitaxel at 100 mg/m2 once a week for 6 weeks, followed by 1 week off (n = 209). Treatment continued until disease progression or unacceptable toxicity.
The major efficacy outcome measure was overall survival. Additional efficacy outcome measures were overall response rate, response duration, and progression-free survival as assessed by investigators using Response Evaluation Criteria in Solid Tumors version 1.1.
Median overall survival was 10.9 months (95% confidence interval [CI] = 9.2–13.3 months) with nivolumab vs 8.4 months (95% CI = 7.2–9.9 months) with taxane chemotherapy (hazard ratio [HR] = 0.77, 95% CI = 0.62–0.96, P = .0189). Median overall survival was 10.9 vs 8.1 months (HR = 0.69, 95% CI = 0.51–0.94) in the PD-L1–positive subgroup and 10.9 vs 9.3 months (HR = 0.84, 95% CI = 0.62–1.14) in the PD-L1–negative subgroup.
The overall response rate was 19.3% vs 21.5% (P = .6323), with median response durations of 6.9 months (95% CI = 5.4–11.1 months) vs 3.9 months (95% CI = 2.8–4.2 months). Median progression-free survival was 1.7 months (95% CI = 1.5–2.7 months) vs 3.4 months (95% CI = 3.0–4.2 months), with a hazard ratio of 1.1 (95% CI = 0.9–1.3).
How It Works
Nivolumab is a human immunoglobulin G4 monoclonal antibody that binds the PD-1 receptor on T cells and prevents its interaction with the ligands PD-L1 and PD-L2, thereby releasing PD-1 pathway–mediated inhibition of immune response, including antitumor 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 results in decreased tumor growth.
How It Is Used
The recommended dosage of nivolumab in the current indication is 240 mg every 2 weeks via 30-minute intravenous (IV) infusion or 480 mg every 4 weeks via 30-minute IV infusion, with treatment continued until disease progression or unacceptable toxicity. Infusion should be interrupted or slowed in patients with mild or moderate infusion-related reactions and discontinued in patients with severe or life-threatening infusion-related reactions.
Nivolumab prescribing information provides instructions on dose modification, including withholding or discontinuation of treatment for colitis, pneumonitis, hepatitis/nonhepatocellular carcinoma, hepatitis/hepatocellular carcinoma, hypophysitis, adrenal insufficiency, type 1 diabetes, nephritis and renal dysfunction, skin toxicity, encephalitis, persistent grade 2 or 3 adverse reactions, other grade 3 adverse reactions, life-threatening or grade 4 adverse reactions, grade 3 myocarditis, and requirement for ≥ 10 mg/d of prednisone or equivalent for more than 12 weeks. There are no recommended dose modifications for hypothyroidism or hyperthyroidism.
In clinical trials, the most common adverse events of any grade (> 20%) with nivolumab as a single agent 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.
In the ATTRACTION-3 trial, the median duration of exposure to study treatment was 2.6 months (range = 0–29.2 months) with nivolumab and 2.6 months (range = 0–21.4 months) with taxane chemotherapy. Among patients receiving nivolumab, 26% had exposure for more than 6 months and 10% for more than 1 year.
The most common adverse events of any grade (> 15%) in patients receiving nivolumab were rash (22% vs 28% with chemotherapy), decreased appetite (21% vs 35%), diarrhea (18% vs 17%), constipation (17% vs 19%), musculoskeletal pain (17% vs 26%), upper respiratory tract infection (17% vs 14%), cough (16% vs 14%), and pyrexia (16% vs 19%). The most common grade 3 or 4 adverse events included anemia (8%) and pneumonia (5%). The most common grade 3 or 4 laboratory abnormalities were lymphopenia (19%), hyponatremia (11%), and anemia (9%).
Serious adverse events occurred in 38% of patients receiving nivolumab, with those occurring in at least 2% of patients consisting of pneumonia, esophageal fistula, interstitial lung disease, and pyrexia. Adverse events led to treatment delay in 27% of patients and to treatment discontinuation in 13%. The following fatal adverse events occurred in patients receiving nivolumab: interstitial lung disease or pneumonitis (1.4%), pneumonia (1.0%), septic shock (0.5%), esophageal fistula (0.5%), gastrointestinal hemorrhage (0.5%), pulmonary embolism (0.5%), and sudden death (0.5%).
Nivolumab has warnings/precautions for immune-mediated adverse reactions including pneumonitis, colitis, hepatitis, endocrinopathies, nephritis and renal dysfunction, skin adverse reactions, and encephalitis; infusion-related reactions; complications of allogeneic hematopoietic stem cell transplantation; and embryofetal toxicity. Patients should be advised not to breastfeed while receiving the drug.
1. U.S. Food and Drug Administration: FDA approves nivolumab for esophageal squamous cell carcinoma. Available at https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-nivolumab-esophageal-squamous-cell-carcinoma. Accessed July 9, 2020.
2. Opdivo (nivolumab) injection prescribing information, Bristol-Myers Squibb Company, June 2020. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/125554s081lbl.pdf. Accessed July 9, 2020.
3. Kato K, Cho BC, Takahashi M, et al: Nivolumab versus chemotherapy in patients with advanced oesophageal squamous cell carcinoma refractory or intolerant to previous chemotherapy (ATTRACTION-3): A multicentre, randomised, open-label, phase 3 trial. Lancet Oncol 20:1506-1517, 2019.