ON AUGUST 16, 2018, nivolumab (Opdivo) was granted accelerated approval for treatment of patients with metastatic small cell lung cancer (SCLC) with disease progression after platinum-based chemotherapy and at least one other line of therapy.1,2
Supporting Efficacy Data
APPROVAL WAS BASED on findings of durable responses among 109 patients in a subgroup of the SCLC cohort of the CheckMate-032 trial who had disease progression after platinum-based therapy and at least 1 other prior line of therapy regardless of tumor programmed cell death ligand 1 (PD-L1) status.2 All patients received nivolumab at 3 mg/kg every 2 weeks. The trial excluded patients with active autoimmune disease, medical conditions requiring systemic immunosuppression, and symptomatic interstitial lung disease.
Patients had a median age of 64 years (range = 45–81 years, 45% ≥ 65 years); 94% were white; Eastern Cooperative Oncology Group performance status was 0 in 29% and 1 in 70%; 93% were former/ current smokers; 7% had central nervous system metastases; 94% received 2 or 3 prior lines of therapy, and 6% received 4 or 5 prior lines of therapy; and approximately 65% had platinum-sensitive SCLC (disease progression ≥ 90 days after the last dose of platinum-containing therapy).
The overall response rate using Response Evaluation Criteria in Solid Tumors, version 1.1 on blinded independent central review was 12% (95% confidence interval = 6.5%–19.5%). Among the 13 responders, response was ≥ 6 months in 77%, ≥ 12 months in 62%, and ≥ 18 months in 39% of the 13 responding patients. PD-L1 tumor expression status did not appear to be predictive of response.
How It Works
NIVOLUMAB IS A human immunoglobulin G4 (IgG4) monoclonal antibody that binds the programmed cell death protein 1 (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 DOSE of nivolumab in the current indication is 240 mg via intravenous infusion over 30 minutes every 2 weeks until disease progression or unacceptable toxicity.
Infusion should be interrupted or slowed in patients with mild or moderate infusion reactions. Nivolumab should be discontinued for severe or life-threatening infusion reactions.
In patients receiving single-agent nivolumab, treatment should be withheld for the following conditions: grade 2 or 3 diarrhea or colitis; grade 2 pneumonitis; for hepatitis/non–hepatocellular carcinoma (HCC)—if alanine transaminase (ALT) or aspartate transaminase (AST) > 3 up to 5 times upper limit of normal (ULN) or total bilirubin > 1.5 up to 3 times ULN; for hepatitis/HCC—if AST/ALT is within normal limits at baseline and increases to more than 3 and up to 5 times ULN, if AST/ALT is > 1 and up to 3 times ULN at baseline and increases to > 5 and up to 10 times ULN, or if AST/ALT is > 3 and up to 5 times ULN at baseline and increases to > 8 and up to 10 times ULN; grade 2 or 3 hypophysitis; serum creatinine > 1.5 to 6 times ULN; grade 2 adrenal insufficiency; grade 3 hyperglycemia; grade 3 rash or suspected Stevens-Johnson syndrome or toxic epidermal necrolysis; new-onset moderate or severe neurologic signs or symptoms; and first occurrence of other grade 3 adverse reactions.
Nivolumab should be permanently discontinued for the following conditions: grade 4 diarrhea or colitis; grade 3 or 4 pneumonitis; for hepatitis/non-HCC—for AST or ALT > 5 times ULN or total bilirubin > 3 times ULN; for hepatitis/HCC—if AST/ALT increases to > 10 times ULN or total bilirubin increases to > 3 times ULN; grade 4 hypophysitis; grade 3 or 4 adrenal insufficiency; grade 4 hyperglycemia; serum creatinine > 6 times ULN; grade 4 rash or confirmed Stevens-Johnson syndrome or toxic epidermal necrolysis; immune-mediated encephalitis; recurrence of grade 3 adverse reactions; life-threatening or grade 4 adverse reactions; grade 3 myocarditis; requirement of ≥ 10 mg/d of prednisone or equivalent for > 12 weeks; and persistent grade 2 or 3 adverse reactions lasting ≥ 12 weeks.
IN CLINICAL TRIALS, the most common adverse events (> 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, and abdominal pain.
Safety data are from 245 patients in CheckMate-032 with metastatic SCLC with disease progression following platinum-based chemotherapy who received at least 1 dose of nivolumab at 3 mg/ kg every 2 weeks. The toxicity profile in patients with metastatic SCLC was generally similar to that among patients with other solid tumors receiving nivolumab as a single agent. The most common (≥ 20%) adverse events of any grade were fatigue, decreased appetite, musculoskeletal pain, dyspnea, nausea, diarrhea, constipation, and cough. Adverse events led to dose interruption in 25% of patients and permanent treatment discontinuation in 10%. Serious adverse events occurred in 45% of patients, with the most common (≥ 2%) being pneumonia, dyspnea, pneumonitis, pleural effusion, and dehydration.
Nivolumab carries warnings/precautions for immune-mediated adverse reactions including pneumonitis, colitis, hepatitis, endocrinopathies, nephritis and renal dysfunction, skin adverse reactions, and encephalitis. It also carries warnings/precautions for infusion reactions, complications of allogeneic hematopoietic stem cell transplantation after nivolumab treatment, and embryofetal toxicity. Patients should be monitored for changes in liver, thyroid, kidney, and neurologic function and for hyperglycemia. Breastfeeding women should discontinue breastfeeding while receiving nivolumab. ■
1. U.S. Food and Drug Administration: FDA grants nivolumab accelerated approval for third-line treatment of metastatic small cell lung cancer. Available at www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm617370.htm. Accessed September 6, 2018.
2. Opdivo (nivolumab) injection prescribing information, Bristol-Myers Squibb Company, August 2018. Available at www.accessdata.fda.gov/drugsatfda_ docs/label/2018/125554s067lbl.pdf. Accessed September 6, 2018.