On June 30, 2020, avelumab was approved for maintenance treatment of patients with locally advanced or metastatic urothelial carcinoma that has not progressed with first-line platinum-containing chemotherapy.^1,2

Supporting Efficacy Data

Approval was based on findings in the randomized, multicenter, open-label phase III JAVELIN Bladder 100 trial (ClinicalTrials.gov identifier NCT02603432).² The results from this study supported the conversion of accelerated approval of avelumab to a regular approval. In the trial, 700 patients with unresectable, locally advanced, or metastatic urothelial carcinoma that had not progressed with four to six cycles of first-line platinum-containing chemotherapy were randomly assigned to receive either avelumab at 10 mg/kg intravenously (IV) every 2 weeks plus best supportive care (n = 350) or best supportive care alone (n = 350). Treatment was initiated within 4 to 10 weeks after the last chemotherapy dose. Randomization was stratified by best response to chemotherapy (complete/partial response vs stable disease) and site of metastasis (visceral vs nonvisceral) at the time of initiating first-line chemotherapy. Patients with autoimmune diseases or conditions requiring systemic immunosuppression were excluded from the trial.

Treatment with avelumab was continued until Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1–defined progression of disease as assessed by blinded independent central review or unacceptable toxicity. Treatment was permitted beyond RECIST-defined disease progression if patients were clinically stable and considered to be deriving clinical benefit. Tumor status was assessed at baseline, 8 weeks after randomization, then every 8 weeks up to 12 months after randomization, and every 12 weeks thereafter.

Median patient age was 69 years (range = 32–90 years, 66% ≥ 65 years and 24% ≥ 75 years), 77% were male, 67% were White, and 22% were Asian. Eastern Cooperative Oncology Group performance status was 0 (61%) or 1 in all. Moreover, 56% had received prior gemcitabine/cisplatin, 38% gemcitabine/carboplatin, and 6% both. Best response to first-line chemotherapy was a complete or partial response in 72% and stable disease in 28%; 55% had visceral and 45% nonvisceral metastases prior to chemotherapy; and 51% had PD-L1 –positive tumors, 39% had PD-L1–negative tumors, and 10% had an unknown PD-L1 tumor status.

The main efficacy outcome measures were overall survival in all patients and in patients with PD-L1–positive tumors. Overall, another PD-1 or PD-L1 inhibitor was received by 6% of patients in the avelumab group and 44% of the best-supportive-care group after discontinuation of study treatment. Among all patients, median overall survival was 21.4 months (95% confidence interval [CI] = 18.9–26.1 months) in the avelumab group vs 14.3 months (95% CI = 12.9–17.9 months) in the best-supportive-care group (hazard ratio [HR] = 0.69, 95% CI = 0.56–0.86, P = .001). Among patients with PD-L1–positive tumors, the hazard ratio was 0.56 (95% CI = 0.40–0.79, P < .001). In an exploratory analysis of patients with PD-L1–negative tumors, the hazard ratio was 0.85 (95% CI = 0.62–1.18). Consistent results were observed in the subgroups of patients with a complete/partial response vs stable disease as a response to first-line chemotherapy.

How It Works

Avelumab is a PD-L1–blocking antibody. PD-L1 may be expressed on tumor cells and tumor-infiltrating immune cells and can contribute to the inhibition of the antitumor immune response in the tumor microenvironment. Binding of PD-L1 to the PD-1 and B7.1 receptors found on T cells and antigen-presenting cells suppresses cytotoxic T-cell activity, T-cell proliferation, and cytokine production. Avelumab binds PD-L1 and blocks the interaction between PD-L1 and PD-1 and B7.1 receptors. This interaction releases the inhibitory effects of PD-L1 on the immune response, resulting in the restoration of immune responses, including antitumor immune responses. Avelumab has also been shown to induce antibody-dependent cell-mediated cytotoxicity in vitro. In syngeneic mouse tumor models, blocking PD-L1 activity resulted in decreased tumor growth.

How It Is Used

In the current indication, the recommended dose of avelumab is 800 mg via IV infusion over 60 minutes every 2 weeks until disease progression or unacceptable toxicity. Patients should be premedicated with an antihistamine and acetaminophen prior to the first four infusions of avelumab; premedication should be administered for subsequent doses based on clinical judgment and the presence/severity of prior infusion reactions. Infusion should be interrupted or infusion rate slowed for grade 1 or 2 infusion-related reactions; treatment should be permanently discontinued for grade 3 or 4 reactions.

Product labeling provides detailed information on clinical and laboratory monitoring guidelines for early detection of adverse reactions to avelumab and recommended management, including immunosuppressant treatment guidelines.

Product labeling provides detailed information on dose modification, including withholding and discontinuing treatment for adverse reactions including pneumonitis, hepatitis, colitis, endocrinopathies (including but not limited to hypothyroidism, hyperthyroidism, adrenal insufficiency, and hyperglycemia), nephritis and renal dysfunction, other immune-mediated adverse reactions (including but not limited to myocarditis, pancreatitis, myositis, psoriasis, arthritis, exfoliative dermatitis, erythema multiforme, pemphigoid, hypopituitarism, uveitis, Guillain-Barré syndrome, bullous dermatitis, Stevens Johnson syndrome/toxic epidermal necrolysis, rhabdomyolysis, myasthenia gravis, histiocytic necrotizing lymphadenitis, demyelination, vasculitis, hemolytic anemia, hypophysitis, iritis, and encephalitis), and infusion-related reactions.

Safety Profile

In the JAVELIN Bladder 100 trial, 47% of patients receiving avelumab were exposed to treatment for more than 6 months and 28% for more than 1 year. Patients with autoimmune diseases or conditions requiring systemic immunosuppression were excluded from the trial.

The most common adverse events of any grade (> 20%) in patients receiving avelumab were fatigue (35% vs 13% in best supportive care group), musculoskeletal pain (24% vs 15%), urinary tract infection (20% vs 11%), and rash (20% vs 2%). The most common grade 3 or 4 adverse events included urinary tract infection (6% vs 4%) and fatigue (1.7% vs 1.7%). Any-grade infusion-related reactions occurred in 10% of patients receiving avelumab (grade 3 or 4 in 0.9%). The most common grade 3 or 4 laboratory abnormalities were decreased hemoglobin (4.4% vs 3.2%) and increased potassium (3.8% vs 0.9%).

Overall, 31 patients (9%) taking avelumab received an oral prednisone dose equivalent to at least 40 mg daily for an immune-mediated adverse event. Serious adverse events occurred in 28% of patients, with those occurring in at least 1% including urinary tract infection (including kidney infection, pyelonephritis, and urosepsis; 6.1%), pain (including abdominal, back, bone, flank, extremity, and pelvic pain; 3.2%), acute kidney injury (1.7%), hematuria (1.5%), sepsis (1.2%), and infusion-related reactions (1.2%). Adverse events led to dose interruption in 41% of patients, excluding temporary interruptions due to infusion-related reactions. The most common causes were urinary tract infection (including pyelonephritis; 4.7%) and increased blood creatinine (including acute kidney injury, renal impairment, and renal failure; 3.8%). Adverse events led to permanent discontinuation of treatment in 12% of patients, with the most common causes being myocardial infarction (including acute myocardial infarction and increased troponin T; 1.5%) and infusion-related reaction (1.2%). A fatal adverse event occurred in one patient, who died of sepsis.

Avelumab has warnings/precautions for immune-related pneumonitis, hepatotoxicity and immune-mediated hepatitis, immune-mediated colitis, immune-mediated endocrinopathies, immune-mediated nephritis and renal dysfunction, infusion-related reactions, major cardiovascular adverse events, and embryofetal toxicity. Patients should be monitored for changes in liver function and management of cardiovascular risk factors should be optimized. Patients should be advised not to breastfeed while receiving avelumab. 

REFERENCES

1. U.S. Food and Drug Administration: FDA approves avelumab for urothelial carcinoma maintenance treatment. Available at https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-avelumab-urothelial-carcinoma-maintenance-treatment. Accessed August 26, 2020.

2. Bavencio (avelumab) injection, for intravenous use, EMD Serono and Pfizer, June 2020. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/761049s009lbl.pdf. Accessed August 26, 2020.