As reported in The New England Journal of Medicine by Thomas Powles, MD, Barts Cancer Institute, Queen Mary University of London, and colleagues, the phase III JAVELIN Bladder 100 trial found that maintenance treatment with avelumab plus best supportive care significantly improved overall survival vs best supportive care alone among patients whose disease had not progressed on first-line platinum-based chemotherapy.¹

Thomas Powles, MD

The trial supported the June 2020 approval of avelumab for maintenance treatment of patients with locally advanced or metastatic urothelial carcinoma that has not progressed with first-line platinum-containing chemotherapy.

Study Details

In the open-label trial, 700 patients from sites in 29 countries were randomly assigned between May 2016 and June 2019 to receive best supportive care with (n = 350) or without (n = 350) avelumab at 10 mg/kg every 2 weeks, with treatment continued until disease progression or unacceptable toxicity. Patients had unresectable locally advanced or metastatic urothelial cancer without disease progression on first-line chemotherapy consisting of four to six cycles of gemcitabine plus cisplatin or carboplatin.

Randomization was stratified according to best response to first-line chemotherapy (complete or partial response vs stable disease) and according to the metastatic site when first-line chemotherapy was initiated (visceral vs nonvisceral). The nonvisceral site stratum also included patients with unresectable locally advanced disease. The primary endpoint was overall survival in the overall population and among patients with PD-L1–positive tumors.

Patients were classified as having PD-L1–positive status if one of the following criteria was met: ≥ 25% of tumor cells stained for PD-L1; ≥ 25% of immune cells stained for PD-L1 if > 1% of the tumor area contained immune cells; or 100% of immune cells stained for PD-L1 if no more than 1% of the tumor area contained immune cells.

Among patients evaluated for PD-L1 status, tumors were PD-L1–positive in 189 (57.6%) of 328 patients in the avelumab group and in 169 (56.3%) of 300 in the control group. Best response to first-line chemotherapy was complete or partial response in 72.3% of the avelumab group and 72.0% in the control group. The site of baseline metastasis before chemotherapy was visceral in 54.6% of both groups.

Overall Survival

Median follow-up for overall survival was > 19 months in both groups. 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 control group (stratified hazard ratio [HR] = 0.69; 95% CI = 0.56–0.86, P = .001). Rates at 1 year were 71.3% vs 58.4%.

In stratification subgroups, hazard ratios were 0.69 (95% CI = 0.53–0.89) among patients with best response of complete/partial response, 0.70 (95% CI = 0.46–1.05) among those with stable disease, 0.82 (95% CI = 0.62–1.09) among those with visceral metastases, and 0.54 (95% CI = 0.38–0.76) among those with nonvisceral metastases/unresectable locally advanced disease.

In the PD-L1–positive population, median overall survival was not reached (95% CI = 20.3 months to not estimable) in the avelumab group vs 17.1 months (95% CI = 13.5–23.7 months) in the control group (hazard ratio = 0.56, 95% CI = 0.40–0.79, P < .001). Rates at 1 year were 79.1% vs 60.4%.

Among patients with PD-L1–negative tumors, median overall survival was 18.8 months (95% CI = 13.3–22.5 months) in the avelumab group vs 13.7 months (95% CI = 10.8–17.8 months) in the control group (HR = 0.85, 95% CI = 0.62–1.18).

Median progression-free survival was 3.7 months (95% CI = 3.5–5.5 months) in the avelumab group vs 2.0 months (95% CI = 1.9–2.7 months) in the control group (HR = 0.62, 95% CI = 0.52–0.75) in the overall population. In the PD-L1–positive population, median progression-free survival was 5.7 months (95% CI = 3.7–7.4 months) in the avelumab group and 2.1 months (95% CI = 1.9–3.5 months) in the control group (HR = 0.56, 95% CI = 0.43–0.73). In the PD-L1–negative population, median progression-free survival was 3.0 months (95% CI= 2.0–3.7 months) in the avelumab group vs 1.9 months (95% CI = 1.9–2.1) in the control group (HR = 0.63, 95% CI = 0.47–0.85).

Subsequent anticancer drug therapy was received by 148 patients (42.3%) in the avelumab group and 216 patients (61.7%) in the control group, including a PD-1 or anti–PD-L1 antibody in 22 patients (6.3%) in the avelumab group and in 153 patients (43.7%) in the control group.

Adverse Events

The incidence of adverse events from any cause was 98.0% in the avelumab group and 77.7% in the control group. Adverse events of grade ≥ 3 occurred in 163 patients (47.4%) in the avelumab group vs 87 (25.2%) in the control group, the most common in the avelumab group including urinary tract infection (4.4%), anemia (3.8%), fatigue (1.7%), and hematuria (1.7%). Infusion-related reactions of any grade occurred in 21.5% of the avelumab group. Serious adverse events occurred in 27.9% vs 20.0% of patients, the most common in the avelumab group being urinary tract infection (4.7%) and acute kidney injury (1.7%). Adverse events in the avelumab group led to treatment discontinuation in 41 patients (11.9%). Immune-mediated adverse events of any grade occurred in 29.4% of the avelumab group (grade ≥ 3 in 7.0%), the most common being hypothyroidism (10.2%) and rash (4.9%).

Death was considered treatment related in two patients in the avelumab group, with causes consisting of sepsis after urinary tract infection in one and ischemic stroke 100 days after receiving a single dose of avelumab and after limb venous thrombosis, pulmonary embolism, and acute myocardial infarction in one.

The investigators concluded: “Maintenance avelumab plus best supportive care significantly prolonged overall survival, as compared with best supportive care alone, among patients with urothelial cancer who had disease that had not progressed with first-line chemotherapy.” 

DISCLOSURE: The study was funded by Pfizer and Merck. Dr. Powles has received honoraria from AstraZeneca, Bristol-Myers Squibb, Ferring, GLG Group, Janssen Research & Development, Merck, Novartis, Pfizer, Roche/Genentech, and Seattle Genetics/Astellas; has served in a consulting or advisory role for AstraZeneca, Bristol Myers Squibb, Genentech/Roche, Incyte, Ipsen, Merck, Novartis, Pfizer, and Seattle Genetics; has received research funding from AstraZeneca/MedImmune and Roche/Genentech; and has been reimbursed for travel, accommodations, or other expenses by AstraZeneca, Bristol Myers Squibb, Ferring, MSD, Novartis/Ipsen, Pfizer, Research to Practice, and Roche/Genentech.

REFERENCE

1. Powles T, Park SH, Voog E, et al: Avelumab maintenance therapy for advanced or metastatic urothelial carcinoma. N Engl J Med 383:1218-1230, 2020.