Avelumab sBLA Filed for Frontline Maintenance in Urothelial Carcinoma, Breakthrough Designation Granted

A supplemental Biologics License Application has been filed with the FDA for avelumab for the frontline maintenance treatment of patients with locally advanced or metastatic urothelial carcinoma.

Petros Grivas, MD, PhD

A supplemental Biologics License Application (sBLA) has been filed with the FDA for avelumab (Bavencio) for the frontline maintenance treatment of patients with locally advanced or metastatic urothelial carcinoma, according to EMD Serono (Merck KGaA) and Pfizer, the codevelopers of the PD-L1 inhibitor.1

The sBLA and breakthrough designation are based on findings from the phase III JAVELIN Bladder 100 study (NCT02603432), in which frontline maintenance therapy with avelumab plus best supportive care demonstrated a statistically significant improvement in overall survival (OS) compared with best supportive care alone in patients with previously untreated locally advanced or metastatic urothelial carcinoma, regardless of PD-L1 expression, meeting the primary endpoint of the trial.2

“For the past 30 years, chemotherapy has been the first-line standard of care for patients with advanced urothelial carcinoma. While this is an effective short-term option for many patients, most will ultimately experience disease progression, underscoring a need for additional treatment options,” Petros Grivas, MD, PhD, one of the principal investigators in the JAVELIN Bladder 100 trial, said in a press release. “Based on the positive overall survival results from JAVELIN Bladder 100, I believe avelumab has the potential to be practice-changing.”

Avelumab was previously granted an accelerated approval by the FDA in 2017 for the treatment of patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy, or who have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. JAVELIN Bladder 100 is the confirmatory trial to convert the existing accelerated approval into a full approval.

In the multicenter, international, open-label, parallel-arm, randomized, phase III JAVELIN Bladder 100 trial, investigators evaluated first-line maintenance therapy with avelumab plus best supportive care versus best supportive care alone in 700 patients with locally advanced or metastatic urothelial cancer whose disease did not progress as per RECIST v1.1 criteria, following completion of frontline platinum-containing chemotherapy.

Avelumab was given as a 1-hour infusion every 2 weeks in 4-week cycles, while best supportive care could include antibiotics, nutritional supportive, correction of metabolic disorders, and symptom control and pain management.

To be eligible for enrollment, patients must have histologically confirmed, unresectable locally advanced, or metastatic transitional cell carcinoma of the urothelium, have stage IV disease at the beginning of frontline chemotherapy, measurable disease prior to receiving chemotherapy, and have no evidence of progressive disease after receiving first-line chemotherapy.

Those who had previously received neoadjuvant or adjuvant systemic therapy within 12 months of randomization, had prior immunotherapy or any drug targeting T-cell co-stimulation or immune checkpoint pathways, persisting grade>1 toxicity related to prior treatment, known symptomatic central nervous system metastases that required steroids, or any cancer diagnosis within 5 years prior to randomization were excluded from enrollment.

The primary endpoint is OS in the coprimary populations of all randomized patients and also in those with PD-L1—positive disease. Secondary endpoints include progression-free survival (PFS), antitumor activity, safety, pharmacokinetics, immunogenicity, predictive biomarkers, and patient-reported outcomes in the coprimary populations.

The FDA’s initial approval of avelumab for this patient population was based on data from the urothelial carcinoma cohorts of the single-arm, open-label JAVELIN Solid Tumor trial, in which the overall response rate was 13.3% (95% CI, 9.1-18.4) among 226 patients who had been followed for ≥13 weeks, and was 16.1% (95% CI, 10.8-22.8) among 161 patients who had been followed for ≥6 months.3

In the ≥6-month follow-up cohort, the 26 responses included 9 (5.6%) complete responses (CRs) and 17 (10.6%) partial response (PRs). In the ≥13 weeks follow-up group, the 30 responses included 9 CRs (4%) and 21 PRs (9.3%).

Moreover, the median duration of response (DOR) had not yet been reached for either arm and ranged from 1.4+ to 17.4+ months for both groups. The median time to response was 2 months (range, 1.3-11.0) for both groups.

PD-L1 expression was evaluable in 84% of patients across both cohorts. Among this population, there was no distinguishable variation in response rates based on tumor expression levels of PD-L1.

Longer follow-up of this cohort was presented at the 2019 Genitourinary Cancers Symposium. At a median follow-up of 2.7 years, the confirmed ORR in all evaluable patients (n = 242) was 16.5% (95% CI, 12.1%-21.8%) with a CR rate of 4.1%.4 The median DOR was 20.5 months, and the Kaplan-Meier estimate of the 12-month DOR was 65.4%.

Additionally, the median PFS was 1.6 months (95% CI, 1.4-2.7), the median OS was 7.0 months (95% CI, 5.9-8.5), and the Kaplan-Meier 12-month and 24-month OS rates were 35.9% and 20.1%, respectively.

Regarding safety, any-grade treatment-related adverse events (TRAEs) occurred in 71.1% of patients and were most commonly infusion-related reactions (24.1%), fatigue (18.1%), and rash (18.1%). Grade ≥3 TRAEs occurred in 11.6% of patients, the most common ones were fatigue (1.6%), elevated lipase (1.6%), and pneumonitis (1.2%). There were 10 patients who discontinued treatment with the PD-L1 inhibitor due to a TRAE; there was 1 treatment-related death, which was due to pneumonitis.


  1. US FDA Breakthrough Therapy Designation And Submit Application For Bavencio® For First-Line Maintenance Treatment Of Locally Advanced Or Metastatic Urothelial Carcinoma. Published April 9, 2020. https://bit.ly/2RngcwX. Accessed April 9, 2020.
  2. Bavencio significantly improved overall survival in patients with locally advanced or metastatic urothelial carcinoma [news release]. Merck and Pfizer Inc. Published January 6, 2020. https://yhoo.it/2SXElLT. Accessed January 6, 2020.
  3. Avelumab prescribing information. Revised November 2017. https://bit.ly/2uj032I. Accessed January 6, 2020.
  4. Apolo AB, Ellerton JA, Infante JR, et al. Avelumab treatment for metastatic urothelial carcinoma in the phase Ib JAVELIN Solid Tumor study: updated safety and efficacy analysis with ≥ two years of follow-up. J Clin Oncol. 2019;37(suppl; abstr 425). doi: 10.1200/JCO.2019.37.7_suppl.425.


The PD-L1 inhibitor demonstrated the survival benefit in both coprimary patient populations, which were all randomized patients and those with PD-L1—positive tumors. Additionally, the safety profile with avelumab was found to be consistent with previous trials of the immunotherapy. Results of the trial will be presented at an upcoming medical meeting.