A strategy of front-line maintenance treatment with the PD-L1 inhibitor avelumab combined with best supportive care improved both progression-free and overall survival vs best supportive care alone across prespecified subgroups of patients with advanced or metastatic urothelial carcinoma that had not experienced disease progression on first-line platinum-based chemotherapy. These results of a subgroup analysis of the phase III JAVELIN Bladder 100 trial were presented at the European Society for Medical Oncology (ESMO) Virtual Congress 2020.1
“The JAVELIN Bladder 100 study demonstrated that avelumab significantly prolonged overall survival and progression-free survival, and this benefit was shown regardless of which induction chemotherapy the patient received or the best response to that chemotherapy,” said lead study author Petros Grivas, MD, PhD, Clinical Director of the Genitourinary Cancers Program at the University of Washington School of Medicine and Associate Professor at the Fred Hutchinson Cancer Research Center, Seattle Cancer Care Alliance.
Petros Grivas, MD, PhD
Avelumab was approved by the U.S. Food and Drug Administration (FDA) in June 2020 as a maintenance treatment for patients with locally advanced or metastatic urothelial carcinoma that had not experienced disease progression with first-line platinum-based chemotherapy. Approval was based on the results of the JAVELIN Bladder 100 study presented at the ASCO20 Virtual Scientific Program.2 At that time, front-line maintenance avelumab therapy achieved a 7.1-month improvement in median overall survival—21.4 months with avelumab plus best supportive care vs 14.3 months with best supportive care alone—translating to a 31% reduction in the risk of death in the overall patient population (P = .001).
The primary results of JAVELIN 100 were considered practice-changing. “Based on these data, the FDA approved avelumab as switch maintenance therapy in the front-line setting…, and subsequently the National Comprehensive Cancer Network and ESMO guidelines changed, showing that this study was completely practice-changing,” Dr. Grivas said. At the ESMO meeting, he focused on results in prespecified subgroups.
The multicenter, international, open-label, parallel-arm, randomized, phase III JAVELIN Bladder 100 trial was designed to evaluate front-line avelumab maintenance therapy in combination with best supportive care (n = 350) compared with best supportive care alone (n = 350) in a total of 700 participants with unresectable locally advanced or metastatic urothelial cancer whose disease had not progressed on four to six cycles of previous therapy with standard gemcitabine plus cisplatin or carboplatin.
Patients enrolled on the trial could have had a complete response, a partial response, or stable disease on cisplatin- or carboplatin-based chemotherapy. Treatment with avelumab (10 mg/kg intravenously every 2 weeks in 4-week cycles) was administered 4 to 10 weeks after induction chemotherapy. Best supportive care included antibiotics, nutritional support, and symptom control. Overall 51% of patients had PD-L1–positive tumors.
Co-primary endpoints were overall survival in all randomly assigned patients and in the PD-L1–positive population. Secondary endpoints of the trial included antitumor activity, safety, pharmacokinetics, immunogenicity, predictive biomarkers, and patient-reported outcomes.
Baseline characteristics were similar in both induction chemotherapy arms. At baseline, the median age in gemcitabine/cisplatin–treated patients was 66.5 years compared with 72.5 years among gemcitabine/carboplatin recipients. More patients on gemcitabine/cisplatin had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 (median = 67%) vs those on gemcitabine/carboplatin (median = 52%).
The median follow-up was 19.6 months in the avelumab arm and 19.2 months in the best supportive care–alone arm. In the PD-L1–positive patient population, median overall survival was not yet reached in the avelumab group vs 17.1 months the best supportive care–alone group (P = .0003).
Response by Chemotherapy Regimen
Results stratified by chemotherapy regimen showed that patients had an overall survival and progression-free survival benefit from avelumab plus best supportive care irrespective of induction chemotherapy regimen. For patients who received front-line chemotherapy with gemcitabine/carboplatin plus avelumab, median progression-free survival was 3.0 months vs 1.9 months—a 41% improvement. The median overall survival was 19.9 months and 12.9 months, respectively, a 44% improvement for front-line avelumab maintenance therapy over best supportive care alone.
Median progression-free survival was 4.6 months with gemcitabine/cisplatin plus avelumab maintenance vs 2 months for gemcitabine/cisplatin alone. Median overall survival was 25.3 months for avelumab vs 16.5 months for best supportive care alone.
“The different baseline characteristics were relatively well balanced between best supportive care and the avelumab-plus–best supportive care arm, and this was the case in the subset of patients with complete response, partial response, or stable disease prior to induction chemotherapy,” Dr. Grivas said.
The survival benefits with front-line maintenance avelumab plus best supportive care were achieved in all categories of response to induction chemotherapy. For patients who had a complete response (n = 179), median progression-free survival was 7.4 months for avelumab plus best supportive care and 3.8 months for best supportive care alone. Median overall survival was not reached in either arm.
For patients who had achieved a partial response on induction chemotherapy (n = 326), median progression-free survival in the avelumab arm was 3.1 months and 1.9 months with best supportive care alone. Median overall survival was 19.2 months and 12.1 months, respectively.
Among patients who achieved stable disease, median progression-free survival was 3.7 months and 2.1 months, respectively. Median overall survival was 19.9 months for avelumab-treated patients and 14.0 months for best supportive care alone.
Other Subgroups Benefit
The overall survival benefit with avelumab as front-line maintenance therapy was seen across additional subgroups, regardless of age (≥ 65 or < 65 years), ECOG performance status of 0 or 1, creatinine clearance of lower or higher than 60 mL/min, or PD-L1 status (positive, negative, or unknown). The benefit of front-line avelumab maintenance therapy was also observed in all sites of metastasis (visceral or nonvisceral). As might be expected, the benefit was greater in patients without lung and liver disease compared with their counterparts.
A benefit for avelumab maintenance therapy was seen regardless of gender (male, female); race (White, Asian, or “other”); or geographic region (Europe, North American, Asia, and the rest of the world).
DISCLOSURE: Dr. Grivas has served as a consultant or advisor to AstraZeneca, Bayer, Bristol Myers Squibb, Clovis Oncology, Driver Inc, EMD Serono, Exelixis, Foundation Medicine, Genentech, Genzyme, GlaxoSmithKline, Heron, Janssen, Merck, Mirati Therapeutics, Pfizer, QED Therapeutics, and Roche; and has received institutional research funding from Bavarian Nordic, Bristol Myers Squibb, Clovis Oncology, Debiopharm Group, GlaxoSmithKline, Immunomedics, Kure It Cancer Research, Merck, Pfizer, and QED Therapeutics.
1. Grivas P, Park S, Voog E, et al: Avelumab first-line (1L) maintenance + best supportive care (BSC) vs BSC alone with 1L chemotherapy for advanced urothelial carcinoma: Subgroup analyses from JAVELIN Bladder 100. ESMO Virtual Congress 2020. Abstract 704MO. Presented September 18, 2020.
Formal discussant Kilian M. Gust, MD, of the Medical University of Austria, Vienna, reminded listeners that JAVELIN Bladder 100 was designed at a time when no checkpoint inhibitor was approved for the treatment of metastatic urothelial cancer. In the past 5 years, five immune checkpoint inhibitors...