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JAVELIN Bladder 100 Demonstrates Significantly Prolonged OS in Advanced Urothelial Cancer

Results of first-line maintenance avelumab plus best supportive care reported at ASCO 2020 Virtual Meeting
10 Jun 2020
Urothelial Cancer

First-line maintenance therapy with avelumab in patients with advanced urothelial cancer whose disease has not progressed with platinum-based induction chemotherapy represents a new first-line standard of care according to the JAVELIN Bladder 100 researchers. Prof. Tom Powles of the Barts Cancer Institute in London, UK presented the results on behalf of study team at ASCO 2020 Virtual Meeting. He reported that the study met its primary endpoint by showing significantly longer overall survival (OS) with avelumab first-line maintenance plus best supportive care (BSC) vs BSC, both in the overall and PD-L1-positive populations. The OS was longer with avelumab across all prespecified subgroups. The safety profile was manageable and consistent with previous studies of avelumab monotherapy.

Although most patients with advanced urothelial cancer have disease control with first-line platinum-based chemotherapy, progression-free survival (PFS) and OS are short because of chemotherapy resistance. After first-line chemotherapy, only 25% to 55% of patients receive second-line treatment. Outcomes with second-line therapy remain suboptimal because of rapid disease progression. PD-L1/PD1 inhibitors are standard second-line treatment for patients with disease progression after platinum-based chemotherapy. Although PD-L1/PD1 inhibitors have antitumour activity in urothelial cancer, only a minority of patients obtain a durable clinical benefit with second-line treatment, the authors explained in study background.

Maintenance therapy with an anti-PD-L1 monoclonal antibody, avelumab in patients whose disease has not progressed with first-line platinum-based chemotherapy is an attractive treatment strategy. Disease control achieved with chemotherapy may provide time for immunotherapy to have an anti-tumour effect. Initiating immunotherapy before disease progression occurs may results in more patients receiving treatment, explained Prof. Powles.

This randomised, phase III trial evaluated avelumab as maintenance therapy following response or stable disease with first-line platinum-based chemotherapy in patients with advanced urothelial cancer. Eligible patients with unresectable locally advanced or metastatic urothelial cancer without disease progression after 4-6 cycles of gemcitabine with either cisplatin or carboplatin were randomised 1:1 to receive maintenance avelumab every 2 weeks plus BSC or BSC alone, stratified by best response to first-line chemotherapy (complete/partial response vs stable disease) and by visceral vs non-visceral disease when initiating first-line chemotherapy.

The study primary endpoint was OS, assessed from randomisation in 2 primary populations: all randomised patients and patients with PD-L1-positive tumours as assessed by Ventana SP263 assay. Secondary endpoints included PFS, objective response, and safety.

In total, 700 patients were randomly assigned to maintenance avelumab plus BSC (n=350) or BSC alone (n=350) and were followed for a median of 19.6 and 19.2 months, respectively. Overall, 358 patients (51%) had PD-L1-positive tumours.

Avelumab plus BSC significantly prolonged OS vs BSC alone in all randomised patients (hazard ratio [HR] 0.69; 95% confidence interval [CI] 0.56, 0.86; 1-sided p = 0.0005). Median OS with avelumab plus BSC vs BSC alone was 21.4 vs 14.3 months, respectively. Avelumab plus BSC also significantly prolonged OS vs BSC alone in patients with PD-L1-positive tumours (HR 0.56; 95% CI 0.40, 0.79; 1-sided p = 0.0003). Median OS was not reached vs 17.1 months, respectively. An OS benefit was also observed across all prespecified subgroups.

The HR for PFS based on blinded independent central review with avelumab plus BSC vs BSC alone was 0.62 (95% CI 0.52, 0.75) in all randomised patients and 0.56 (95% CI 0.43, 0.73) in patients with PD-L1-positive tumours.

In treated patients in the avelumab plus BSC (n=344) vs BSC alone (n=345) arms, respectively, all-causality adverse events (AEs) were reported at any grade in 98.0% vs 77.7% and at grade ≥3 in 47.4% vs 25.2%. Most frequent grade ≥3 AEs were urinary tract infection (4.4% vs 2.6%), anaemia (3.8% vs 2.9%), haematuria (1.7% vs 1.4%), fatigue (1.7% vs 0.6%), and back pain (1.2% vs 2.3%). No grade 4/5 immune-related AEs (irAEs) occurred. High-dose corticosteroids were administered following irAE in 9% of avelumab-treated patients.

Prof. Elizabeth R. Plimack of the Fox Chase Cancer Center who discussed the study findings said that after a long drought, novel therapies for metastatic urothelial cancer emerge. The JAVELIN Bladder 100 data change paradigm in two ways. First, the data provide a new framework around which to consider a treatment break vs maintenance therapy post platinum and second, they mark a shift in selection of first-line systemic therapy.

She explained that for most patients in post platinum setting, switch maintenance checkpoint inhibition is preferred over a treatment break followed by second-line due to longer OS with switch maintenance. Delay in PFS is meaningful, particularly if progression is symptomatic, and not all patients will be caught by the second-line safety net. However, if you can guarantee a patient access to second-line checkpoint after a treatment break (crossover) their survival may not be impacted. Some patients will have durable response to platinum and not require checkpoint for months if at all. These patients will be overtreated.

JAVELIN 100 ushers in two paradigm shifts in the treatment of metastatic urothelial cancer. In first-line, platinum-based chemotherapy is best initial therapy with highest overall response rate, ‘tail on the curve’ with durable treatment free survival for some, sets patient up for best OS to subsequent checkpoint inhibitor. Furthermore, it does not require PD-L1 testing for treatment selection. It is unlikely that a non-responder to platinum would have benefited from first-line checkpoint inhibition. Post platinum switch maintenance is preferred over treatment break as timing for next line checkpoint inhibitor in patients with stable disease or response. It delays progression of disease and potentially symptoms. The OS can be similar, only if access to second-line checkpoint is guaranteed according to Prof. Plimack.

The JAVELIN Bladder 100 trial was sponsored by Pfizer as part of an alliance between Pfizer and Merck KGaA. 


Powles T, Park SH, Voog E, et al. Maintenance avelumab + best supportive care (BSC) versus BSC alone after platinum-based first-line (1L) chemotherapy in advanced urothelial carcinoma (UC): JAVELIN Bladder 100 phase III interim analysis. J Clin Oncol 38: 2020 (suppl; abstr LBA1). DOI:10.1200/JCO.2020.38.18_suppl.LBA1.

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