What are the findings of the JAVELIN (Judgment of Avastin (bevacizumab) and Avelumab (avelumab) in cancer) Bladder 100 trial regarding the use of avelumab (avelumab) as maintenance treatment for locally advanced or metastatic urothelial carcinoma?

JAVELIN Bladder 100 Trial Overview

The JAVELIN Bladder 100 trial established avelumab first-line maintenance therapy plus best supportive care as a standard of care for patients with locally advanced or metastatic urothelial carcinoma who achieve disease control (stable disease or better) following first-line platinum-based chemotherapy, demonstrating a significant overall survival benefit. 1, 2

Trial Design and Patient Population

The JAVELIN Bladder 100 was a randomized, multi-center, open-label phase III trial that enrolled 700 patients with unresectable, locally advanced or metastatic urothelial carcinoma 2. Key eligibility criteria included:

• Disease status: Patients must not have progressed after 4-6 cycles of first-line platinum-containing chemotherapy (gemcitabine plus cisplatin or carboplatin) 1, 2
• Timing: Treatment was initiated within 4-10 weeks after the last dose of chemotherapy 2
• Exclusions: Patients with autoimmune disease or medical conditions requiring immunosuppression were excluded 2
• Randomization stratification: By best response to chemotherapy (complete response/partial response vs. stable disease) and site of metastasis (visceral vs. non-visceral) 2

The median age was 69 years, with 66% of patients ≥65 years old and 24% ≥75 years old 2. Most patients were male (77%) and White (67%) 2.

Treatment Arms and Intervention

Patients were randomized 1:1 to receive either 2:

• Experimental arm: Avelumab 10 mg/kg intravenous infusion every 2 weeks plus best supportive care (BSC)
• Control arm: Best supportive care alone

Treatment with avelumab continued until RECIST v1.1-defined disease progression by blinded independent central review or unacceptable toxicity 2. Administration was permitted beyond RECIST-defined progression if the patient was clinically stable and deriving clinical benefit 2.

Primary Efficacy Results: Overall Survival

The trial demonstrated a statistically significant and clinically meaningful improvement in overall survival, which was the primary endpoint 1, 2:

Initial Analysis (Primary Endpoint)

• Median OS: 21.4 months with avelumab + BSC vs. 14.3 months with BSC alone 2
• Hazard ratio: 0.69 (95% CI: 0.56-0.86; p=0.001) 2
• Death events: 41.4% in avelumab arm vs. 51.1% in BSC arm 2

Updated Analysis

• Median OS: 23.8 months with avelumab + BSC vs. 15.0 months with BSC alone 2
• Hazard ratio: 0.76 (95% CI: 0.63-0.92) 2
• Death events: 61.4% in avelumab arm vs. 67.7% in BSC arm 2

PD-L1 Positive Subgroup

In the pre-specified analysis of patients with PD-L1-positive tumors (51% of enrolled patients), the hazard ratio for OS was 0.69 (95% CI: 0.52-0.91) 2. However, benefit was observed regardless of PD-L1 status, and PD-L1 testing is not required for treatment selection 3, 2.

Secondary Efficacy Results

Progression-Free Survival

While specific PFS data from the primary publication are limited in the provided evidence, subgroup analyses showed:

• Asian subgroup: Median PFS was 5.6 months with avelumab + BSC vs. 1.9 months with BSC alone (HR 0.58; 95% CI: 0.38-0.86) 4
• Japanese subgroup: Median PFS was 5.6 months vs. 1.9 months (HR 0.63; 95% CI: 0.36-1.11) 5

Consistency Across Subgroups

Consistent results were observed across pre-specified subgroups, including patients with complete response/partial response versus stable disease to first-line chemotherapy 2. The benefit was maintained in both cisplatin-eligible and cisplatin-ineligible patients 1.

Safety Profile

Treatment-Related Adverse Events

The safety profile of avelumab maintenance was manageable 2:

• Fatal adverse reactions: One patient (0.3%) experienced sepsis 2
• Serious adverse events: Occurred in 28% of patients receiving avelumab + BSC 2
• Grade ≥3 treatment-related AEs: 13.9% in avelumab arm vs. 0% in BSC arm (Japanese subgroup) 5
• Permanent discontinuation: 12% of patients discontinued due to adverse reactions 2

Most Common Adverse Events (≥20%)

The most frequent adverse reactions in patients receiving avelumab + BSC were 2:

• Fatigue (35%)
• Musculoskeletal pain (29%)
• Urinary tract infection (20%)
• Rash (25%)

Immune-Related Adverse Events

• High-dose corticosteroids: 9% of patients required oral prednisone dose equivalent to ≥40 mg daily for immune-mediated adverse reactions 2
• Dose interruptions: 41% of patients had dose interruptions due to adverse reactions, most commonly urinary tract infection (4.7%) and increased blood creatinine (3.8%) 2

Patient-Reported Outcomes and Quality of Life

A critical finding was that avelumab maintenance therapy prolonged survival without compromising quality of life 6:

• PRO completion rates: >90% for scheduled on-treatment assessments 6
• Quality of life measures: Results from FBlSI-18 (bladder symptom index) and EQ-5D-5L assessments were similar between arms 6
• Time to deterioration: Similar between arms (HR 1.26; 95% CI: 0.90-1.77) 6

This is particularly important as it demonstrates that the survival benefit comes with minimal impact on patient quality of life, supporting the favorable benefit-risk profile 6.

Real-World Evidence

The PATRIOT-II study confirmed the trial findings in real-world US practice 7:

• Median PFS: 5.4 months (95% CI: 3.8-6.9) from avelumab initiation 7
• Median OS: 24.4 months (95% CI: 20.4-28.4) from avelumab initiation 7
• Grade ≥3 TRAEs: 9.4% of patients 7
• Hospitalizations: 27.5% during treatment period, with 8.1% due to treatment-related AEs 7

These real-world results align closely with the clinical trial data, supporting the generalizability of JAVELIN Bladder 100 findings 7.

Clinical Implementation and Current Treatment Paradigm

Position in Treatment Algorithm

Avelumab first-line maintenance should be offered to all patients with locally advanced or metastatic urothelial carcinoma who achieve stable disease or better with platinum-based chemotherapy and have no contraindications to immunotherapy 3, 2:

• Timing: Initiate within 4-10 weeks after completing chemotherapy 3, 2
• Duration: Continue until disease progression or unacceptable toxicity 2
• No biomarker testing required: PD-L1 testing is not necessary for treatment selection 3, 2

Important Clinical Context

While JAVELIN Bladder 100 established maintenance immunotherapy as standard of care, the treatment landscape has evolved significantly with the EV-302 trial demonstrating superior outcomes with enfortumab vedotin plus pembrolizumab as first-line therapy 1, 8:

• EV-302 results: Median OS of 31.5 months vs. 16.1 months with chemotherapy (HR 0.47) 1, 8
• Current first-line preference: Enfortumab vedotin plus pembrolizumab is now recommended as the preferred first-line option for eligible patients 8, 3

However, avelumab maintenance remains the standard approach for patients who receive first-line platinum-based chemotherapy 3, particularly in settings where enfortumab vedotin is not available or patients are not candidates for combination therapy 3.

Key Pitfalls and Practical Considerations

Timing of Initiation

• Critical window: Must start within 4-10 weeks after last chemotherapy dose 2
• Common error: Delaying initiation beyond this window may compromise efficacy

Patient Selection

• Appropriate candidates: Only patients with stable disease or better after chemotherapy 2
• Exclusions: Patients with autoimmune disease or requiring immunosuppression 2
• Performance status: ECOG 0-1 in the trial 2

Monitoring and Management

• Infusion-related reactions: Occurred in 26% of patients in earlier trials 1
• Immune-related toxicities: Require prompt recognition and management with corticosteroids 2
• Continuation beyond progression: May be considered if patient is clinically stable and deriving benefit 2

Cross-Trial Comparisons

Only 6% of patients in the avelumab arm received another PD-1/PD-L1 inhibitor after discontinuation, while 44% in the BSC arm did 2. This crossover pattern should be considered when interpreting the magnitude of survival benefit.