METHODS: In this pooled analysis of two cohorts from the phase 1 dose-expansion JAVELIN Solid Tumor study, patients aged 18 years and older with histologically or cytologically confirmed locally advanced or metastatic urothelial carcinoma that had progressed after at least one previous platinum-based chemotherapy were enrolled from 80 cancer treatment centres or hospitals in the USA, Europe, and Asia. Eligible patients had adequate end-organ function, an Eastern Cooperative Oncology Group performance status of 0 or 1, life expectancy of at least 3 months, and at least one measurable lesion. Cisplatin-ineligible patients who might have been previously treated in the perioperative setting, including platinum-naive patients, were also eligible. Patients unselected for PD-L1 expression received avelumab (10 mg/kg, 1 h intravenous infusion) every 2 weeks until confirmed disease progression, unacceptable toxicity, or other criterion for withdrawal. The primary endpoint for this efficacy expansion cohort was confirmed best overall response (according to RECIST version 1.1), adjudicated by independent review. Safety analysis was done in all patients who received at least one dose of avelumab. Antitumour activity was assessed in post-platinum patients who received at least one dose of avelumab. This trial is registered with ClinicalTrials.gov, number NCT01772004; enrolment in this cohort of patients with metastatic urothelial carcinoma is closed and the trial is ongoing.
FINDINGS: Between Sept 3, 2014, and March 15, 2016, 329 patients with advanced metastatic urothelial carcinoma were screened for enrolment into this study; 249 patients were eligible and received treatment with avelumab for a median of 12 weeks (IQR 6·0-19·7) and followed up for a median of 9·9 months (4·3-12·1). Safety and antitumour activity were evaluated at data cutoff on June 9, 2016. In 161 post-platinum patients with at least 6 months of follow-up, a best overall response of complete or partial response was recorded in 27 patients (17%; 95% CI 11-24), including nine (6%) complete responses and 18 (11%) partial responses. The most frequent treatment-related adverse events (any grade in ≥10% patients) were infusion-related reaction (73 [29%]; all grade 1-2) and fatigue (40 [16%]). Grade 3 or worse treatment-related adverse events occurred in 21 (8%) of 249 patients, the most common of which were fatigue (four [2%]), and asthenia, elevated lipase, hypophosphataemia, and pneumonitis in two (1%) patients each. 19 (8%) of 249 patients had a serious adverse event related to treatment with avelumab, and one treatment-related death occurred (pneumonitis).
INTERPRETATION: Avelumab showed antitumour activity in the treatment of patients with platinum-refractory metastatic urothelial carcinoma; a manageable safety profile was reported in all avelumab-treated patients. These data provide the rationale for the therapeutic use of avelumab in metastatic urothelial carcinoma and it has received accelerated US FDA approval in this setting on this basis.
FUNDING: Merck KGaA, and Pfizer Inc.
Lancet Oncol. 2017 Dec 5 [Epub ahead of print]
Manish R Patel, MD,1 John Ellerton, MD,2 Jeffrey R Infante, MD,3 Manish Agrawal, MD,4 Michael Gordon, MD,5 Raid Aljumaily, MD,6 Carolyn D Britten, MD,7 Luc Dirix, MD,8 Keun-Wook Lee, MD,9 Mathew Taylor, MD,10 Patrick Schöffski, MD11 Ding Wang, MD,12 Alain Ravaud, MD,13 Arnold B Gelb, MD,14 Junyuan Xiong, MS,14 Galit Rosen, MD,14 James L Gulley, MD,15 Andrea B Apolo, MD,16
1. Florida Cancer Specialists/Sarah Cannon Research Institute, Sarasota, Florida.
2. Nevada Cancer Research Foundation, Las Vegas, Nevada
3. Sarah Cannon Research Institute/Tennessee Oncology, Nashville, Tennessee
4. Associates in Oncology, Rockville, Maryland
5. Pinnacle Oncology Hematology, A Division of Arizona Center for Cancer Care, HonorHealth Research Institute Clinical Trials Program at the Virginia G Piper Cancer Center, University of Arizona College of Medicine, Phoenix, Scottsdale, Arizona
6. Oklahoma University Medical Center, Oklahoma City, Oklahoma
7. Medical University of South Carolina, Division of Hematology/Oncology, Charleston, South Carolina
8. Sint-Augustinus Hospital, Oncology Center, Medical Oncology, Antwerpen, Belgium
9. Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, South Korea
10. Oregon Health and Science University, Knight Cancer Institute, Portland, Oregon
11. Department of General Medical Oncology, Leuven Cancer Institute, University Hospitals Leuven, Leuven, Belgium
12. Henry Ford Hospital, Detroit, Michigan
13. Groupe Hospitalier Saint André, Hôpital Saint André, CHU de Bordeaux, Bordeaux Cedex, France
14. EMD Serono Research & Development Institute, Inc, Billerica, Massachusetts
15. Genitourinary Malignancies Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA; Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
16. Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, Magnuson Clinical Center, Bethesda, Maryland