A combination of the checkpoint inhibitor avelumab with best supportive care following chemotherapy significantly extends overall survival (OS) in patients with advanced urothelial cancer.
Avelumab has been shown to be effective in metastatic disease, but these data are the first to demonstrate efficacy of frontline avelumab treatment following initial chemotherapy in bladder cancer. Avelumab improved OS by 7.1 months over best supportive care and may now be considered the new standard of care in this setting.
The current standard of care is first-line, platinum-based chemotherapy; however, OS and progression-free survival (PFS) are usually short because of resistance to chemotherapy. Checkpoint inhibitors, such as avelumab, are standard second-line treatment for patients who fail platinum-based chemotherapy. From one-quarter to about one-half of these patients receives second-line therapy and obtains a durable benefit.
"The JAVELIN Bladder 100 study gives immune checkpoint inhibition directly sequenced with chemotherapy instead of waiting for the cancer to return. Essentially, it is a maintenance first-line approach for urothelial patients who have not progressed on first-line chemotherapy," said lead author Thomas Powles, MD, Professor of Genitourinary Oncology and Director of Barts Cancer Centre in London, at a press briefing before the ASCO 2020 Annual Meeting (Abstract LBA1).
"The maintenance setting is an attractive time for using a checkpoint inhibitor. Patients have gone through chemotherapy and the disease is under control. But instead of waiting for disease to progress after chemotherapy, which it will quickly do in patients with advanced urothelial cancer, adding avelumab significantly improves survival."
Study Details
This randomized, phase III trial included 700 patients with unresectable locally advanced or metastatic urothelial carcinoma, with no disease progression following chemotherapy, which consisted of either gemcitabine with either cisplatin or carboplatin for 4-6 cycles. The trial randomized 350 patients to receive maintenance avelumab at 10 mg/kg intravenously every 2 weeks along with best supportive care, and 350 patients to best supportive care alone. Treatment was continued until disease progression, toxicity, or death.
Patients were followed for a median of more than 19 months. Just more than half (51%) of them had tumors that were positive for programmed death-ligand 1 (PD-L1).
Avelumab works by blocking the PD-L1 protein on the surface of cancer cells. "In urothelial cancer, patients have high PD-L1 expression and high tumor mutational burden. Response rates associated with immune therapy are pretty high," said Powles. "This means that checkpoint inhibitors can work quite well in urothelial cancer."
The drug has received FDA approval for the treatment of advanced urothelial cancer that has progressed on platinum-based chemotherapy and is also approved for renal cell carcinoma and Merkel cell carcinoma.
The combination of avelumab plus best supportive care significantly prolonged OS by 31 percent. When combined with best supportive care, avelumab treatment resulted in a median OS of 21.4 months compared with 14.3 months for best supportive care alone.
The researchers also examined response in the group of patients with tumors that were positive for PD-L1. Avelumab plus best supportive care significantly prolonged OS in this group of patients, with median OS not yet established. Median overall survival was 17.1 months for patients who received best supportive care alone.
In addition, in all patients and in those with PD-L1-positive tumors, PFS was better with avelumab and best supportive care versus best supportive care alone.
The safety data show adverse events of any grade occurred in 98 percent of avelumab plus best supportive care patients versus 77 percent in the best supportive care-alone patients. Adverse events of grade 3 or higher occurred in 47.4 percent of patients who received avelumab plus best supportive care versus 25.2 percent in those who received best supportive care alone. The most common grade 3 or higher adverse events were urinary tract infection, anemia, hematuria, fatigue, and back pain.
Patients in the control group have been allowed to crossover to the avelumab group. The researchers plan to follow patients to see how long response is maintained.
In conclusion, Powles noted, "This study met its overall primary endpoint by showing significantly longer OS with avelumab in first-line maintenance in both the overall population and the PD-L1-positive population. OS was also longer in a series of pre-specified subgroups of different chemotherapy regimens, responses to chemotherapy, and metastases. The overall safety with avelumab was in line with what we've seen with other checkpoint inhibitors in this setting, which is encouraging.
"Overall, avelumab first-line maintenance therapy in patients whose disease has not progressed with platinum-based induction chemotherapy is a new first-line standard of care for advanced urothelial cancer."
ASCO President Howard A. Burris III, MD, FACP, FASCO, President and Chief Medical Officer of the Sarah Cannon Research Institute, commented: "In patients with advanced urothelial cancer, recurrence frequently happens following initial treatment with chemotherapy. This study shows the largest survival benefit seen to date in advanced urothelial cancer. When used as a maintenance therapy, avelumab significantly extended the period of time until recurrence."
Mark L. Fuerst is a contributing writer.