A national, phase 3 randomized trial will seek to determine whether maintenance therapy with avelumab and a vascular endothelial growth factor (VEGF) tyrosine kinase inhibitor can improve survival among patients with urothelial cancer.
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“The first-line standard of care for metastatic urothelial cancer is platinum-based chemotherapy,” notes the trial’s principal investigator, Shilpa Gupta, MD, Director of Genitourinary Medical Oncology at Taussig Cancer Institute and co-leader of the Genitourinary Oncology Program at Cleveland Clinic Cancer Center. “Patients who achieve stable disease or better were historically followed and in the event of recurrence, treated with immunotherapy, which is approved in this setting.
“A recent phase 3 trial, JAVELIN Bladder 100, showed that moving the immunotherapy agent avelumab to the maintenance setting immediately following chemotherapy for patients who achieve stable disease or better improves overall survival versus waiting until they progress,” she continues.
Based on these findings, avelumab was approved by the Food and Drug Administration in June 2020 for the maintenance treatment of patients with locally advanced or metastatic urothelial carcinoma who had not progressed with first-line platinum-based chemotherapy.
However, there is a subgroup of patients who don’t derive as much benefit from single agent avelumab. “In an effort to address this gap, we are seeking to determine if intensification of maintenance avelumab can further improve the outcomes in these patients,” Dr. Gupta explains.
“The real-world evidence shows that less than 20% of patients with urothelial cancer actually receive second-line and subsequent-line therapies, which is very concerning,” she adds. “The maintenance setting provides a window of opportunity to help patients achieve better survival outcomes.”
Dr. Gupta and colleagues are developing a novel maintenance combination in this patient population — avelumab plus a VEGF tyrosine kinase inhibitor.
“Cabozantinib is an oral medication that affects the VEGF, MET, and AXL receptors,” says Dr. Gupta. “Data from multiple trials has demonstrated that when partnered with an immunotherapy agent, cabozantinib has efficacy in urothelial cancer.
“This is the first study in this setting, and in the field, taking a closer look at the intensification of maintenance therapy and this specific combination,” she notes. “Our team is excited to explore this regimen and its potential impact on patient outcomes.”
The researchers will enroll 654 patients with advanced or metastatic urothelial cancer who have received first-line treatment with platinum-based chemotherapy and do not progress after completion of chemotherapy. The primary outcome of the study is overall survival.
“This study has been in development for the past several years and our team is excited to move forward with its initiation,” Dr. Gupta says. “In addition to evaluating the efficacy of a unique combination, this research will lead us to a better understanding of which patients may be resistant to immunotherapy and how this can be overcome with novel approaches.”
This study has significant implications, including the potential to open the door to a new treatment pathway for patients with metastatic urothelial cancer.
“We hope to further improve outcomes among these patients in the maintenance setting,” Dr. Gupta says. “And we are also hoping to better understand the mechanisms of response and resistance to immunotherapy as well as how the intensification of novel therapies can help overcome these challenges.” The research team also plans to take a closer look at patient-reported outcomes and the quality-of-life implications of this regimen.
Dr. Gupta and colleagues hope to establish that the combination of cabozantinib and avelumab is safe and tolerable and better than avelumab alone in maintenance setting. “If we find that the combination is safe and improves outcomes compared with avelumab alone, this research has the potential to be practice changing,” she concludes.