Shilpa Gupta, MD, on Locally Advanced/Metastatic Urothelial Cancer: Phase III MAIN-CAV Trial

In locally advanced and metastatic urothelial cancer, platinum based chemotherapy has been the standard of care for decades until recently when EV pembro showed that it was better than platinum in the frontline setting. Back in 2020, maintenance avelumab was approved for patients who did not progress on frontline platinum based chemotherapy and it improved survival compared to best supportive care. We wanted to build upon the avelumab backbone to see if we can help patients who don't have durable response and we designed this cooperative group trial to build on avelumab backbone with a VEGF TKI, cabozantinib or the MAIN-CAV trial was built on that. It was a very timely study at the time. We designed it to enroll 654 patients and randomized them to maintenance avelumab versus maintenance avelumab and cabozantinib, limiting the total duration of two years for each arm. Primary endpoint was overall survival and we hypothesized that we could build upon the median 21 month overall survival with the avelumab to 28 months with combination. And while the planned enrollment was for 654 patients, unfortunately we could not accrue the patient because of the new standard with EV and pembro. So we closed the trial after 68 patients were enrolled because EV pembro was approved in the US and we analyzed the patients enrolled and we found that you know 33 and 35 patients were enrolled in avelumab versus avelumab cabozantinib arm. Unfortunately we did not see differences in the progression-free survival or overall survival. But this is an underpowered study which was closed prematurely. So it's difficult to make that determination. But in the limited numbers we have, we did not see a difference and we did not see that cabozantinib even added to the response rate seen when avelumab. As far as toxicities were concerned, there were no new safety signals and there was more toxicity in the combination arm as expected with an IO and TKI. So at this time, we are working on the translational work for this study to guide future development around VEGF.