Advancing Care in Urothelial Carcinoma With the MAIN-CAV Trial


In an interview with Targeted Oncology, Shilpa Gupta, MD, discussed the rationale and potential significance of the MAIN-CAV trial in patients with locally advanced/metastatic urothelial carcinoma.

Shilpa Gupta, MD

Shilpa Gupta, MD

First-line avelumab (Bavencio) maintenance therapy has shown clinically meaningful efficacy benefits compared with best supportive care for the treatment of patients with locally advanced/metastatic urothelial carcinoma, as seen in the phase 3 JAVELIN Bladder 100 trial (NCT02603432). Now, a new study seeks to build upon these previous findings.1,2

The ongoing phase 3 MAIN-CAV study (NCT05092958) is further evaluating this standard of care which gained FDA approval in 2020 for patients with locally advanced or metastatic urothelial cancer who have not progressed on prior platinum-based chemotherapy.3

MAIN-CAV is a randomized, multicenter, international trial evaluating the efficacy and safety of maintenance cabozantinib (Cabometyx) plus avelumab compared with maintenance avelumab alone.1 In the study, 654 patients with metastatic urothelial carcinoma who did not experience disease progression after 4 to 6 cycles of prior platinum-based chemotherapy will be enrolled and randomized in a 1:1 fashion within 3 to10 weeks following the last dose of chemotherapy. Here, they will receive 800 mg of avelumab via intravenous infusion every 2 weeks or avelumab and cabozantinib at a dose of 40 mg daily for up to 2 years.

The primary end point of the study is overall survival, and key secondary end points include progression-free survival, safety, tolerability, and efficacy.

In an interview with Targeted OncologyTM, Shilpa Gupta, MD, director, genitourinary medical oncology, Taussig Cancer Institute, and coleader of the genitourinary oncology program at Cleveland Clinic, discussed the rationale and potential significance of the MAIN-CAV trial in patients with locally advanced/metastatic urothelial carcinoma.

Bladder cancer stages: © pikovit - stock.adobe.comNormal

Bladder cancer stages: © pikovit -

Targeted Oncology: Can you explain the background of the MAIN-CAV trial?

Gupta: The current standard of care for patients with metastatic urothelial cancer who received frontline platinum-based chemotherapy and do not progress after 4 to 6 cycles is avelumab maintenance immunotherapy, which was based on the pivotal JAVELIN Bladder 100 trial. In that, they compared avelumab vs best supportive care, and there was an overall survival improvement with avelumab. That is the current standard. However, in patients who have visceral metastases, the benefit is not as pronounced, and we wanted to build upon that backbone of avelumab.

We designed this study where we are adding cabozantinib, which is a VEGF inhibitor with multiple targets like MET and AXL, which has shown activity along with checkpoint inhibitors in bladder cancer. We combined that and the control arm is avelumab, which is the current standard.

What were the methods and design utilized?

In our study, any use of prior platinum in the metastatic setting for 4 to 6 cycles, and if patients do not progress on that within 3 to 10 weeks, they are randomized to avelumab or avelumab plus cabozantinib for up to 2 years. The primary end point is overall survival, and 654 patients will be randomized to this study. This study is currently active across cooperative groups in the US. It has also been activated in the Canadian cooperative group, and this will be the next step forward. This is really the first study to intensify the avelumab backbone in the switch maintenance space.

What should a community oncologist know about the study moving forward?

For oncologists who are treating patients with bladder cancer, it is important to have patients receive the maintenance therapy and think of combinations that can intensify that because a lot of patients drop out after frontline therapy. It is important to intensify the space to improve outcomes.

What unmet needs exist in this space?

I think the unmet needs are really to make sure that the regimens that are given in this space are well-tolerated and thinking of how much or what duration of treatment is necessary. For example, in the JAVELIN study, treatment was meant to continue indefinitely, but we have restricted it to 2 years to minimize the physical and financial toxicity. I think those questions as to the duration and patient-reported outcomes with such agents are important, and we are looking at that in our study.

What other data has been interesting in this space of late?

We had data coming from the NORSE trial [NCT03473743], which is frontline erdafitinib [Balversa] and checkpoint inhibition in cisplatin-ineligible patients, as well as the THOR trial [NCT03390504] which used erdafitinib vs salvage chemotherapy in refractory, metastatic urothelial cancer. We also presented our Cleveland Clinic experience of a real-world cohort of over 300 patients with metastatic urothelial cancer who received immunotherapy as standard of care, and we looked at whether use of antibiotics before or after immunotherapy affects the efficacy of immunotherapy. We found that patients who receive antibiotics within 30 or 60 days prior to starting immunotherapy had worse overall survival and progression-free survival, which are important findings. We are currently doing translational work at the clinic.

1. Gupta S, Ballman KV, Apollo AB, et al. MAIN-CAV: Phase III randomized trial of maintenance cabozantinib (CABO) and avelumab (Av) vs Av after first-line platinum-based chemotherapy in patients (pts) with metastatic urothelial cancer (mUC; Alliance A032001). J Clin Oncol. 2024;42:4. doi:10.1200/JCO.2024.42.4_suppl.TPS714
2. ​​Powles T, Park SH, Voog E, et al. Maintenance avelumab + best supportive care (BSC) versus BSC alone after platinum-based first-line (1L) chemotherapy in advanced urothelial carcinoma (UC): JAVELIN Bladder 100 phase III interim analysis. Presented at: 2020 ASCO Virtual Scientific Program; May 29-31, 2020. Abstract LBA1.
3. FDA approves Bavencio as first-line maintenance treatment for patients with locally advanced or metastatic urothelial carcinoma. News release. Pfizer. June 30, 2020. Accessed April 30, 2024.
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