Maintenance Cabozantinib/Avelumab Combo Under Investigation in Metastatic Urothelial Cancer

Shilpa Gupta, MD

The addition of cabozantinib (Cabometyx) to avelumab (Bavencio) is under exploration as a maintenance approach in patients with metastatic urothelial cancer following first-line, platinum-based chemotherapy, as part of the phase 3 MAIN-CAV trial (NCT05092958).¹

The primary end point of the trial is to determine whether the combination will improve overall survival (OS) in this population compared with avelumab alone. Investigators hypothesize that the regimen will be synergistic in patients with this disease, with an acceptable toxicity profile.

“For the first time, we are studying whether intensification of maintenance avelumab with the VEGF inhibitor, cabozantinib, can improve OS when compared with maintenance avelumab alone,” lead study author Shilpa Gupta, MD, of the Hematology and Medical Oncology Department at Cleveland Clinic, said in an interview with OncLive®.

Although maintenance avelumab serves as the current standard of care for patients with metastatic urothelial cancer following frontline platinum-based chemotherapy, an unmet need remains to further improve outcomes in this setting. An oral inhibitor of MET, VEGFR, and TAM family receptors, cabozantinib has demonstrated efficacy in those with metastatic urothelial cancer when paired with PD-1/PD-L1 inhibitors.

“Not all [patient] subgroups show benefit with maintenance avelumab, and we want to intensify that with a non–cross-resistant therapy. [We] want to see whether we can push the envelope further,” Gupta explained. “The MAIN-CAV trial is currently activated and accruing [patients] across the United States, and soon will be activated across sites [in Canada].”

The randomized, multicenter trial is enrolling patients with locally advanced or metastatic urothelial cancer, including N3-only disease, who did not experience disease progression after 4 to 6 cycles of platinum-based chemotherapy. Chemotherapy regimens could have included gemcitabine/cisplatin; gemcitabine/carboplatin; methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC); or dose-dense MVAC.

To be eligible for enrollment, patients are required to have an ECOG performance status of 0 or 1, acceptable organ function, and a creatinine clearance of at least 30 mL/min.

Prior chemotherapy is allowed if it was administered more than 12 months before study entry. Those who received prior immunotherapy, except for Bacillus Calmette-Guérin, are not permitted. Other exclusion criteria include having central nervous system metastases, having undergone major surgery within 4 weeks of the trial, having uncontrolled hypertension or cardiovascular disorders, and any contraindication to immunotherapy.

Investigators anticipate accruing 654 patients to the trial. All patients will have received 4 to 6 cycles of platinum-based chemotherapy. Those who achieved a complete response, partial response, or stable disease will then undergo 1:1 randomization 3 to 10 weeks after their last dose of chemotherapy. All patients will receive 800 mg of intravenous (IV) avelumab every 2 weeks. Patients in the investigative arm will also be administered 40 mg of oral cabozantinib daily. Treatment will continue for 2 years or until disease progression.

“This is a first-in-field study, asking an important question [about] how we can further improve outcomes in the frontline maintenance setting,” Gupta said. “In the real world, very few patients make it to second-line therapy. This is for a variety of reasons, and the better therapies we offer earlier to maintain that response can improve [long-term] outcomes.”

Secondary end points of the trial include progression-free survival, safety, tolerability, and activity of the combination based on RECIST v.1.1 criteria. Moreover, quality of life (QOL) will be assessed throughout the trial and compared between the 2 arms.

Response and resistance to avelumab will be assessed by tissue, blood, circulating tumor DNA, stool, and urine. Imaging studies will test the correlation of radiomic signatures with OS, adverse effects, and QOL.

“This is a trial in progress, and it is important to create awareness for the trial in order for it to be supported more widely,” Gupta concluded.

Reference

1. Gupta S, Ballman KV, Galsky MD, et al. MAIN-CAV: Phase III randomized trial of maintenance cabozantinib and avelumab versus avelumab after first-line platinum-based chemotherapy in patients with metastatic urothelial cancer (mUC) (Alliance A032001. J Clin Oncol. 2022;40(suppl 16):TPS4607. doi:10.1200/JCO.2022.40.16_suppl.TPS4607