Cabozantinib/Atezolizumab Shows Clinical Activity in Urothelial Carcinoma

The combination of cabozantinib (Cabometyx), a multikinase inhibitor, and atezolizumab (Tecentriq), a PD-L1 inhibitor, demonstrated encouraging clinical activity with manageable toxicity when used as treatment for patients with metastatic urothelial carcinoma (UC), according to data from the phase 1b COSMIC-021 clinical trial (NCT03170960).

The multicenter, open-label COSMIC-021 trial is evaluating the combination of atezolizumab and cabozantinib in patients with locally advanced or metastatic solid tumors.

Currently, cabozantinib is FDA approved in combination with nivolumab (Opdivo) as a first-line treatment for patients with advanced RCC. For patients with cisplatin-ineligible and PD-L1–positive or platinum-ineligible locally advanced or metastatic UC, atezolizumab is approved for single-agent use.

Findings from an analysis of the COSMIC-021 study were presented at the 2022 American Society of Clinical Oncology Annual Meeting (ASCO) by lead study author Sumanta K. Pal, MD. This analysis included patients with inoperable locally advanced/metastatic UC who had transitional cell histology and an ECOG performance status of 0-1.

A total of 3 patients, 1 patient in cohort 3 and 2 in cohort 4, had complete responses, while partial responses were reached by 5 patients in cohort 3, 7 in cohort 4, and 3 patients in cohort 5, respectively. Further, the objective response rates seen in the trial were 20%, 30%, and 10%, and the disease control rates were 80%, 63%, and 61%.

In an interview with Targeted Oncology^TM, Pal, professor in the Department of Medical Oncology & Therapeutics Research and co-director of the Kidney Cancer Program at City of Hope Comprehensive Cancer Center, discussed the COSMIC-021 study of cabozantinib and atezolizumab across multiple tumor types, including advanced UC.

Targeted Oncology^TM: What were the methods and design used within the COSMIC-021study?

The study is designed to test the principle that targeted therapy and immunotherapy have synergy. We started with dose escalation cohorts to make sure that cabozantinib and pembrolizumab are safe and combinable. Once we reached that we expanded to multiple different disease types where we thought that the combination would have activity. We've already published our results in kidney cancer. We have data that we've presented already in prostate cancer, [and] we have some data in platinum refractory bladder cancer. This represents some of the new data that we have for previously untreated bladder cancer.

To enroll in this study, many different tumor types are included, but in the specific cohorts that we focused on at ASCO 2022, again, patients had to have cisplatin-eligible status, cisplatin-ineligible status or have received a prior immune checkpoint inhibitor. These are patients with metastatic urothelial cancer, defined by the cisplatin eligibility as defined by conventional criteria.

Can you explain the safety and efficacy results seen in the trial?

In terms of efficacy, we determined that the response rate was 30%, 20%, and 10%, across the 3 cohorts ranging from cisplatin-eligible to ineligible to immune checkpoint inhibitor pretreated. In terms of some of the other data that we presented at the meeting, we have the median duration of response that we're reporting out within this cohort, which was 7.1 months amongst those patients that were cisplatin-ineligible, and 4.1 months in those that have received prior immune checkpoint inhibitors. This is what's really compelling. The median duration of response was not reached in those both patients that were cisplatin eligible. It is going to be interesting to see how that pans out.

We saw that the vast majority of patients of a cohort had some degree of tumor shrinkage with a combination irrespective of the cohort. In terms of progression free survival [PFS], the PFS in the cisplatin eligible cohort was 7.8 months. In the cisplatin ineligible cohort, it was 5.6 months. In terms of safety and tolerability, I thought that there weren't any unusual signals that you wouldn't expect from a caveat and that based immunotherapy combination. We have seen that data and renal cell, hepatocellular, and other diseases, so nothing that really stood out in my mind.

How do you interpret these findings?

The study showed ultimately that in patients with cisplatin-eligible disease, the response rate was 30%, patients with cisplatin-ineligible disease response rate was 20%, and in patients who receive prior checkpoint inhibitors, this is a heavily pretreated population, the response rate was around 10%.

I think what's quite impressive is that patients, particularly in the cisplatin-eligible cohort, had a fairly substantial duration of response. It is going to be interesting to see how this data translates to studies that are looking at, for instance, tablets, and then with immunotherapy in the maintenance setting.

What advancements in research do you think are soon to come in the bladder carcinoma space?

I think we are quite excited at the prospect of being able to look at a combination of cabozantinib with immunotherapy as maintenance treatment for bladder cancer. There's a study that my colleague Shilpa Gupta at the Cleveland Clinic is running, looking nivolumab, which is now approved as a maintenance strategy in bladder cancer, plus or minus cabozantinib in a very timely study. Ultimately, I think that large definitive trials like that will establish the role of cabozantinib in bladder cancer.