According to data from the Phase 1b COSMIC-021 clinical trial (NCT03170960), the combination of the multikinase inhibitor cabozantinib (Cabometyx) and the PD-L1 inhibitor atezolizumab (Tecentriq), when used to treat patients with metastatic uroepithelial carcinoma (UC) demonstrated encouraging clinical activity and manageable toxicity when used to treat patients with metastatic uroepithelial cancer (UC).
The multicenter, open-label COSMIC-021 trial is evaluating the combination of atelizumab and cabozantinib for the treatment of patients with locally advanced or metastatic solid tumors.
Cabozantinib is currently FDA approved in combination with nivolumab (Odivo Opdivo) as first-line therapy for patients with advanced RCC. For patients with locally advanced or metastatic UC who are not cisplatin eligible and PD-L1 positive or platinum ineligible, atelelizumab is approved for use alone.
At the 2022 American Society of Clinical Oncology Annual Meeting (ASCO), Dr. Sumanta K. Pal presented the results of an analysis of the COSMIC-021 study. This analysis included inoperable patients with 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 group 3 and 2 patients in group 4) achieved a complete response, while 5 patients in group 3, 7 patients in group 4 and 3 patients in group 5 each achieved a partial response. In addition, the objective response rates seen in the trial were 20%, 30% and 10%, while the disease control rates were 80%, 63% and 61%.
In an interview with Targeted OncologyTM, Pal, professor in the Department of Medical Oncology and Therapeutics Research and co-director of the Kidney Cancer Program at City of Hope Comprehensive Cancer Center, discussed the use of cabozantinib and atezolizumab in multiple tumor types, including advanced UC, in the COSMIC-021 study.
Targeted OncologyTM: What were the methods and design used in the COSMIC-021 study?
The study was designed to test the principle that targeted therapies and immunotherapy have synergistic effects. We started with a dose escalation cohort to ensure that cabozantinib and atelelizumab were safe and combinable. Once we reach that point, we expand to a variety of different disease types where we think this combination will be active. We have already published our results in kidney cancer. We’ve presented data in prostate cancer, and we have some data in refractory bladder cancer. This represents some new data that we have on previously untreated bladder cancer.
To participate in this study, which includes many different tumor types, but in the specific cohort that we are focusing on at ASCO 2022, again, patients must have a cisplatin-eligible status, a non-cisplatin-eligible status, or have received an immune checkpoint inhibitor. These are patients with metastatic urothelial carcinoma that are eligible for cisplatin as defined by traditional criteria.
Can you explain the safety and efficacy results seen in the trial?
In terms of efficacy, we determined response rates of 30%, 20%, and 10% in 3 cohorts ranging from eligible for cisplatin to ineligible for pretreatment with immune checkpoint inhibitors. In terms of some of the other data that we presented at the meeting, the median duration of response that we reported in this cohort was 7.1 months in those patients who were ineligible for cisplatin and 4.1 months in those patients who had previously received immune checkpoint inhibitors. That’s what’s really striking. In those patients who were eligible for cisplatin, the median time to response was not achieved. It will be interesting to see what the results are.
We saw that the vast majority of patients, regardless of the group, had some degree of tumor shrinkage with the combination therapy. In terms of progression-free survival [PFS], the PFS for the cisplatin-eligible cohort was 7.8 months. In the non-cisplatin-eligible cohort, it was 5.6 months. In terms of safety and tolerability, I don’t think there are any unusual signals that you would expect from a combination of caveats and immunotherapy-based therapies. We’ve seen data on renal cells, hepatocytes and other diseases, so there’s nothing that really stands out to me.
How do you explain these findings?
The study ultimately showed a response rate of 30% in patients eligible for cisplatin, 20% in patients eligible for cisplatin, and a response rate of about 10% in patients who had previously received checkpoint inhibitors, which is a severely pretreated population.
What I think is impressive is that patients, particularly in the cisplatin-eligible cohort, had a fairly long response time. It will be very interesting to see how these data translate into studies, for example, with tablets and then with immunotherapy in the context of maintenance therapy.
What advances do you see coming soon in the field of bladder cancer research?
I think we’re quite excited about the prospect of being able to combine cabozantinib with immunotherapy as a maintenance treatment for bladder cancer. My colleague Shilpa Gupta at the Cleveland Clinic is doing a study looking at nivolumab, which is now approved as a maintenance treatment strategy for bladder cancer, plus or minus cabozantinib, and it’s a very timely study. Ultimately, I think large definitive trials like this one will determine the role of cabozantinib in bladder cancer.