Pal Previews Promise of Cabozantinib Plus Atezolizumab in Heavily Pretreated Urothelial Cancer

Sumanta Pal, MD

The combination of cabozantinib (Cabometyx) and atezolizumab (Tecentriq) has shown promising response rates across several tumors types, but now it has also shown encouraging clinical activity in heavily pretreated patients with urothelial carcinoma, according to Sumanta K. Pal, MD.

In the multicenter, phase 1b COSMIC-021 (NCT03170960) trial, investigators evaluated the combination of cabozantinib with atezolizumab in various solid tumors. Results from the urothelial carcinoma expansion cohort 2 (n = 30) were presented at the 2020 ASCO Virtual Scientific Program.

At a median follow-up of 19.7 months, the objective response rate with the combination was 27%, with 2 (6.7%) complete responses and 6 (20%) partial responses. The disease control rate was 63% and 16 (53%) patients experienced a reduction in target lesion size.

Additionally, the median duration of response was not reached with the longest response ongoing at more than 15.6 months. The median time to response was 3.0 months. The median progression-free survival (PFS) was 5.4 months (95% CI, 1.5-7.6) with 22 PFS events observed.

“There’s a real reason to keep an eye on the data emerging from COSMIC-021,” said Pal. “Like a fine wine, the study just keeps getting better and better with more and more interesting data pouring out of it.”

In an interview with OncLive, Pal, a clinical professor in the Department of Medical Oncology & Therapeutics Research and codirector of the Kidney Cancer Program at City of Hope, discussed the clinical implications of this study and other exciting abstracts presented at the 2020 ASCO Virtual Scientific Presentation.

OncLive: Could you provide some background to the COSMIC-021 study?

Pal: COSMIC-021 is a very interesting study. It actually began as a trial that was intended to just enlist patients with genitourinary cancers. We began with 3 cohorts in bladder cancer, kidney cancer, and prostate cancer. Then, gradually, over the course of time, it actually fanned out into this massive entity, and now it focuses on over 20 cohorts of patients, ranging from liver cancer to breast cancer, and so on. At this year's ASCO meeting, we were very excited to unleash some of our data in prostate cancer, bladder cancer, and lung cancer.

What is it about the combination of cabozantinib and atezolizumab that has led to this synergy?

Whenever we talk about a drug like cabozantinib, we first and foremost discuss its properties that [allow it to] inhibit VEGF, but the agent does much more than that. Cabozantinib is a MET inhibitor, an AXL inhibitor, and beyond that, we think that it has complex effects on the immune milieu. [The agent] seems to shift the direction of myeloid-derived suppressor cells away from tumors, and it has several other [components] that we believe augment the impact of immunotherapy. There's real reason to believe that there's true synergy between cabozantinib and immunotherapy.

Could you discuss the urothelial cancer cohort that this combination was evaluated in? What did the patient population look like and what was the clinical activity observed with this approach?

In this particular cohort, we looked at patients who had received prior platinum-based chemotherapy; there were a total of 30 patients in this cohort. One of the main things I would emphasize is that this was a very heavily pretreated cohort. When you look at our data, you'll see in the abstract that amongst these 30 patients, we had a healthy number, 47%, who had received greater than or equal to 2 prior lines of therapy. When you contrast this against some of the other data that's coming out for combinations of immunotherapy and targeted therapy bear that number in mind: 47% really had very, very extensive prior treatment.

Where do you see this combination fitting best in the urothelial cancer treatment paradigm? Do you foresee it being used in the frontline? What does the future hold?

At ASCO this year, we all project that we're going to see some of the maintenance data for immunotherapy in bladder cancer. The earlier we can sequence these combinations of treatment, the better. I can easily envision cabozantinib and atezolizumab really supplanting chemotherapy in the frontline setting. In fact, we have a cohort in COSMIC-021 that's exploring just that premise. However, there are other settings even ahead of that, that I would be inspired to examine. For instance, at the Genitourinary Cancers Symposium [earlier this year], we saw some data for combinations of TKI and immunotherapy in the neoadjuvant setting. I'd love to see that.

It hasn't been lost on me that we haven't done a deep dive into the results from this trial. What we saw in this study was a 27% response rate, and that response rate stands favorably to anything that I've seen in the second-, third-line setting, and beyond in bladder cancer. There's some real reason to believe that if we slide this regimen up front it is going to be even more active.

Are any biomarker research efforts being made with COSMIC-021?

Absolutely. We have a very robust portfolio of relative studies that are accompanying this trial. Particularly, I'm excited about [the work being done] in T-cell populations, where we’re looking at fluxes and effector T cells and cytotoxic T cells as patients go through therapy. Those [efforts] are going to shed light and maybe even offer some perspective on the true contribution of cabozantinib within the study population.

Is there anything that you would like to add regarding this trial?

I will give a quick shout out to COSMIC-021 in the prostate cancer setting because there we're seeing some really remarkable response data, once again. [Those data have] propagated a phase 3 clinical trial that is going to compare cabozantinib plus atezolizumab with standard therapy.

What other studies presented at this year’s ASCO virtual meeting are you most excited about?

I might give some focus to a study that we did in collaboration with my colleagues at The Translational Genomics Research Institute. This abstract is being led by my colleague, Nick Salgia, a brilliant student who is going to be starting medical school next year. He synthesized a lot of nice data pertaining to genomics and kidney cancer. We have a very heavily annotated cohort of patients who received whole-exome sequencing and RNA-sequencing (RNA-seq). [We knew] that TBR1 seemed to bear some association with clinical outcome with immunotherapy, but he also identified and confirmed in RNA-seq data that TERT promoters seems to be a predictor of immunotherapy resistance. I'm very excited about that work.

Is there anything else that you would like to highlight? How has your practice been doing in relation to COVID-19?

COVID-19 has put a damper on so many elements of clinical practice, but a necessary damper. I'm excited to see some operations in our hospital resuming like elective surgeries and so forth. It really is important for us to continue to maintain a conscious stance. For instance, we're really trying our best to prevent overcrowding within our waiting rooms and trying to ensure that patients aren't coming to visits they could otherwise have via telephone or via telemedicine. Those measures are going to really help us as we try to bridge this pandemic.

Reference

Pal SK, Agarwal N, Loriot Y, et al. Cabozantinib in combination with atezolizumab in urothelial carcinoma previously treated with platinum-containing chemotherapy: Results from cohort 2 of the COSMIC-021 study. J Clin Oncol. 2020;38(suppl 15):5013. doi:10.1200/JCO.2020.38.15_suppl.5013