Pal Highlights Encouraging ORR With Cabozantinib Plus Atezolizumab in mCRPC

Sumanta K. Pal, MD

Phase Ib results from cohort 6 of the COSMIC-021 trial suggest that the combination of cabozantinib (Cabometyx) and atezolizumab (Tecentriq) has encouraging clinical activity in patients with metastatic castration-resistant prostate cancer (mCRPC), explained Sumanta K. Pal, MD.

For example, in the study of 44 patients, the objective response rate (ORR) with the combination was 32%, and the median duration of response was 8.3 months.

Regarding safety, the most common any-grade adverse events were fatigue (50%), nausea (43%), decreased appetite (39%), diarrhea (39%), palmar-plantar erythrodysesthesia (32%), and vomiting (25%).

Due to the intriguing clinical activity and tolerable safety profile in patients with mCRPC, the combination of cabozantinib and atezolizumab will continue to be investigated in this patient population in a larger trial.

“We're seeing some very respectable response rates [with this combination],” said Pal, who is senior author of COSMIC-021. “That is serving as the foundation of a phase III clinical trial that should launch soon.”

In an interview with OncLive^® during the 2020 Genitourinary Cancers Symposium, Pal, an associate clinical professor in the Department of Medical Oncology and Therapeutics Research, and co-director of the Kidney Cancer Program at City of Hope, discussed these cohort 6 findings of the COSMIC-201 trial and other key data that were presented during the meeting.

OncLive: Could you provide an overview of the COSMIC-021 trial and its findings?

Pal: Some time ago, I approached my colleagues at Genentech and Exelixis about forging a collaboration around the combination of cabozantinib with atezolizumab. We dreamed up a phase Ib clinical trial that initially launched in a modest number of malignancies.

[This trial] started in renal cell carcinoma, bladder cancer, and prostate cancer. This phase I clinical trial has now morphed to include more than 15 cancer types, including hepatocellular cancer, lung cancer, and triple-negative breast cancer—just to name a few. We started producing very encouraging early results.

Last year, we presented some of the data pertaining to renal cell carcinoma [RCC], showing outstanding response rates, albeit in a very small cohort. We are going to have some updates on those data hopefully later this year. At [the 2020 Genitourinary Cancers Symposium], we are also presenting some data pertaining to prostate cancer, with really compelling response rates in a population of patients who received prior [hormonal] therapy. We are also going over a population of patients that is comprised mainly of individuals with aggressive disease, including extralymphatic nodal disease and visceral metastasis.

Why does the pairing of cabozantinib and atezolizumab work well?

There are a lot of reasons to suspect why cabozantinib would partner well with atezolizumab in the context of the COSMIC-021 study. Cabozantinib, while it is a targeted agent hitting MET, AXL, and multiple other targets, it also has a role in modifying the immune system.

We have had a number of preclinical papers, and now clinical papers, that document the activity of cabozantinib—suggesting that it mediates the recruitment and infiltration of inhibitory immune cells within the tumor milieu. Cabozantinib can enhance the antitumor immune response alongside drugs, such as atezolizumab.

What is the tolerability of this regimen?

The data that we presented for cabozantinib and atezolizumab suggest that there are no overlapping toxicities between the compounds, by and large. I would suggest that most patients demonstrate a very favorable adverse event profile.

What are the next steps of this trial?

It is important to keep in mind that this study is fanning out to include other settings within prostate cancer. We have some modifications to the treatment regimen as well. We are opening a cohort that includes patients who have received prior chemotherapy for mCRPC; that study arm is going to be of great interest. We're also trying to tease out, in the context of COSMIC-021, what the relative contribution is from cabozantinib and atezolizumab. We now have cohorts of monotherapy [for each cabozantinib and atezolizumab] that are open.

Moving onto bladder cancer, could you discuss the findings from the PROOF 302 trial?

PROOF 302 is a study that emerges from a long-standing interest that I've had in FGFR3-positive bladder cancer. We see that this is a disease that is enriched amongst patients who have upper tract urothelial carcinoma. By virtue of that, when I was working early on with the drug infigratinib, a very potent and active FGFR3 inhibitor, I conceived a trial design in which we compared patients who received either infigratinib or placebo, primarily with upper tract disease.

That is essentially the structure of the PROOF 302 clinical trial. We take patients with FGFR3-positive, primarily upper tract disease—although we do allow some patients with lower tract [disease]—and randomize them to infigratinib or placebo, with the primary endpoint of recurrence-free survival.

In bladder cancer, what agents are currently being investigated?

I was pretty heavily involved in terms of the design and the ultimate publication of the phase I data around infigratinib. A lot of folks have asked about where drugs like infigratinib might sit with other agents, such as erdafitinib (Balversa), already on the market. Erdafitinib is also a highly active FGFR3 inhibitor, such as infigratinib.

The design of trials emerging with erdafitinib are slightly different. They are tackling the 2 extremes of bladder cancer, namely non-muscle invasive disease and very advanced disease. We are attacking that sweet spot in the middle: patients who may actually have resected disease that is FGFR3-positive, and we would guess is primarily driving from the upper tract. It addresses an area of unmet need based on trials that we're doing right now for FGFR3 positivity.

What other research presented at the 2020 Genitourinary Cancers Symposium were you excited about?

At the 2020 Genitourinary Cancers Symposium, Toni Choueiri, MD, presented data for the hypoxia-inducible factor (HIF)-2α inhibitor from Merck [in RCC], which is quite compelling. We're seeing response rates in a pretreated population that approach around 25%.

From this, we are going to see the launch of some phase III designs evaluating this particular agent. It's going to probably move the needle for therapy. While we have a number of treatments available for advanced kidney cancer, we have best-in-class [options] for VEGF inhibitors with agents, such as cabozantinib. We have standards in the immunotherapy domain. We need to get past that, and that's where the class of HIF-2α inhibitors really fits in.

Agarwal N, Loriot Y, McGregor BA, et al. Cabozantinib (C) in combination with atezolizumab (A) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC): results of cohort 6 of the COSMIC-021 Study. J Clin Oncol. 2020;38(suppl 6; abstr 139). https://bit.ly/2v5uVof.