COSMIC-021 Data Affirm Activity of Cabozantinib/Atezolizumab in mCRPC

Neeraj Agarwal, MD

The combination of cabozantinib (Cabometyx) and atezolizumab (Tecentriq) displayed unprecedented activity in men with metastatic castration-resistant prostate cancer (mCRPC), according to a cohort analysis from the phase 1b COSMIC-021 trial, said Neeraj Agarwal, MD.

“Prostate cancer is the second most common cause of cancer-related deaths in American men, and to have such limited treatment options is not acceptable to us or to our patients,” said Agarwal. “[The data demonstrated in the COSMIC-021 trial] are historic. I do not think any immunotherapy-based combination has come close to the kind of responses we’re seeing.”

The findings, which were presented at the 2020 ASCO Virtual Scientific Program, revealed a 32% overall response rate (ORR), a 48% stable disease (SD) rate, and an 80% disease-control rate (DCR) with the combination in this patient population. Additionally, the median duration of response (DOR) was 8.3 months (range, 2.8—9.8+).

Notably, the benefit was seen across patient subgroups. In men with high-risk clinical features, such as visceral metastases and/or extra-pelvic lymph node metastases, the ORR was 33%.

In an interview with OncLive, Agarwal, a professor of medicine and director of the Genitourinary Oncology Program at Huntsman Cancer Institute, discussed the COSMIC-021 trial, the findings from cohort 6 in mCRPC, and the planned phase 3 trial that will evaluate the combination on a larger scale.

OncLive: Could you provide some background information on the COSMIC-021 trial?

Agarwal: [COSMIC-021] began as a phase 1 multi-cohort trial, including patients with mCRPC, metastatic renal cell carcinoma (mRCC), both clear cell and non—clear cell, and metastatic urothelial carcinoma. Beyond genitourinary cancers, [we added] several other cohorts, including metastatic lung cancer, non–small cell lung cancer, and gynecological cancers.

COSMIC-021 is a large phase 1 trial with more than 750 patients in more than 15 different cohorts. It's a unique design that was conceptualized to expedite drug development and access to these agents for our patients in [whom we see] promising efficacy.

The strategy has panned out in multiple cancer types. There are multiple registration trials, which have originated from this phase 1 trial.

What is the rationale for combining cabozantinib and atezolizumab in men with mCRPC?

[We know that men with] mCRPC will experience disease progression on novel hormonal therapies, such as abiraterone acetate (Zytiga) or enzalutamide (Xtandi).

At the 2020 ASCO Virtual Scientific Program, we presented data from a large, real-world patient population, which were obtained from [Flatiron Health]. More than 1000 patients were included in the data set. The findings were not surprising, and they [confirm] how poor treatment options are for this patient population.

Overall survival (OS) was in the range of 15 months, whether patients received enzalutamide or abiraterone after progression on 1 of the 2 hormonal therapies. That’s not acceptable and is a huge unmet need.

That is the background with which we started thinking about evaluating the combination of cabozantinib and atezolizumab.

Could you discuss the findings from cohort 6 of the COSMIC-021 trial?

[Cohort 6] was [one of the original cohorts] in the COSMIC-021 trial. In order to be eligible, patients had to have progressive soft tissue disease, meaning they did not necessarily have prostate-specific antigen progression. Based on our experiences, we know that this patient population has aggressive disease.

After seeing encouraging efficacy data, we expanded cohort 6 to 130 patients. At the 2020 ASCO Virtual Scientific Program, we presented longer follow-up compared with the data that were presented at the 2020 Genitourinary Cancers Symposium. Of 44 patients with mCRPC, we reported a median OS of 12.6 months with the combination of cabozantinib and atezolizumab. We also saw an ORR of 32%, a SD rate of 48%, and a DCR of 80%.

Beyond that, the DOR, which is an important parameter to measure, was [over] 8 months. Therefore, we not only saw high levels of response and stability of disease, but meaningful and durable responses. The efficacy data appear to be very promising. [As such], the combination will be evaluated in a phase 3 trial that will accrue patients around the world.

How is this regimen tolerated by patients? Were any new safety signals observed in this cohort of patients?

The median duration of treatment is one of the most reliable parameters of tolerability in any patient population. How long are patients able to tolerate a regimen? [In this cohort of patients], the median treatment duration was about 6 months with the combination.

This is a gratifying sign that these patients are responding and tolerating the treatment.

The overall adverse effect (AE) profile did not show any new safety signals. Cabozantinib is an approved agent for multiple cancer types, and we have been using it for about 4 or 5 years if you look at the approval in mRCC. It is also approved in hepatocellular carcinoma and thyroid cancer. We did not see any new safety signals in mCRPC.

Very interestingly, the [frequency of] immune-related AEs (irAEs) was much less than what I would have expected. This combination has synergistic activity, so I would expect it would show synergistic toxicity. However, we did not see that, and less than 10% of patients developed irAEs.

We are looking at a very promising combination, and a phase 3 trial will be available to all patients in the United States within the next few months.

This study is a registration trial in patients with mCRPC who have experienced disease progression on abiraterone or enzalutamide. In COSMIC-021, patients had to have disease progression on abiraterone or enzalutamide. In fact, 50% of patients had disease progression on both agents, and 27% of patients had received chemotherapy with docetaxel in the metastatic castration-sensitive setting.

The phase 3 study is essentially mimicking that eligibility criteria with the exception that only 1 novel hormonal therapy is allowed. Otherwise, prior chemotherapy in the castration-sensitive setting is allowed, as well as 1 novel hormonal therapy in the castration-sensitive or castration-resistant settings.

Agarwal N, Loriot Y, McGregor BA, et al. Cabozantinib in combination with atezolizumab in patients with metastatic castration-resistant prostate cancer: results of cohort 6 of the COSMIC-021 study. J Clin Oncol. 2020;38(suppl 15; abstr 5564). doi:10.1200/JCO.2020.38.15_suppl.5564