Sumanta K. Pal, MD, associate clinical professor, Department of Medical Oncology and Therapeutics Research, co-director, Kidney Cancer Program, medical oncologist, City of Hope, discusses the background of the COSMIC-021 trial in urothelial cancer.

COSMIC-021 is an exciting multicenter, phase 1b study that was designed to enroll patients with genitourinary cancers, says Pal. Investigators began with 3 cohorts of patients ​with bladder cancer, kidney cancer, and prostate cancer. ​However, the ​trial was expanded ​to over 20 cohorts ​of patients.

Patients enrolled in the trial received a combination of cabozantinib (Cabometyx) and atezolizumab (Tecentriq).

In cohort ​2, investigators looked at a total of 30 patients ​with urothelial carcinoma who had received prior platinum-based chemotherapy, says Pal. Moreover, investigators found that 43%* of patients received greater than or equal to 2 ​or more prior lines of ​anti-cancer therapy. The fact that these patients were heavily pretreated should be taken into consideration when comparing the results from cohort 2 of the trial with other data sets regarding combinations of immunotherapy and targeted therapy, concludes Pal.

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Sumanta K. Pal, MD, discusses the background of the COSMIC-021 trial in urothelial cancer.

Dr. Pal on the Background of the COSMIC-021 Trial in ​Urothelial Cancer

Neeraj Agarwal, MD, professor of medicine, and director of the Genitourinary Oncology Program, Huntsman Cancer Institute, discusses the rationale for novel combination therapies in metastatic castration-resistant prostate cancer​ (mCRPC).

Oftentimes, patients with mCRPC experience disease progression on hormonal therapies, such as abiraterone acetate (Zytiga) or enzalutamide (Xtandi), says Agarw​al.

At the 2020 ASCO Virtual Scientific Program, findings from a large, real-world study of over 1000 patients were presented, which was obtained from Flatiron Health, Agarwal explains. Although these data were not surprising, they confirm that noveltreatment options need to be available for this patient population, Agarwal adds.

The overall survival ​(OS) after first-line abiraterone was 15​.7 months with enzalutamide ​compared with 9.4 months with docetaxel. The OS after first-line enzalutamide was 13.3 months with abiraterone versus 9.7 months with docetaxel. These data show that this is an area of high unmet need.

To that end, the​ phase 1b COSMIC-021 trial is evaluating the combination of cabozantinib (Cabometyx) and atezolizumab (Tecentriq) in patients with mCRPC, Agarwal concludes.

Neeraj Agarwal, MD, discusses the rationale for novel combination therapies in metastatic castration-resistant prostate cancer​. 

Dr Agarwal on the Rationale for ​Novel Combination​ ​Therapies in ​mCRPC

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 

.

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.”

, 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.

: Could you provide some background to the

: 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. 

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. 

. 2020;38(suppl 15):5013. doi:10.1200/JCO.2020.38.15_suppl.5013

Articles

Sumanta K. Pal, MD, discusses the clinical implications of the COSMIC-021 trial and highlights other exciting research efforts being made in genitourinary cancers.

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

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

“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%.

, 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.

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

: [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. 

. 2020;38(suppl 15; abstr 5564). doi:10.1200/JCO.2020.38.15_suppl.5564

Neeraj Agarwal, MD, discusses the COSMIC-021 trial, the findings from cohort 6 in metastatic castration-resistant prostate cancer, and the planned phase 3 trial that will evaluate the combination on a larger scale.

ASCO 2020: Update on Genitourinary Cancers | Supplements and Featured Publications

Dr. Pal on the Background of the COSMIC-021 Trial in Urothelial Cancer

Dr Agarwal on the Rationale for Novel Combination Therapies in mCRPC

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

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

ASCO 2020: Update on Genitourinary Cancers | Supplements and Featured Publications

Dr. Pal on the Background of the COSMIC-021 Trial in ​Urothelial Cancer

Dr Agarwal on the Rationale for ​Novel Combination​ ​Therapies in ​mCRPC

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

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

Dr. Pal on the Background of the COSMIC-021 Trial in Urothelial Cancer

Dr Agarwal on the Rationale for Novel Combination Therapies in mCRPC