Cabozantinib in Combination with Atezolizumab in Metastatic Castration-Resistant Prostate Cancer: COSMIC-021 - Neeraj Agarwal

January 29, 2021

Treatment options in metastatic castration-resistant prostate cancer (mCRPC) who have soft-tissue progression after second-generation anti-androgen therapies are limited. Single-agent studies of cabozantinib, a tyrosine kinase inhibitor (TKI) that regulates cell growth, angiogenesis, and immune cell regulation, and the anti-PD-L1 antibody atezolizumab each showed limited efficacy as monotherapy. (Smith JCO 2012; Kim JCO 2018). As cabozantinib may target pathways related to immune suppression, the phase 1b multinational COSMIC-021 study is evaluating this drug in combination with atezolizumab in various solid malignancies, cohort 6 specifically in mCRPC. Dr. Neeraj Agarwal presented this data at ASCO 2020 and reviews the study hypothesis of the study and the encouraging results recently presented.  


Neeraj Agarwal, MD, Professor in the Division of Oncology, Department of Medicine, at the Huntsman Cancer Institute (HCI) at the University of Utah School of Medicine. He is the Huntsman Cancer Institute (HCI) Presidential Endowed Chair of Cancer Research, and the Director of the Genitourinary Oncology Program, Dr. Agarwal also serves as the physician-scientist and senior director of clinical research innovation at HCI, Salt Lake City, Utah

Alicia Morgans, MD, MPH Associate Professor of Medicine in the Division of Hematology/Oncology at the Northwestern University Feinberg School of Medicine in Chicago, Illinois.

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Alicia Morgans: Hi, my name is Alicia Morgans, and I'm a GU medical oncologist and Associate Professor of Medicine at Northwestern University in Chicago in the United States. I'm so excited to have here with me today a friend and colleague, Dr. Neeraj Agarwal. He's a Professor of Medicine at Huntsman Cancer Institute, as well as being a GU medical oncologist and the Director of the GU Medical Oncology team. Thank you so much for being here with me today, Neeraj.

Neeraj Agarwal: Thank you very much for having me. It's always a pleasure.

Alicia Morgans: Wonderful. Always a pleasure for us, too. I wanted to speak with you a little bit about the COSMIC-021 study, specifically about Cohort 6, which I know you presented and have spoken about it at ASCO, for example. But just to refresh everyone's memory, I think this was a really exciting trial with some very maybe unexpected results. Can you tell us a little bit about it?

Neeraj Agarwal: Yeah. Unexpected results in a positive way, I would say. This whole story, I like to call it a story because all these clinical trials, drug development, is a story for us, right? For us clinical investigators. This started two or three years ago when we thought cabozantinib, which is an oral TKI, as we know, with a combination of atezolizumab, which is a pretty well-established immune checkpoint inhibitor. So we thought maybe a combination of cabozantinib with atezolizumab will have a good synergy. And there was a lot of laboratory data with a very robust rationale backing this combination.

We started with a 750 patient-large Phase I trial with 20 different cohorts. So, various disease groups. This was by itself an example of how can we do test novel combinations across disease types in a very efficient fashion.

I'm going to talk about Cohort 6, which was focused on metastatic castration-resistant prostate cancer. As we know, the treatment paradigm of metastatic prostate cancer has not really changed much since we had enzalutamide and abiraterone approved early on in this last decade, actually. It is a different decade now. Since then, we have had cabazitaxel, docetaxel, chemotherapy. Docetaxel was already there, cabazitaxel was coming up, but not really a humongous change. All these are modest changes.

So we decided to pick up this disease setting where patients are progressing on enzalutamide or abiraterone or both. Fifty percent of patients had disease progression on both. One very unique aspect of this trial was that patients had to have measurable disease which was progressive at the time of registration on the trial. So, measurable and progressive measurable disease. They could not have progressive measurable disease, they could not go on the trial. This was the patient population.

In this context, patients were enrolled in the trial with and received treatment with cabozantinib with atezolizumab. I'll come straight to the efficacy data. The overall objective responses were 33%. Disease control rate or others say stable disease rates were additional 47%. So if you look at either complete response or partial response, 33%. An additional 47% of patients had stable disease as the best response, which basically translates into a disease control rate of 80%. I do not think we have seen this kind of data in the context of at least immunotherapy in metastatic CRPC, which is very encouraging.

Another positive attribute of this whole experience was that patients were able to tolerate this combination therapy. Approximately six months was the duration of therapy, and these responses were relatively well-maintained and preserved, and the median duration of response is approximately eight months plus some weeks. So, the duration of response is pretty good, patients were able to be on this combination for six months, and we are seeing historic overall responses and disease control rate.

Alicia Morgans: I think it's so exceptional too that on their own, cabozantinib and atezolizumab probably have very limited efficacy in this patient population. It was something about putting them together and perhaps the effects on the tumor micro-environment that really have allowed us to see this combination have quite a synergistic response, and have perhaps given us an opportunity to make patients who generally have had a very cold tumor immune micro-environment into one that clearly seems to be responsive at least in terms of stabilizing the disease progression. Which I think is really exceptional. Can you comment a little bit on how you think this combination might be working?

Neeraj Agarwal: Absolutely. I still remember the bone scans being presented by Dr. Maha Hussain about 10 years ago at the ASCO main meeting with cabozantinib. There's a lot of enthusiasm for single-agent cabozantinib, which led to a major Phase III trial. In that trial, progression-free survival was superior with cabozantinib, though overall survival was not met. So this drug has a single-agent activity. And I always like to state this, at least to my colleagues, friends, and fellows, that if we are banking on a combination, we need to have a backbone that has its own activity. If the backbone doesn't have an activity, then it's likely the combination is not going to work.

So, in that backdrop, when we combine atezolizumab with cabozantinib, we also know the data now, we have heard the data from a nine-year trial in kidney cancer, in metastatic RCC, cabozantinib with nivolumab, fascinating historic responses, and median PFS. I think this combination together, cabozantinib with the ICI, whether it's nivolumab or atezolizumab, I think they have this unique synergy that starts from cabozantinib's effect on multiple other receptor kinases, including TAM, including MET, which do allow cabozantinib to synergize with ICI. I think it goes beyond a VEGF-TKI effect. So, I think it is very promising overall.

Alicia Morgans: Absolutely. And you are still continuing to monitor this cohort. When do you expect to have more finalized data to give us all an update?

Neeraj Agarwal: Yeah. I should have mentioned that the data we presented last year was in 48 patients, so obviously we had to expand the cohort. The cohort started as a 30-patient cohort, expanded to a 60-patient cohort. Now we have finished accrual in the 130-patient cohort. So, this is relatively a pretty good-sized Phase I trial now, Phase I cohort if you will. We are going to present the data hopefully in ESMO in 2021, and I'm really hoping at least to be able to be there in person. Whether that happens or not, I think we are positive that we'll be able to present the data there.

The good news is, for our patients, for all of us, we have started a Phase III trial known as the CONTACT-02 trial. Well, as you can imagine, a Phase III trial has to have a control arm. And the control arm in this patient population is very difficult to determine, knowing that from seminal studies by Dan George and team just published [inaudible] and data set, uses of therapies in metastatic castrate-resistant prostate cancer, the most preferred to sequencing among doctors in the US is, NHT followed by NHT. The vast majority of patients are receiving enzalutamide followed by abiraterone or vice versa.

We will publish our paper very soon showing that chemotherapy with docetaxel in second-line setting has never been shown to improve survival, has improved outcomes compared to arsenic NHT. The CARD trial was a third-line trial. Most patients were in third-line. So what to do in this line where patients are progressing on one NHT. So we decided to keep alternate NHT as that control arm and cabozantinib with atezolizumab as the experimental arm. The trial just got activated in a few sites in the US, and we plan to open more than 200 sites across the planet. And I'm really hoping that we accrue on the trial soon and we'll have a chance to present and talk to you about those results on UroToday in two or three years.

Alicia Morgans: That would be wonderful. Just to clarify the patient population, Neeraj, are these going to be patients again only who have soft tissue measurable disease by RECIST, or are these patients, is this a broader patient population?

Neeraj Agarwal: Again, that's a fantastic question. I'm not surprised Alicia, you have such an in-depth knowledge of how cabozantinib works. As you know, cabozantinib can attenuate bone lesions, and that may not be associated with survival benefits. So I think it was mandated to us by the regulatory bodies that we have to have measurable disease, because, without measurable disease, that may be difficult to discern the independent effect of cabozantinib on the bone lesion.

So keeping that in mind, we have to have measurable disease, but we don't have to have progressive measurable disease in the Phase III trial. So we will have measurable disease, lymph node, which is measurable. It can be visceral measurable disease for anyone, any patient who's progressing on one NHT, one and only one NHT, which is not very uncommon to see now. We will present our Medicare real-world data that NHTs have become the preferred first-line therapy in metastatic castration-sensitive prostate cancer, hopefully in ASCO this year. So with that, I don't have any doubts when the patients are developing castrate-resistant disease after one NHT therapy, that will be the patient population we like to serve in this clinical trial.

Alicia Morgans: Well, I commend you on making sure that your trial design actually really reflects what we're doing in clinical practice, because it's that kind of forethought that will allow us to actually integrate the findings into the treatment algorithm pretty seamlessly when you ultimately hopefully change practice. I think a lot of people hope that you continue to make progress and to find ways to take care of these men and get them the outcomes that we all wish for them. So as a final thought, what is your conclusion on this exciting work with this combination of cabozantinib and atezolizumab?

Neeraj Agarwal: I think it is time that we bring a novel combination for our patients with metastatic castrate-resistant prostate cancer to our clinic. I think novel hormonal therapies are there. They are a highly well-tolerated treatment, but every single patient for progression on these therapies is universal and we need novel treatment options. And I'm really hoping that this combination will serve that purpose down the line.

Alicia Morgans: I don't think you're alone in hoping that. I think many of us are, and I look forward to seeing the data that supports that truth. And I really appreciate your efforts for the community, your work in this trial, and in all of the other things that you do. And thank you again for your time today.

Neeraj Agarwal: Thank you very much again.