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Alicia Morgans: Hi, my name is Alicia Morgans and I'm a GU Medical Oncologist at Dana-Farber Cancer Institute. I am so excited to have here with me today a good friend and colleague, Dr. Neeraj Agarwal, who is a Professor of Medicine and the Presidential Endowed Chair of Cancer Research at the Huntsman Cancer Institute. Thank you so much for being here with us today, Dr. Agarwal.

Neeraj Agarwal: Thank you very much for having me, it's always a pleasure and an honor to be here.

Alicia Morgans: Always a pleasure to talk to you too, especially given the phenomenal presentations that you had at ESMO 2021. Actually, some of them were in person, which is really, really exciting, I think, for all of us on a global level. I'd like to talk to you first about the COSMIC-021 study cohort 6, which was really a phenomenal investigation into the combination of cabozantinib and atezolizumab in patients who have metastatic CRPC. Can you tell us a little bit about this and what you presented at ESMO 2021?

Neeraj Agarwal: Absolutely. So this was a phase one trial known as the COSMIC-021 trial, which had multiple cohorts testing the combination of cabozantinib, a very well-established tyrosine kinase inhibitor, and a PD-L1 inhibitor atezolizumab. So a combination of cabozantinib with atezolizumab in multiple cancer types. Metastatic castrate-resistant prostate cancer was one of the cohorts. It was cohort 6, actually, when the trial opened. Over time, when... and each of those cohorts was 30 patients in different disease types. Over time, the study oversight committee really found the results in cohort 6 to be very promising, and that led to the expansion of cohort 6 to a total of 132 patients. And I presented the efficacy and safety results from those 132 patients with metastatic castrate-resistant prostate cancer, treated with cabozantinib with atezolizumab. And I am very thankful to the ESMO program committee for having me present these results as an oral presentation on behalf of my co-investigators.

Alicia Morgans: So Dr. Agarwal, I would love for you to really describe the cohort because this is somewhat unique in an mCRPC population. These patients needed to have measurable disease by RECIST, and this is sort of because of the historical changes that we have seen in the past on bone scans related to cabozantinib. So I'd love to hear your thoughts on what are the inclusion criteria, and of course, you can continue on to what you found as well.

Neeraj Agarwal: That is a wonderful question. I was going to get to the inclusion criteria first because this trial is unique from that perspective. So if you look at the metastatic castrate-resistant prostate cancer trial, usually patients are allowed to enroll on the trial based on PSA progression alone, based on bone scan progression alone, or based on measurable disease progression. In fact, in most of the trials with metastatic CRPC, the patients entered the trial based on PSA progression or bone progression. That is a standard with prostate cancer trials. Having said that, as we know, cabozantinib can modulate bone lesions and have a unique effect on the bones, which may not be associated necessarily with the traditional responses we see with anti-cancer agents.

Because of that, and to keep the trial inclusion criteria or eligibility criteria extremely stringent, patients were required to have progressive measurable disease in the soft tissue metastasis to be eligible. Bone scan progression and PSA progression were not sufficient for eligibility. So every patient had progressive soft tissue metastasis, meaning on or after abiraterone or enzalutamide therapy. It means if they do not get any effective therapy, they would experience disease progression on the next scan or the following scan within three months.

Alicia Morgans: Absolutely. And so when you gave them the combination of cabozantinib and atezolizumab obviously in a single-arm trial, what did you find?

Neeraj Agarwal: So the overall... the primary endpoint of the study was the investigator-assessed response by RECIST 1.1. That's number one. Number two, because we found patients who had visceral metastases and soft tissue metastases in the lymph node beyond the aortic bifurcation, what we call distant lymph node metastases. So we know any time we see patients with visceral metastases or distant lymph node metastases such as mediastinal lymph node, or supraclavicular lymph node, they usually reflect more aggressive disease. Intriguingly, when we were looking at the results of this COSMIC-021 study cohort 6 of 132 patients, 101 patients had this soft tissue metastasis in distant lymph nodes or in visceral tissue, and these patients had a better response, actually. And that is why we decided to present the study results in all patients and these high-risk patients. So if you look at all patients, the investigators assessed responses were 23% and high-risk patients, the investigator-assessed responses were 27%. The disease control rate was 88% in these patients, 84 to 88%.

We also had an independent radiology assessment, which was done as an afterthought. It was not a part of the initial critical design, but it was thought necessary before we went on to start a phase 3 trial and this phase 3 trial is actually the CONTACT-02 trial, which is happening, which is enrolling all over the world right now in different parts of the world. So if you look at the independent radiology assessment, the responses were 19% and 15% instead of 27% and 23% in the high-risk cohort and all patients. However, the disease control rate by independent radiology was 80 to 84%. So it looks like three or four patients moved from a 32% response to 29% response. So from being partial responders, they were categorized to have stable disease, but the rate of primary progressive disease was so low across the cohort.

Doesn't matter whether it was independent radiology or it was investigator-assessed, which was the primary endpoint. The rate of primary progressive disease was less than 20% across the board, and hence the disease control rates are very high. The two other things I would like to highlight, radiographic progression-free survival by independent radiology assessment in the visceral metastasis, and distant soft tissue metastasis. The radiographic progression-free survival was 6.8 months, almost seven months, other cohorts, 5.7 months, almost six months. So seven months and six months. The duration of response was high, it was close to seven months, and the duration of treatment was six months. So all of this tells us that the real response rate of primary progressive disease is low. Radiographic progression-free survival in patients with progressive soft tissue metastases at the time of entry, we are able to achieve a pretty durable disease control rate, disease control, and radiographic progression-free survival. And more importantly, patients are able to tolerate this combination for six months.

Alicia Morgans: So I think that's phenomenal. Can you tell us a little bit about the adverse event profile as it relates specifically to immunologic events? And of course, overall, it sounds like it was tolerable. Patients clearly stayed on treatment. What was your perception and what were those immunologic AEs?

Neeraj Agarwal: Yes. So these patients, elderly, frail patients, relatively speaking, compared to other cancer types, median ages above 70 years, these patients are progressing on novel hormonal therapy. In fact, almost half of the patients had progressed on both enzalutamide and abiraterone. So with that patient population in mind, the most common side effects were diarrhea, dry mouth, mucosal symptoms, and altered taste. Most of them are really reflective of cabozantinib's side effects. So if you look at the grade three and four side effects, 55% of patients had them, but if you look at grade four side effects, only 3% of patients had them. That was the overall side effect. Now, regarding the immune-related adverse events, which we categorized as an adverse event of special interest, there were, overall, if you just look at... I'll basically summarize it. How many patients require high-dose corticosteroids, which is prednisone at more than 40 milligrams or more than, actually anyone receiving prednisone 20 milligrams or more. So 17% of patients received high-dose corticosteroids for management of the side effects, which were supposed to be immune related.

Now, it is possible some patients got started on high-dose corticosteroids because of the perception of diarrhea being immune-related when diarrhea was in fact because of cabozantinib. And then after six, seven days, when their colonoscopy showed that there was no evidence of immune-related colitis, the attribution was changed to non-immune related colitis, but it was still categorized as a high dose corticosteroid. So you can see the patients overall were not experiencing any new side effects other than what we have already seen in the context of metastatic RCC, for example.

Alicia Morgans: So I think that's a great, a great benchmark, and a great way for us to sort of consider these side effects. There are not many metastatic CRPC treatments that will actually cause such diarrhea, but to consider across folks who actually receive cabozantinib on a regular basis, makes a lot more sense, and thank you for putting that into context. So if you had to summarize this presentation at ESMO 2021, your data from the phase 1 expansion, what would it be?

Neeraj Agarwal: So this is a novel combination of cabozantinib with atezolizumab. We know that both drugs are synergistic based on their individual responses being 5% and 0% in individual trials. When we see a combined response of almost 20% in patients with aggressive disease and a disease control rate of more than exceeding 8% with a median PFS of over six months to seven months, I think this combination really holds a lot of promise. A phase 3 trial has already started and is enrolling patients across the different centers in the world. So a very promising combination, and I remain very hopeful that someday we will have this combination available in the clinic.

Alicia Morgans: Wonderful. I really appreciate you sharing this update and letting us know about phase III. We congratulate you and your co-authors of course, and the patients who participated, and we do look forward to interim and then final analyses from that phase 3 to really understand the implications of this combination of cabozantinib and atezolizumab, an unexpected combination, perhaps, in metastatic CRPC, but one that seems to be somewhat efficacious. So, looking forward to that, and thank you again for your time today.

Neeraj Agarwal: Thank you very much.