Episode 133: Cabozantinib and atezolizumab in prostate cancer

Dr. Neeraj Agarwal describes the study on cabozantinib and atezolizumab in prostate cancer patients.

 

Brian:
Welcome, everyone to another 2021 ESMO podcast. Tom and I are here with Neeraj Agarwal from Huntsman Cancer Institute, and we’re going to talk about the expanded cohort 6 of the COSMIC-21 study. This was an abstract about cabo and atezo in patients with metastatic castrate resistant prostate cancer. So Neeraj, welcome. If you want to give a brief introduction, give us any relevant conflicts of interest, and then maybe you can just launch into the background and the setup of the study, that’d be great.

Neeraj Agarwal:
Thank you. Thank you, Brian, thank you, Tom, for having me on board. It’s an honor. So I’m very happy to talk about the study I presented in ESMO 2021 annual meeting, testing the combination of cabozantinib with atezolizumab in patients with metastatic castrate resistant prostate cancer. So this was, overall, a COSMIC-021 trial, and I presented the data on cohort 6. Regarding conflict of interest, I consult with multiple drug companies and have received honorarium. And these are many over the last 10, 15 years, and these are already mentioned in my presentation. I also receive research funding from multiple drug companies, including Exelixis and Genentech, to my institution.

Brian:
Great. So tell us just about the… Tell us who you are, give us a brief introduction of yourself and then tell us the basis for this study.

Neeraj Agarwal:
Yeah, so I’m a [g-oncologist 00:02:00] and I lead the genito uterine oncology program at the Huntsman Cancer Institute. It is one of the NCI designated comprehensive cancer centers at the University of Utah, and I’ve been here for more than 10 years as a faculty. Regarding this study, we conceived this [inaudible 00:02:26] five years ago, and this was based on the emerging data that tyrosine kinase inhibitors may have synergy with the PD1, PDL1 inhibitors, and this kind of combination strategies were being conceived for across the tumor types. Brian, you presented the data on axitinib and pembrolizumab, and Tom, you have done multiple… Lead so many studies.

Tom:
That’s sweet of you.

Neeraj Agarwal:
This combination… These tyrosine kinase PD1, PDL1 inhibitor combinations are already approved for multiple of… Many of them are approved for kidney cancer. And it is a matter of time, we saw this combination of lenvatinib with pembrolizumab being approved for endometrial cancer. So it’s a matter of time before we see these combinations emerging for other cancers. For prostate cancer, specifically, we know from the trials reported 10 years ago, the COMET trial, COMET-1 trial, where single agent cabozantinib was associated with significantly improved progression-free survival, but trial did not meet primary endpoint of overall survival.

Neeraj Agarwal:
Single agent PD1, PDL1 inhibitors do not seem to have a whole lot of activity in patients with metastatic castrate resistant prostate cancer, as also evident by the trial you led Tom, IMbassador250 trial, where enzalutamide plus atezolizumab, compared to enzalutamide, did not show improved survival outcomes. However, based on the encouraging activity of cabozantinib, at least a signal was there of efficacy in prostate cancer patients. And based on the data of synergy between cabozantinib and immune checkpoint inhibitors, we decided to do this phase I trial, multi-cohort phase I trial, which I had the privilege and honor of leading with Monty Pal, in multiple cancer types, including prostate cancer. This trial, which was started five years ago, had more than 10 cohorts.

Tom:
Now, Neeraj, you’ve got 132 patients, you’ve got a patient population, castrate resistant prostate cancer, you’ve got radiological progression, after enzalutamide or [abi 00:04:57], so it’s [LHRH 00:04:57] plus or minus essentially a second hormone therapy, and you’ve got cabo at 40, atezo, 120, so the slightly lower dose of cabo, rather than cabo 60 that we sometimes use in some of our trials. The primary endpoint was response. Was there anything exciting in the patient population that was outstanding, that we should know about, that might have biased the results?

Neeraj Agarwal:
Absolutely. I would say the opposite. We actually selected a patient population, which had to have radiographically progressive soft tissue disease, which was measurable. So, I just said two points, which is very important to note, in my perspective. One was radiographically measurable disease in the soft tissue, and second was, it had to be radiographically progressive for eligibility on prior treatment with abiraterone or enzalutamide or both. So I think those two factors in the eligibility criteria make the overall eligibility criteria more rigorous than other contemporary trials, which have been reported in this context.

Brian:
Then Neeraj, why did you choose that? I’m looking at your demographics, you had almost 20% with longer liver metastases, which is, as you just said, a big number for this kind of trial. I assume that was intentional, I guess I’m just wondering the rationale to do that?

Neeraj Agarwal:
Yes. So, that’s a great question, Brian. So, first of all, we did not want patients to be going on the study based on bone only progression or PS only progression, because we wanted to have a very stringent response criteria for allowing us to assess the combination stringently enough before proceeding towards the phase III trial, if you will.

Tom:
Okay, Neeraj, this is a difficult question.

Neeraj Agarwal:
Yeah.

Tom:
So, the difficulty is, in the phase III trial, you’re going to probably end up enrolling patients who don’t have this visceral metastasis, so this won’t be representative of your phase III study one way or another. Is that a fair comment?

Neeraj Agarwal:
Absolutely. Let me modify that statement a bit. So, we will enroll visceral metastasis patients in the phase III trial, because the phase III trial also requires measurable disease, visceral and extra pelvic lymphadenopathy. [crosstalk 00:07:32].

Tom:
So this exactly your phase III population?

Neeraj Agarwal:
Yes.

Tom:
Okay, so I’ve got that wrong. Okay, nice. That’s the first thing… I’m going to get a lot of things wrong today, by the sound of things. So Neeraj, listen, you’ve got response rate here… Overall response rate, of investigator of 23%, and you’ve got a 15% response rate by blinded independent review. So this is a RECIST one point so on radiological response of 23% or 15% in the central review. And you’ve got progression as the commonest flaw in 14 or 17… in 15% of patients. You’ve quoted disease control rates of 84%. What do you think about that? And do you think that’s encouraging?

Neeraj Agarwal:
So just taking a step back, Tom, the study had 130 patients, and 23% response by investigator-assessed criteria was seen in 23% patients of 132 patients. But if you look at those 101 patients with measurable extra pelvic lymph nodes and visceral metastasis, the investigator-assessed response was 27%. If you look at the waterfall plot for the reduction in the target lesion size in my presentation, it was slide seven in my presentation, 77% patients overall and 70% patients by independent radiology assessment… So 77% by investigator assessment and 70% by independent blinded radiology assessment had shrinkage in the target lesion. Now-

Tom:
Neeraj, question for you…

Neeraj Agarwal:
Yeah.

Tom:
Just, the 132, the metastatic CRPC population, and the 101 in the visceral lymph node population, what characteristics do the other 32 patients have? Or 31 patients? So there’s some-

Neeraj Agarwal:
Yeah, they had regional lymphadenopathy only. So, under the… below the aortic bifurcation.

Tom:
Okay, that’s cool. So, you’ve got genuine activity and you’ve got progression-free survival of five and a half months in both arms, which looks great, and you’ve got overall survival of 18.4 months, which also sounds promising. Would you agree on that?

Neeraj Agarwal:
Yeah. So, just to highlight, the radiographic progression-free survival in patients with visceral or [extra evaluate 00:09:56] lymph nodes, by independent blinded radiology assessment, was 6.8 months. So seven months almost. And duration of response was seven months. Yes, talk.

Brian:
I was going to say… So, I don’t remember the cabo single agent data from way back when. I guess maybe it wasn’t a perfectly similar population, but I’m just trying to benchmark this against some of the single agent data. If you could remind me if you know those numbers.

Neeraj Agarwal:
Yeah, so Brian, great question. That-

Brian:
Two great questions for me, Tom, just for the record.

Tom:
Mm, I’m a bit worried. I’m a bit worried.

Neeraj Agarwal:
So Tom, first of all, you guys are asking very challenging questions and preparing me very well for handling the questions on my phase III trial [crosstalk 00:10:43].

Tom:
We’re both going to be in the audience.

Neeraj Agarwal:
Yes, yes. So, first of all, regarding the COMET-1 trial, I don’t think the comparison is fair, because people have criticized or questioned the real efficacy of cabozantinib in bone metastasis only population. So when [Maha Husan 00:11:07] presented the data… Gosh, in the 2013 ASCO meeting, almost 10 years ago… She showed fantastic bone scan resolutions, like those metastatic spots in bone scans were resolving. And we did not really see the translation of those findings in survival benefit. So we know, moving forward, 2021, that cabozantinib has unique activity as far as modulation of bone scan is concerned, or bone metastasis is concerned, which may not be associated with survival outcomes.

Brian:
I see, and is that one of the reasons that you chose a measurable population in this trial?

Neeraj Agarwal:
Exactly.

Brian:
I got it.

Neeraj Agarwal:
Exactly. Yeah, yeah.

Brian:
So I guess the ultimate question… You’ve alluded to the phase III, which you can describe as… I think I know the answer. What was the activity in this study that led you to the phase III? Was it response rate, was it PFS? Was there one thing or was it just the aggregate data?

Neeraj Agarwal:
I think it was a combination of all of it. Radiographic progression pre-survival of 6.8 months, almost seven months, independent radiology assessment. Of course, the investigator-assessed responses are 27% in this patient population, and duration of response, as well as duration of therapy. If you look at median duration of therapy, it’s almost six months. So I think it’s a combination of efficacy and tolerability.

Tom:
Now, Neeraj, coming… I’m going to re ask Brian’s excellent question. So what was the single agent activity for cabo? What was the response rate like? I know it’s hard to interpret and I know that in bone metastasis patients… But you’re probably going to end up with some of those patients in your randomized phase III, one way or another.

Neeraj Agarwal:
Yeah.

Tom:
What are you… So-

Neeraj Agarwal:
So, depending-

Tom:
What is the single agent data like for cabo?

Neeraj Agarwal:
So, I won’t talk about one trial, I’ll just give you the overall activity. It had varied from 5% to 10%, depending upon the earlier phase II trials or phase III trials, the COMET trial, the earlier trial, which was presented in ASCO 2013, I think… If you combine all those trials, we are talking about between 5 to 10%. But different disease population, because in those patient population, they were not required to have measurable disease. So a lot of those responses were based on bone scan or, of course, the regional lymph nodes.

Brian:
And what was PFS in those? In that collective experience?

Neeraj Agarwal:
PFS was, again, I would say four months, 3.5 to four months, if I’m able to put together all of that data together, yeah.

Tom:
One of my… Chris Sweeney and I were involved in the IMbassador250 study with [Silke 00:13:56] and [Karim 00:13:56] and a number of other people… In that trial, we really found it hard to find activity for atezolizumab in unselected patients. We did show some activity in some subsets and we are hoping to broadcast that at some point in the not too distant future, but I think the conclusion was that this is a drug that we’re probably… When I looked at this trial, looked at the two drugs and said, “Well, neither have enough activity by themselves to get over the line, in my opinion.” And therefore one would expect… Unless there was a synergistic interaction in between the two, which is really hard to get in oncology, that you would expect this to struggle. The results you’re presenting here today are either questioning the results of the single arm trials and the randomized trials, or they are suggesting that there was a bias associated with this trial, or there is something synergistic going on between these two drugs. What do you think… Which of those three do you think is most likely?

Neeraj Agarwal:
I have the bias of being an investigator on this trial-

Tom:
Good for you!

Neeraj Agarwal:
Far away, far away. And I’m talking to two smartest people in my field. So I have to be very cautious in how I respond.

Tom:
I’m not sure that’s true.

Brian:
Yeah, [crosstalk 00:15:20].

Neeraj Agarwal:
Yeah. So I can tell you, Tom and Brian, when you look at patient population, you know better than me, if they are… They have to have radiographically progressive disease at the time of entry. If we do not do anything, they will progress with the next scan. And based on that observation and based on… We saw multiple TKIs showing, at least in my view, synergy with PD1, PDL1 inhibitors in renal cell carcinoma population. I like to believe… and based on our data… that we are looking at true synergy, and hopefully we will validate these results in the larger phase III trial.

Brian:
I want to ask about toxicity and dose reduction before we get onto the phase III. So it looked like this had, I would say, expected toxicity for an IO-TKI combo, but maybe even a little more, given some of the other combos, at least in other diseases. It looked like almost 43% had to have a cabo dose reduction, same percentage atezo, dose delay, et cetera. Do you want comment on that? Just the general tolerability, especially in a population that tends to be, I think, a little less fit than, say, our metastatic renal populations.

Neeraj Agarwal:
Yes. Elderly patient population. Before that, if I may just point out one more efficacy data, which is PSA responses. In this trial, almost half of the patients, 45% patients had PSA reduction and 23% had PSF 50% response. And based on all, we know that if a drug is associated with PSA responses in prostate cancer population, they do seem to have activity down the line. So just wanted to highlight that.

Neeraj Agarwal:
Coming to your question, Brian, regarding the toxicity… As you rightly said, the toxicity was driven by cabozantinib. So if you look at grade three and four toxicity, seems like a lot of grade three and four toxicity, but then you look at the type of toxicity. We are looking at diarrhea, fatigue, nausea, which are hallmark of TKI and not so much of atezolizumab. In fact, out of 55% patients who experience grade three and four toxicities, only 3% experienced grade four toxicities. If you look at immune related toxicities, 17% patients required high dose corticosteroids for treatment of immune related adverse event. And grade three and four toxicities were experienced by 20% patients, with no grade five events. So overall, if I put these all these together, the immune related side effects and TKI related side effects and the age of the patient population, elderly patient population, I would like to think this is a fairly well tolerated combination, again, with my investigator bias. And we didn’t see any new safety signal.

Tom:
I’m a bit worried about the adverse [fem 00:18:25] profile. I think 51% grade three or four adverse event is… Or 55, I think that is quite high. I think clinicians are quite… I don’t know how you feel about this, Brian? I think that we… I’m not sure how good we are at differentiating between grade three and grade four, and so I think that… I’ve been critical of the CTC grading system for some time. I think the difference between one and two, three and four is pretty arbitrary and I’m not sure clinicians are very good at differentiating, but I do think three and four is more significantly… We all obviously know what five is. You didn’t have that many discontinuations though, to be fair to you. So you’ve got 21% of one or the other, 10% of both. What was the median duration of treatment?

Neeraj Agarwal:
I must say, this is a great question, Tom, [crosstalk 00:19:11].

Tom:
That’s 2-1.

Neeraj Agarwal:
So 20% patients discontinued treatment because of side effects, and I think that speaks of the relatively safe profile overall. If you ask me what is the treatment duration? The duration of treatment was six months, so 5.8 months. Again, compared to other recent combinations, especially with… I don’t want to bring up any of the combination here for the sake of criticism, but six month median duration of treatment is pretty good in this patient population who are progressing on abiraterone, enzalutimide or both.

Brian:
So the toxicity, to me, sort of in summary, it sounds like expected IO-TKI toxicity. I would say that expected toxicity might be a little rougher in an older population, and it sounds like more cabo toxicity as opposed to immune mediated, which I… I don’t know if that’s a good thing or a bad thing, but it’s, of course, all going to come down to the randomized trial efficacy, because if there’s a strong survival signal, then obviously patients and providers will put up with that toxicity, so to speak. So do you want to talk about the ongoing phase III design and the endpoints briefly?

Neeraj Agarwal:
Yeah, so phase III trial, which is already enrolling patients in multiple countries, is a randomized phase III trial comparing cabozantinib plus atezolizumab versus an alternative novel hormonal therapy. So these patients have to have measurable disease, visceral disease or extra pelvic lymphadenopathy, by [RECIST 00:20:48] 1.1. And these patients had to have disease progression and one novel hormonal therapy, and they are being randomized to the combination of cabozantinib with atezolizumab versus the alternate novel hormonal therapy. The co-primary endpoints are overall survival and radiographic progression-free survival, by RECIST 1.1.

Brian:
So, I guess the good and bad news is that the efficacy of alternative hormonal therapy in that circumstance is pretty low. So do you assume that those patients are going to go on and get other life extending therapies, chemo and Xofigo and the [inaudible 00:21:28] eventually.

Tom:
Neeraj, is that the right control arm?

Brian:
Yes.

Neeraj Agarwal:
I was absolutely expecting this question, and my answer is, what is the best control? I have always learned from you guys, both of you. And if you can tell me what is the best control arm here, when the real world use of chemotherapy is… We have just looked at the real world patient population, hundreds of… Tens of thousands of patients, we presented in ASCO, we are going to present in ESMO. How many patients actually receive chemotherapy with docetaxel in hormone sensitive setting? Less than 7% in the United States. How many patients are receiving docetaxel in CRPC? Less than 24% patients. It would have been very difficult to have a docetaxel control arm. I’m coming right to the point, reading your minds.

Tom:
Yeah, Neeraj, and between you and I… I guess it’s not between you and I, because other people might hear this. I’m not sure… I’m not sure very many, but I suppose, you, I’m sure lots will… I got quite a lot of headwind from people around the control arm of this study, and it’s going to be an issue. I think with hindsight, because I think these data are… I think these data are pretty good and I’ve been as critical as I can do today. I think the combination looks more active than I was expecting. I don’t think there’s anything wrong with the patient population that you picked and it’s always danger in a phase II trial, but you’ve got 130 patients, it’s actually quite a lot. And it’s better than I expected for the two single agent therapies.

Tom:
I can’t explain what’s going on [inaudible 00:23:10]. Maybe it’s to do with T-cell trafficking, maybe your immune… But we’ve been trying to do that sort of work for years and years, and not particularly successfully. Whether you’ve got the unique combination here, who knows? But the reality is I do think it looks a bit better than you’d expect, but I think in the current environment, with so many new agents, and particularly with chemotherapy, not as [inaudible 00:23:29] people, where even if you hit some of the endpoints you’re looking for, you might struggle. And that makes me a bit nervous.

Neeraj Agarwal:
As you said, and Brian said, ultimately, it’ll be driven by the efficacy signal in the phase III trial. If the combination is efficacious, show a decent, acceptable, reasonable survival benefits, I think it will be used. And if it doesn’t, it will not be.

Tom:
I agree.

Neeraj Agarwal:
And that’s why we need phase III trial.

Tom:
So I think the answer to that question for me is it depends on the… Brian and I, and lots of other people, have done trials where we’ve had suboptimal controls. At times the field moves faster than you can keep up with. And whether that’s the case in this trial or not is a discussion for a different day. But the point is, if you come in with a 0.60 for overall survival, that becomes somewhat less relevant, and people will make indirect comparison with historical controls. It becomes more complicated when you come in the 0.78, 75, that’s a lot more complicated.

Neeraj Agarwal:
Yeah.

Brian:
It’s the same when we had Mike on talking about the VISION study, right? That study was criticized for the control arm, but at the end of the day, the FDA doesn’t have a comparative efficacy standard. It just has a safety and efficacy standard, right? And if you show activity in that setting, you will get criticized for the control arm, but that doesn’t mean it’s not active. It just means when applied in a real world setting, the benefit may be less.

Tom:
Neeraj, last question for me. Biomarker is obviously going to be difficult in this setting, none that spring out from the back of the room, you can’t pick on immune biomarkers because it’s five or 10% of the population, the trial’s never going to be successful. And obviously you’re showing unusual results that we haven’t explained. Is there any biomarker work you’re going to show on the day? Or is there any other exciting biomarker work that you’re going to do with this?

Neeraj Agarwal:
So far, we have not seen any correlation with any biomarker. PDL expression, I presented in [GO ASCO 00:00:25:26] in 2020, we didn’t see any correlation with tumor PDL1 expression. And so far, I’m not planning to present any biomarker-based data, because we are not seeing any signal or correlation with any specific biomarker. Which is good and bad in a way, because we did not select this patients based on a biomarker.

Tom:
But the randomized phase III may help you with that. And if it was positive, you might well find a subset, which would be super cool. Brian, last question from you.

Brian:
I think it’s really just around… This combo’s been around a while, shown activity here or there, I don’t think it has found a true home yet. So I guess my big picture question is… And understanding your bias as a prostate cancer investigator, where do you think the best home for this combo is going to be? Because clearly each drug has single agent activity in various settings, but the combo hasn’t quite found a home. So where do you think that might be?

Neeraj Agarwal:
For metastatic CRPC patients, this will be a very novel combination compared to, say, metastatic RCC patients. So I, personally, like to think that this combination will be a really novel combination for our patients with metastatic CRPC. If that was you were asking, Brian?

Brian:
Yeah, just in the context of other diseases, do you think this is going to be the place where it finds a home? And obviously I understand your bias. That was the question.

Neeraj Agarwal:
Yes, yes. I think it will be a combination for metastatic CRPC. It’s a large patient population with huge unmet need, despite other medications coming up. And of course, CONTACT-03 trial is going on in metastatic RCC, in post PD1 setting. Post PD1, PDL1 inhibitor setting. So, looking forward to see the data in that setting also.

Tom:
Neeraj, this randomized phase III is one of the most interesting trials for me, it’s a real paradox between what we know and what the phase II data shows, and I wish you the best of luck. Thank you for joining us today. It’s been a really great podcast. I hope you can come back and join us another time in the not too distant future.

Neeraj Agarwal:
Thank you very much.

Brian:
Congrats on your presentation.

Tom:
[crosstalk 00:27:32]

Brian:
Take care, guys.

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