Single Priming Dose of 177Lu-PSMA-617 Followed by Pembrolizumab in mCRPC in a Phase 1b Trial - Rahul Aggarwal

August 27, 2021

Alicia Morgans and Rahul Aggarwal, discuss the recent presentation on the phase 1b study of lutetium-177 combined with pembrolizumab. This phase I/II trial is evaluating the safety signals of the treatment combination. 

Biographies:

Rahul Aggarwal, MD Assistant Professor of Hematology/Oncology, Director of STAND Clinic, UCSF Helen Diller Family Comprehensive Cancer Center

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.


Read the Full Video Transcript

Alicia Morgans: Hi, my name is Alicia Morgans and I am a GU Medical Oncologist and Associate Professor of Medicine at Northwestern University in Chicago. I'm so excited to have here with me today, a good friend and colleague, Dr. Rahul Aggarwal, who is an Associate Professor of Medicine and a GU Medical Oncologist at UCSF.  Thank you so much for being here with me today, Rahul.

Rahul Aggarwal: Thank you, Alicia. Happy to be here.

Alicia Morgans: Wonderful. So I wanted to talk with you a little bit about an ASCO 2021 presentation that you and your team had looking at lutetium-177 combined with pembrolizumab. This is really a phase 1 study to really understand the safety, but also we have some early efficacy and response rate data as well with this presentation. Can you tell us a little bit about it?

Rahul Aggarwal: Sure. Happy to. So this was, as you said, a phase I/II type of trial that we are doing, and the ASCO abstracts & posters we had are really just on phase 1 or what we call "part A" portion of the study. So the study was designed to really look at one dose of lutetium followed by pembrolizumab. And in part A of the study, we really looked at three different schedules. So we didn't really alter the dose of lutetium. Everyone got the approved or soon-to-be-approved phase III dose of lutetium 7.4 GBq, but we looked at three different schedules, either lutetium first followed by pembro, started concurrently on the same day. And then the third schedule we looked at was the lutetium actually after the start of the pembrolizumab.  And we enrolled six patients per schedule, but this abstract, relatively a small number of patients, but we did summarize the overall results for those 18 patients that we enrolled in the first part of this study.

Alicia Morgans: Great. So can you tell us what kind of safety signals did you end up seeing? Did things look tolerable with these structures?

Rahul Aggarwal: Definitely tolerable, correct. We did not see any safety signals. We kind of expected that we wouldn't because we are only giving a single dose of lutetium. So we certainly didn't see any significant cumulative problems with blood counts and bone marrow effects, no significant dry mouth, or some of the other side effects that we see in lutetium dosing. And then the immune side effect profile with relation to pembrolizumab was what you would expect with pembro monotherapy, I think we had one patient with a grade III inflammatory arthritis, otherwise, no other grade III or higher or any other immune related adverse events. [crosstalk 00:02:17].

Alicia Morgans: And that's definitely an important addition and I'm glad to hear all of that. What about response rates? I know you looked at PSA responses as well as objective responses. What did you find?

Rahul Aggarwal: So I think just to back up in terms of the eligibility, this was a pre-chemotherapy population, so this was different than the phase III VISION study. These patients were less heavily pretreated and our hypothesis really for this combination is, can we use the lutetium as a single dose to try to prime the immune response and sort of extend the duration of response that we might otherwise expect? We know in the lutetium you see a pretty high response rate, but maybe not as durable as you'd like, and you get the side effects of repeated lutetium dosing and effects on the bone marrow. So that was why we chose to use a single dose. And we did see a pretty encouraging activity, it's definitely a small number of patients, and so there is certainly hypothesis-generating, but we saw an overall objective response rate of 44%, eight out of 18 patients.

We did require a measurable soft tissue disease. So we did get a valuable response in all 18 patients, so eight out of 18 with an objective response. And then getting to the question of the durability of those eight responses, five seem to be pretty durable with a duration of response of over eight months. So I do think there is something about potentially the combination that the pembro may extend that duration of response, but again, hypothesis-generating.  We need more numbers and we are looking at some of the correlatives we've built-in looking at pre, post lutetium biopsies to understand what is going on in the immune microenvironment within the tumor.

Alicia Morgans: It's really fascinating. So let's dig a little bit into this. How often were you giving the pembro and how many doses? What was the median number of doses?

Rahul Aggarwal: The medium number of doses, I don't have that data off the top of my head. The pembro was really given at the standard 200mg, 2-3 weeks until progression or toxicity. I think we had one patient may be stopped for adverse events, but basically, everyone continued until progression. And so that was the sort of standard schedule that we use.

Alicia Morgans: And how many of the patients actually had high TMB or really were MSI high?

Rahul Aggarwal: So that was the other encouraging thing, is that this was really an unselected patient population. And so we have other clinical trials at our institution that the patients that were MSI high or high TMB, or even a DNA repair pathway mutation may have been funneled towards. So we had really no patients with TMB high, no patients that were MSI high out of the 18 that were enrolled, including all eight responders. No one had a genomic profile that would necessarily predict a high degree of response to pembrolizumab alone.

Alicia Morgans: And I think that's one of the things that I find most intriguing about this study. So especially when we have early phase studies, we're not necessarily expecting to see these longer-term responses and you have just under half of the patients actually having responses. To me, that is actually highly encouraging in this unselected patient population. And remember to the audience, that patients with MSI high and prostate cancer at max, we are thinking maybe 3%. You were not enriching for this population for that, in fact, had no patients with that. So I think that is really intriguing. What are your thoughts?

Rahul Aggarwal: I [inaudible 00:05:38] about that. That was one of the key things that we put in the baseline characteristics table. And I think we continue to see the same pattern hold. We are in the midst of enrolling in part B of the study. Intentionally, to some degree, not enrolling those types of patients because I think we really want to get at, is there something about this combination that is worth taking forward?

Alicia Morgans: Great. So what are your thoughts now? This one's going to be really even a bit more challenging to answer. What are your thoughts on the potential long-term responses in terms of PSA and even radiographic responses to lutetium? We, at this point, as far as the data I've seen, do not have data on patients who have gotten one cycle and really understanding what response rates might be,  particularly, as you said, this sort of less heavily pretreated patient population. So how do you think lutetium on its own might do and is the pembro really adding anything?

Rahul Aggarwal: That's a great question. You're right. We don't have that data. I think we do know the kinetics of lutetium response, certainly from the patients that we treat and we treated in the VISION study, there certainly are patients that got one or two doses of lutetium then for one reason or another couldn't continue, even if their cancer hadn't progressed. And generally speaking, I think the duration of exposure-response on average tends to be a little bit more short-lived.  There is a little bit more V-shaped, you do get regression and then you get growth back. It'll take, ultimately, of course, a randomized study to really understand what the pembro is adding to lutetium alone. I think one thought we have in terms of how you would position this from a drug development or registrational path is, as lutetium moved earlier, and we do think that there is a high likelihood of success of lutetium in the pre-chemotherapy mCRPC setting and those studies are underway.

That is where we may see that home and why we designed the study in this pre-chemo population. So if you have the combination and the pembro may extend the time that you need between lutetium doses. So maybe it's not one dose, but maybe it's one dose with pembro. And then at the time of subsequent PSA progression, perhaps you re-dose, [inaudible 00:07:42] so lutetium then can recapture that response, giving a total number fewer of lutetium doses, but longer duration of response. I think the other practical matter is, just given the demand and the availability of lutetium, is there a value in having a combination approach that maybe lessens the overall need for the total number of lutetium doses? I think that is an interesting question as well.

Alicia Morgans: I completely agree. Or even just lessening, as you said of the frequency. So you could stretch this treatment over years, perhaps and continue retreatment and have more durable responses. I think there is so much to learn and I love that you and the team are trying to really understand not just what drugs work, but how can we use them in combinations that might allow us to optimally dose them maximizing their efficacy, even in patients, we wouldn't necessarily expect to have efficacy in and also minimizing the toxicity. So this is really fascinating work and I sincerely congratulate you and your team and I look forward to seeing updates. So what would your message be? I know it's an early phase study, but what would your message be to listeners who are curious and looking forward to your ongoing work?

Rahul Aggarwal: I think just like you said, I think the message has been that we are encouraged, but it is early. And I think there is still a lot to learn about not just this combination, but undoubtedly other combinations of lutetium plus other drugs. And I think to your point, there are so many factors from toxicity, duration of response, costs, all these things go into it, but I think we're excited about it and I think I'm looking forward to learning more with our study.

Alicia Morgans: Well, great work. Thank you to you. Thank you to your patients. Thank you, of course, to your team. As always, I'm impressed and really excited by the discoveries and the advances that you have made and that I'm sure you will continue to make. So thank you so much for your time today, Rahul.

Rahul Aggarwal: Thank you so much. I appreciate it.
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