Immunotherapy Across Genitourinary Malignancies - James Gulley

In this interview, James Gulley recaps the Keynote Lecture he gave at the GU ASCO 2019 annual symposium discussing immunotherapy across genitourinary malignancies and the different advancements in prostate, kidney and bladder cancer. 

Biographies:

James L. Gulley, MD, PhD, Chief Genitourinary Malignancies, Director, Clinical Trials Group and of the Medical Oncology Service, Office of the Clinical Director, National Cancer Institute, Bethesda, MD

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. I'm thrilled to have here with me today Dr. James Gulley who's the Director of the Medical Oncology services at the National Cancer Institute. Thank you so much for being here today.

James Gulley: My pleasure. 

Alicia Morgans: Of course. Well, you gave a wonderful talk this morning at GU ASCO really helping us think about immunotherapy across the genitourinary malignancies. And I'd love to hear your thoughts on that topic.

James Gulley: Well thank you so much. So really what I tried to display is where we are today, what we've learned in the last year, and where hopefully we're going to go. Bottom line is really we have different areas of advancement with immuno oncology in the different GU spaces. 

So with bladder cancer what we have is multiple agents approved in the second line setting, a couple of agents in the first line setting, but what we're seeing is that we need to have PDL1 high in the first line setting. 

What we're seeing though is data earlier on. So data was presented today about in the adjuvant setting where there's impressive response rates. And data was published earlier this year in the neoadjuvant setting again, with very strong response rates of between 30 and 45%.

So, I think bladder cancer we're really pushing monotherapy earlier on and I think there's also combination approaches coming down the pipe.

With renal cell carcinoma, we have already the Ipi/Nivo approved earlier last year but now we're seeing data that's emerging at this meeting and at ESMO with combinations of PD1 and PDL1 inhibitors with alectinib really pushing the response rates very nicely. And now for the first time seeing improvements in both progression-free survival and overall survival.

And I believe that will lead to FDA approvals in these indications in the coming months.

And finally, in prostate cancer, we did have data that was presented at this meeting as well as other meetings, but I think what we're seeing in prostate cancer is we're going to need to have combination therapy approaches to really get objective responses in prostate cancer.

Alicia Morgans: Absolutely. So some of the really exciting studies that were presented in prostate cancer at this meeting at least, were notable. And I'd love to hear what do you think about the Ipi/Nivo combination that Pam Sharma presented particularly in prostate cancer?

James Gulley: Yeah so that was a great presentation yesterday by Pam and really highlighting what we are seeing in this combination. So just to remind ourselves, this was 3 mg/kg of ipilimumab and 1 mg/kg of nivolumab given every three weeks.

90 patients enrolled. 45 in the pre-chemotherapy setting, pre-docetaxel setting and 45 in the post-docetaxel setting. What they saw in the pre-docetaxel setting in those patients evaluable for response, there was about a 25% response rate. In the post-chemotherapy setting about a 10% response rate.

Now there were indications that there was subsets of patients that maybe more likely to respond. Small numbers but it looked like high tumor mutation burden. There was a statistically significantly better chance of responding if you had a higher than median tumor mutation burden, which is about 75 mutations per patient, not per mega base.

In addition, those patients who were PDL1 positive also had a higher response rate. So both groups, about 50% for tumor mutation burden high in pre- and post-chemotherapy setting, and about a 30-40% in the PDL1 positive. 

In addition, what was interesting to me was that if you looked at the radiographic progression free survival in the PDL1 positive patients, there was a tail on the curve of about 30% of the patients not progressing out many months. So indicating a signal that is typically seen with immunotherapies.

Now finally what I would mention is there was a lot of discussion about the toxicities that we see with this. So, unfortunately, the majority of the patients could not make it through all four planned doses of the anti-CTLA4 with the nivolumab. And it was only four doses.

So only about 29% of the patients made it through that. In addition, you saw about 40% of the patients had to stop because of side effects.

Alicia Morgans: Yeah, so what did you think about that? And there were actually two deaths on each arm I think that were treatment-related, which was surprising to me particularly in the pre-chemotherapy patient population. And so I would love to hear what do you think about that?

And are these patients different maybe than patients that are getting these kinds of doses with other solid malignancies? Is it the patients? Is it the doses? What is going on here?

James Gulley: There may be a combination of things going on here. So certainly we know that in general prostate cancer patients are older; however, these were all patients that had good performance status before going on study. So I want to discount that a little bit. 

We also know actually, interestingly, from other data that older patients do just as well or perhaps even better than younger patients in terms of immune responses. So does that mean that maybe they had more vigorous immune response? 

Actually interestingly enough it appears, and this data is not as strong, but it appears that there's less likelihood of immune-related adverse events with older patients. But clearly, there is some potential for frailty as you get older.

I think really where we're going though is, could this be a difference between 3 mg of Ipi and 1 mg of Nivo versus 1 mg of Ipi and 3 mg of Nivo? So that does for instance, in front line renal cell carcinoma is 3 mg of Nivo and 1 mg of Ipi. Potentially that's a less toxic dose and really, we don't have enough data to confirm that head-to-head but it makes sense because ipilimumab certainly is associated with more severe and more frequent side effects than nivolumab.

Alicia Morgans: Yes, and there was actually a fair amount of colitis which I usually think of in connection with CTLA4 targeting agents. So ...

James Gulley: Yes.

Alicia Morgans: So, lets' see where that goes. But importantly I think there was a signal there of some activity. There were some complete responses, ...

James Gulley: Yes.

Alicia Morgans: ... Which is really interesting. And I also agree that tail on the curve was impressive and really encouraging. And something for us to continue to look into.

James Gulley: I think one other thing to note is perhaps what we're seeing here is the ipilimumab igniting an underlying low-level immune response and the nivolumab allowing that immune response to be effective within the tumor microenvironment. 

So the question to me is, this approach in general sounds like a very good approach and is associated with a signal. But is there a way to do this more safely? And so I think we and others are looking at opportunities to combine other agents that can induce an immune response that may not have the side effect profile of anti-CTLA4 targeted agents, along with PD1 and PDL1 inhibitors. 

And so we have several studies ongoing at the NCI with vaccines, combining them with immune checkpoint inhibitors. Doug McNeil earlier last year showed an interesting paper with vaccine in pembrolizumab suggesting an improvement in clinical responses in patients that had the combination but not sequential, not vaccine followed by pembro.

Alicia Morgans: Interesting. So we'll have to see where things go. 

And speaking of combinations, there was another combination trial. So that pembrolizumab/olaparib oral abstract presented by Evan Yu ...

James Gulley: Yes.

Alicia Morgans: High level thoughts on that. 

James Gulley: So, this was a rapid abstract review. So what we see from that is that there is a signal there. There were patients who did not have DNA damage response pathway mutations, that were treated with a PARP inhibitor plus the pembrolizumab and there were a low level of responders, you know, small numbers of patients still. But there is some signal and something that you can't say was just due to the PARP inhibition.

And if you look at pembrolizumab, unless you have PDL1 expression you're probably not going to have activity. In a study that was published last year they looked at I believe it was over 300 patients that they had to screen to get about 35 patients that were PDL1 positive. And then they still only got a 17% response rate there.

So I think that this is another way potentially of engaging the immune ... Getting the immune system started. Perhaps because PARP inhibition can lead to up regulation of the sting pathway by causing double-stranded DNA breaks, when you get the DNA trapped. And those double-stranded DNA breaks causing, being recognized in the cytosol and being ... The cGAS-sting pathway being activated and gamma interferon being made. 

Alicia Morgans: Absolutely. Well thank you so much for sharing your expertise, your take on immunotherapy in GU malignancies generally. And really, some wonderful commentary on these abstracts from GU ASCO yesterday. So thank you for your time.

James Gulley: My pleasure.

Edited By: Mary Ann Johnston, Pharm. D, Digital Science Press,Inc. 
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