Andrew Armstrong: Thank you, Tanya. It's great to be here with you.
Tanya Dorff: I was so fascinated when I saw your presentation on the CHAMP study looking at chemoimmunotherapy for patients with the most aggressive prostate cancers, significant unmet need. How did you define the patient population that was enrolled in the study?
Andrew Armstrong: Yeah, thank you for asking that. We defined it two different ways. One is pure small cell or some component of neuroendocrine prostate cancer, histologic diagnosis. But we all know there's a group of patients out there that we call aggressive variant or double-negative prostate cancer, where they exhibit low AR activity, bulky disease, high CEA, chromogranin, or molecular features, like tumor suppressor losses, p53, RBP10, the MD Anderson criteria that Ana Aparicio and Paul Corn defined when they were studying the cabazi-carbo regimen.
Tanya Dorff: And I think there's precedent. A lot of studies in this space include a broad swath, and perhaps we'll learn more about how these different groups behave differently and respond differently to treatment. But in your study, you gave chemotherapy with a platinum and then ipilimumab and nivolumab. And I thought the dosing also, beyond all of that, was very interesting, that the ipilimumab wasn't just those four induction doses that we use in other diseases. So describe a little bit the regimen. Was everything started right upfront?
Andrew Armstrong: Yep. The idea behind the CHAMP regimen was to try to improve radiographic progression-free survival above and beyond what we know platinum doublet chemotherapy provides, which is generally about six months. So patients can respond, but that response is short-lived. So the idea of doublet immunotherapy or a quadruplet regimen is to really bring an aggressive cocktail of chemoimmunotherapy to patients with an even more aggressive disease. And so, the IPI was given continuously every six weeks. That was based on a CheckMate 9LA study from the non-small cell lung cancer regimen that did improve survival in non-small cell lung cancer. And prostate cancer probably needs that kind of accelerator boost of CTLA-4 blockade to maintain it. The nivolumab was given every three weeks. The chemotherapy could stop early if you're a patient who's responding, but you can give up to 10 cycles of the cabazi-carbo standard of care regimen.
Tanya Dorff: Yeah. I think there's certainly something about ipilimumab in prostate cancer and CTLA-4 maybe more broadly. But in the past, that's been really tough for patients to tolerate. In a lot of the ipi/nivo studies, people aren't even getting through their induction. So you did use a lower dose.
Andrew Armstrong: Yes.
Tanya Dorff: But is there anything else about the regimen or the patients that you think accounted for their ability to tolerate, and how many doses did they get?
Andrew Armstrong: It's a great question. The chemotherapy, certainly, we didn't give most patients 10 cycles. When we would scan patients every about three months, if a patient had a great response, they could stop the chemotherapy and then move to immune therapy doublet maintenance. So that spares patients the toxicity of the chemo, but allows them to experience cytoreduction. A lot of these patients are experiencing rapid progression, symptomatic progression, and then they need that chemotherapy to get their cancer into remission. And then, the immune therapy's goal is to maintain that and hopefully improve their survival.
Tanya Dorff: And so, the study was quite positive.
Andrew Armstrong: Yes.
Tanya Dorff: You set your benchmark for rPFS at six months and clearly exceeded it.
Andrew Armstrong: Yeah. So from Paul Corn's randomized data in Lancet Oncology, we hit the 55% six-month PFS benchmark and we exceeded that at 74%. The median rPFS by iRECIST was 12 months. And so, we hit our primary endpoint. Again, it's historic data, so it's not a randomized trial. We're beating the pre-specified endpoint. We're excited because 74% of men are now making it past that six-month.
I would point out that using iRECIST was really important in this trial. We had some key anecdotes of patients where they would have a transient progression or pseudo-progression followed by a partial remission. And so, that's what we know that can happen with immune therapy, that there can be a transient immune infiltration or pseudo-progression, and we treated beyond that and then saw ongoing responses. So I have a number of patients who are alive and doing well past 24 and even 30 months now in remission and doing reasonably well, one patient who's been totally off therapy for three years now.
Tanya Dorff: Wow. I think that's such an important point. I mean, even just with regular prostate cancer chemo, sometimes PSA goes up before it goes down and we need to stick with it a little bit.
Andrew Armstrong: Absolutely.
Tanya Dorff: But all the more so in the immunotherapy context.
Andrew Armstrong: And many of these patients, their tumors don't make PSA, and so we can track other tumor markers, like we saw great CEA and chromogranin responses. We'll be going into some of the deeper dives on the correlative studies and future analyses. The PCF, Prostate Cancer Foundation, has funded a number of immune monitoring correlative studies that will help us with the next generation of immune therapies down the road.
Tanya Dorff: And anything you can say about your long-term non-progressors? Were they different? Because it was a bit of a heterogeneous group defined by both small cell and aggressive variants.
Andrew Armstrong: Yeah. So there's extraordinary responders, where, for example, I have a patient who has no disease at all, on no therapy, and he's a horse farmer and doing amazing and very happy that he's a CHAMPer. We call him our CHAMPion. Second patient had a very durable response from his neuroendocrine transformed prostate cancer with gigantic liver metastases that melted away completely, and I present this at ASCO. But eventually, over two to three years, his PSA-positive and PSMA-positive disease reemerged. So that's now, it's kind of a paradoxical. It's almost like transformed AR-positive disease that became resistant to the immune checkpoint inhibition. So we seem to have eradicated his small cell tumor, but are still dealing with his adenocarcinoma. So that lineage plasticity can go both ways.
Tanya Dorff: Yeah. Or I think of it as just heterogeneity in different populations, but it is interesting to think about that other population reemerging.
Andrew Armstrong: Exactly.
Tanya Dorff: Yeah. Well, fascinating. Congratulations to you. And I guess it was run through the PCCTC?
Andrew Armstrong: Yes. This was a multicenter study done through the consortium, MD Anderson, Weill Cornell. My colleagues, Ana Aparicio, Cora Sternberg, Dave Nannis, and colleagues, and our MISTIC multicenter team at Duke oversaw all those operations.
Tanya Dorff: Yeah. I think we're all looking for options for these patients, and hopefully we'll be able to access this kind of CHAMP regimen.
Andrew Armstrong: I'd love to see randomized trials happen. There's a number of companies looking at dual CTLA-4/PD-1 blockade. I think neuroendocrine and aggressive variant prostate patients really have a major unmet need, and a lot of companies should focus their attention in that big unmet need. It's probably about 20%, 30% of all men with lethal prostate cancer.
Tanya Dorff: Yeah, absolutely. Well, great work. Thank you so much.
Andrew Armstrong: Thank you, Tanya.