Feladilimab Alone and in Combination with Pembrolizumab In Previously-Treated Urothelial Carcinoma Patients, An expansion Cohort of the INDUCE-1 Trial - Arjun Balar

June 8, 2021

Arjun Balar, MD, joins Alicia Morgans, MD, MPH in a discussion on INDUCE-1, the a first-in-human trial evaluating feladilimab as monotherapy and in combination with pembrolizumab. In an oral abstract session at the 2021 ASCO annual meeting, Dr. Arjun Balar presented results of INDUCE-1 assessing preliminary efficacy, safety, and biomarker data of feladilimab ± pembrolizumab in urothelial carcinoma expansion cohorts. Expansion cohorts include tumor types, such as urothelial carcinoma, with high inducible T-cell co-stimulatory expression and immunotherapy-favorable features. 

Clinical trial information: NCT02723955


Arjun V. Balar, MD, Associate Professor, Department of Medicine at NYU Grossman School of Medicine, Medical Director, Clinical Trials Office, Perlmutter Cancer Center, and Director of the genitourinary medical oncology program at NYU Langone’s Perlmutter Cancer Center. NYU Langone Health, New York, New York.

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.

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Alicia Morgans: Hi, my name is Alicia Morgans and I'm a GU Medical Oncologist and Associate Professor of Medicine at Northwestern University in Chicago, Illinois. I'm so excited to have here with me today, Dr. Arjun Balar, who is an Associate Professor of Medicine and the Director of the GU Medical Oncology Program at the NYU Langone's Perlmutter Cancer Center in New York.

Arjun Balar: Thanks so much for having me.

Alicia Morgans: Well, thank you so much for being here with me today to talk about one of the presentations you are going to be making at ASCO 2021. This is really an expansion cohort of the INDUCE-1 trial, looking at previously treated urothelial carcinoma patients who are receiving feladilimab alone and in combination with pembrolizumab. Can you tell us a little bit about this trial?

Arjun Balar: Absolutely, Alicia. So just to give a little bit of background, INDUCE-1 is the broader program for GSK that looked at feladilimab. Feladilimab is an ICOS receptor agonist molecule. Now more specifically, what does ICOS stand for? It stands for inducible T-cell co-stimulatory receptor. So it is part of the CD28 IgE receptor superfamily, which includes also CTLA-4 and PD-1. ICOS may be familiar to some people because actually it was discovered as a pharmacodynamic biomarker of actually anti-CTLA-4 therapy. So when patients receive anti-CTLA-4 based therapy in the peripheral blood mononuclear cells, you can actually see ICOS being up-regulated on PBMCs. So we've known that it is actually relevant in immune-based therapies for quite some time, and it is found to be kind of a, and again, it's an inducible receptor, so this is something, that actually from an agonist viewpoint if we develop agonistic molecules, if given at the right dose and schedule can actually lead to enhanced T-cell based responses. This was the first inhuman study that eventually led to dose escalation and dose expansions.

And part of the program that we are presenting this year at ASCO is the dose-expansion cohorts that specifically looked at patients with advanced urothelial cancer. The primary goal of the dose-expansion course that I presented was to look at its role in monotherapy in PD-1 experienced patients who had progressed on PD-1 based therapy. And then admittedly, these patients were heavily pretreated with other agents, such as platinum-based chemotherapy and others. And then also to look at its role in combination with pembrolizumab, which is a PD-1 antibody in patients who had, or were PD-1 naive. And so looking at both safety, as well as efficacy in these patient populations. Again. So PD-1 experienced monotherapy, PD-1 naive in combination with immunotherapy.

Alicia Morgans: So when you did that, you were looking of course, for response rate and for toxicity, how did these two cohorts seem to fair?

Arjun Balar: So I'll first cover safety because ultimately, when you are doing trials like this and to be true to the phase one model, you're not enrolling a lot of patients, right? So, just to kind of quickly cover in the monotherapy cohort, it was 14 patients, in the PD-1 combination cohort, PD-1 naive patients, it was 32 patients. So you're not going to get a real big sense in terms of, efficacy in numbers like that. But you are going to get a good sense, at least a preliminary sense of safety in groups like this. So the primary focus was safety. And what we observed in the monotherapy cohort in PD-1 refractory patients was that overall treatment was very well tolerated. The majority of treatment-related adverse events were grade one or two.

Immune-related adverse events were not formally evaluated. So, when the data are collected and in the EDC and how these toxicities are labeled, it's important to understand that, you know, the sponsor did not formally evaluate these events as necessarily immune-related or not. But when we looked back at, at ECRFs, you know, ones that were potentially immune-mediated overall were generally of low grade and low frequency, and very few patients needed concomitant steroids for any sort of immune-related adverse events. So that was in the monotherapy cohort. And similarly, only nine patients who were treated in the combination cohort received concomitant steroids, only two of which were for suspected immune-related adverse events. So overall very low-grade toxicities and very few grade three adverse events, actually only one patient I think developed a grade three adverse event.

Alicia Morgans: So that's actually, I think really, really encouraging because when we are really kind of trying to up-regulate this immune response to not see toxicities that are highly concerning, even in these low numbers, I think it is very helpful and good to hear as clinicians. What kind of responses did you see, of course, recognizing that this is not a randomized trial or even a trial where we are necessarily looking for a response at the endpoint, that's not the goal of a phase one, but did you see responses?

Arjun Balar: Yeah we did, and I think, when we start doing these dose expansions, they are more or less, phase twos that are embedded in phase ones. And, we start getting inklings or kind of a preliminary, sense of activity. And so in the 14 patients that were treated in the monotherapy cohort, there was actually a response and this was a patient who was previously heavily pretreated. And I will be describing this data in more detail during the ASCO presentation. But this is a patient who received platinum-based chemotherapy, actually, even flunine and subsequently PD-1, plus an OX-40 agonist in the advanced metastatic setting. And importantly, this is a patient who would actually only have achieved stable disease with nivolumab therapy and then went on to receive feladilimab at 1mg/kg every three weeks, and actually achieved a partial response in lung metastasis, a very decently sized lung metastasis.

And that patient achieved a response that lasted up to 18 weeks on treatment. So what we saw is clearly evidence of some activity. Now, granted, that was one response out of the 14 patients that were treated. This is proof of concept, right? And so what we need to now do is to look at this in perhaps a larger group of patients to understand, what are the factors that ultimately led to this? And can we test this in a larger patient population to really see what the rate of responses is?

In the next group we actually looked at responses, but remember, this is a group of patients that are PD-1 naive. So we already know that these patients are generally going to respond fairly well to PD-1 monotherapy off the bat. The response rate was 22% in the 32 patients in the combination cohort, to what degree the ICOS is contributing to an enhanced response there again, 22%, that's not all that different than the 20% response rate that you'd expect in the PD-1 monotherapy. But in terms of the combination in terms of safety, there is no enhanced immune-based toxicity, randomized trials are truly needed. So here any [inaudible 00:06:32] has a pembrolizumab plus feladilimab to really know the contribution of the component as well.

Alicia Morgans: Great. Well, are you and the team planning to continue to move things forward? Do you know, at this point in time, if you're pursuing phase two and other trial designs?

Arjun Balar: So that is to be determined.  One of the development strategies for the sponsor was to look at, first other disease groups, disease cohorts, such as head-neck cancer, which was also part of, the induced program where they also saw preliminary, very promising activity. They had a phase two, three-program, but unfortunately, they halted further enrollment in their phase two, three programs based, I believe on, a preliminary evaluation of efficacy, not safety. And so they have had a press release and unfortunately, they've halted further development in head-neck. What that implication is for bladder cancer is yet to be seen. However, I will tell you that, when you at least have some evidence of monotherapy activity in a PD-1 refractory population in a visceral metastasis, I think it really does warrant further investigation. And so I do think that there is reason to believe that there is activity as monotherapy. So we need to test this further, when and how that's going to happen. I still don't know yet.

Alicia Morgans: Well, that makes complete sense. And I congratulate you, the team, and of course,  we appreciate the patient's participation in these trials. They can be somewhat stressful and definitely high intensity for patients to come in and do these early phase trials. But the work is done. The presentation is really important and I'm very glad to see, that toxicity is actually quite low in this combination. Thank you so much for your efforts and for taking the time today.

Arjun Balar: Thank you.