Results of a Phase II Randomized Double Blind Trial of PF-04518600, OX40 Antibody, in Combination with Axitinib - Sarmad Sadeghi

October 17, 2022

Sarmad Sadeghi and Pedro Barata discuss the results of a randomized Phase II that explored OX40in combination with axitinib in patients with renal cell carcinoma. Patients in the trial had progressive disease after receiving immunotherapy with the usual PD-1/PD-L1 antibodies. The primary endpoint was progression-free survival. Dr. Sadeghi describes the rationale for the trial design, why the trial failed to meet the futility requirements to proceed to full accrual, and how he foresees moving forward with what was learned from this study.


Sarmad Sadeghi, MD, MS, Ph.D., Associate Professor of Clinical Medicine, Keck School of Medicine of USC, Los Angeles, CA

Pedro C. Barata, MD, MSc, Assistant Professor of Medicine, Hematology & Medical Oncology, Tulane University, New Orleans, Louisiana

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Pedro Burata: Hi. My name is Pedro Burata. I'm a GU medical oncologist at Tulane Medical School in New Orleans, and it is my distinct pleasure to have Dr. Sarmad Sadeghi who's an associate professor at the Department of Medicine and Neurology at USC in California. Thank you so much, Dr. Sadeghi for joining us today.

Sarmad Sadeghi: My pleasure. It's good to be here today.

Pedro Burata: Appreciate it. So we're here to talk about a very interesting results from investigator-initiated study that you led that you just presented at ASCO '22 with a new molecule exploring OX40 in combination with axitinib, that's a matter of fact is a randomized Phase II trial. Can you tell us more about the rationale for that combination and how you came up with that design?

Sarmad Sadeghi: Of course. So OX40 or CD134 is a member of the tumor necrosis family of receptors. And it is expressed on activated T cells, but not the native T cells, and it's a stimulatory receptor. So if you stimulate it, you theoretically reactivate exhausted T cells. So in a way, it was interesting to test this molecule in patients who had progressive disease after immunotherapy with the usual PD-1/PD-L1 antibodies.

It was also interesting to observe that data suggested that axitinib could have some effects on the immune system as well as you know, which if when overexpressed or upregulated has some immunosuppressive effects. So when you block it, then you allow the immune system to remain active. So it seemed like if we want to try this OX40 molecule in kidney cancer, it made sense to combine it with a vagus targeting agent and to have a clean design. We decided to do it in a randomized and double-blind setting, and everybody got access in it, both arms, the control arm had a placebo and the intervention arm had this Pfizer product, which was a humanized antibody for OX40. It was a stimulatory antibody. So that was a rationale for the study.

Pedro Burata: Got you. That's very interesting. And by the way, kudos to make it happen and-

Sarmad Sadeghi: Thank you.

Pedro Burata: ... so I know you corresponded to a big effort, right? Take patients with clear cell RCC in the refractory setting, and you just presented the results. Can you summarize for me, for the audience, the key point that you'd like to make about the findings of your Phase II trial?

Sarmad Sadeghi: Of course. So the design of this study was a double-blind randomized with placebo control. So the primary endpoint was progression-free survival. We wanted to see a hazard ratio of 0.5 in favor of the experimental agent. With the power of 80% and now for 5%, this resulted in a sample size of 104 patients, 52 in each arm. We had stratification based on Memorial Sloan Kettering risk groups, as well as the number of lines of therapy, one or two versus three or more. And we had the usual secondary endpoints of overall survival duration of response and objective response rate. We had an interim analysis planned after we had 33 events and for the final, we needed 66 events. In October of last year, we had our 33 events. This was a study and we had it open at six different centers across the country, University of Virginia, Cleveland Clinic, UC Davis, Pittsburgh, and USC, of course, and University of Kansas.

Unfortunately, we didn't meet the futility requirements to proceed to full accrual. We found that there wasn't sufficient activity in the drug to go to full accrual and the study was closed to new accrual. We still have patients that are continuing on treatment, but no new patients. The median progression-free survival was 10.2 months for OX40 and it was 8.5 months for axitinib and placebo. This corresponded that has a ratio 0.88, and it wasn't statistically significant. Our median survival was 22.5 months and OX40 arm and 20.3 months and the placebo group. Again, not statistically significant. The objective response rate was 31% in the OX40 group and 40% in the placebo group. Duration of response was also not statistically significantly different between the two groups. So we concluded that this study should not continue to full accrual and the patients who are already on treatment will receive the treatment until progression of disease.

Pedro Burata: Thank you for that very nice summary. I appreciate that very much. And so, despite that we haven't found a clear advantage of the combination, it seems like the rationale was there and it speaks highly, speaks volumes about how important the investigator-initiated studies are for us to ask these kinds of questions in a right way, methodologically correctly way, right? So in your opinion, what's the future for that target? You think perhaps a combination with immunotherapy would make sense, not really? What are your thoughts about that?

Sarmad Sadeghi: It's a very good question. I think my co-investigators and I, we thought about why didn't we see the results we were expecting and we were hoping for. And it is unclear to me why exactly this did not work. We, of course, have a lot of correlative specimens that we are planning to process and try to understand why this failed.

You can look at another factor, whether this was a dosing question. I don't think that's the issue here. I have had conversations with Pfizer and based on what they have shared with me, I don't think dosing was an issue. The Phase I study went up to, I think, 3 milligrams per K and event 10, without having those limiting toxicities. We selected the dose of 0.3 because the data suggested that the biologic effect was maximized with that dose. So, I'm still convinced that that was the right dose and going to a higher dose probably would have changed the outcome of the study. And then there's this question of whether those stimulatory interventions with checkpoint inhibitors is as good a strategy as inhibitor interventions are and again, I don't know the answer to that question.

Pedro Burata: Thank you so much. And I appreciate how you thoughtfully walk us through the trial. Any highlights you like to make in relation or not quite related to your particular trial from we just came from ASCO '22. Is there any highlight in the advanced RCC arena that you'd like to point out for us today?

Sarmad Sadeghi: I'd like to refrain from commenting on other investigators' work. I just want to focus on this work, unfortunately, was negative, but as you pointed out, it is important to have these kinds of early studies. It's about science and investigators who are coming up with investigator-initiated studies. They're the ones taking chances, taking risks, and taking new ideas to trials, and it should continue.

Pedro Burata: I couldn't agree more. And I'm very happy that you brought the point about translational studies and correlative. So it sounds like we should stay tuned for what's going to come back out of it. We definitely need biomarkers to understand who's responding to what. Based on the outcome data that you revealed, it doesn't sound that the drugs underperform either right in that particular setting, but it sounds like you guys are going to come up with exciting data from the correlative work that you'll do to understand it'll be better if there's a role for exploring the combination of angiogenic with that particular target.

Sarmad Sadeghi: I certainly hope so.

Pedro Burata: Good. So with that, that's a go. Thank you so much for being here with us today. It's a true honor, and I hope to see you soon.

Sarmad Sadeghi: My pleasure. Thank you very much.

Pedro Burata: Thank you.