Deciphering Immunotherapy Responses in Advanced RCC: A Deep Dive into the HCRN Study - Nourhan El Ahmar

June 15, 2023

Pedro Barata interviews Nourhan El Ahmar to discuss the significant work conducted by El Ahmar's team. The work focused on a subgroup analysis of the HCRN GU16-260 platform study that investigated the use of nivolumab with ipilimumab as salvage therapy for patients with advanced renal cell carcinoma. El Ahmar delves into the specifics of the trial, explaining how their lab played a crucial role in examining biomarkers of response to immunotherapy, using methodology applied in previous trials. The team's research hinged on analyzing tumor tissue samples from patients, with a particular emphasis on pre-treatment samples. Findings demonstrated that patients exhibiting high density of the IF biomarker and positive PD-L1 expression on tumor cells presented the most favorable outcomes.


Nourhan El Ahmar, MD, Postdoctoral Research Fellow, Brigham and Women’s Hospital, Boston, MA

Pedro C. Barata, MD, MSc, Leader of the Clinical GU Medical Oncology Research Program, University Hospitals Seidman Cancer Center, Associate Professor of Medicine, Case Western University, Cleveland, OH

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Pedro Barata: Hi, I'm Pedro Barata. I'm a GU Oncologist at University Hospital Seidman Cancer Center at Case Western University in Cleveland, Ohio. I'm very, very happy to be joined today by Dr. El Ahmar from the Brigham Hospital, particularly the Pathology Department of Dr. Signoretti. Really well known in the kidney cancer fields, particularly. Welcome. Thank you for joining us today.

Nourhan El Ahmar: Thank you so much for having me.

Pedro Barata: Absolutely. We're here today to chat a little bit about great work that you guys presented at this last ASCO in Chicago. Very, very important work that comes out of an irrelevant trial conducted in the context of a cooperative group study, HCRN platform, that investigated nivolumab with ipilimumab as salvage for patients with advanced renal cell carcinoma. And based off that trial, you actually were able to conduct a subgroup analysis looking specifically for biomarkers and see how much we can learn from that and how we can take it and maybe apply it to other therapies and maybe other settings. So I'm looking forward to these conversations. First, congratulations for the work.

Nourhan El Ahmar: Thank you.

Pedro Barata: Really well done and it's always one of the most important platforms for us to get our work to be presented. Do you mind just remind us really brief for the audience who might be less familiar with this trial, can you just tell us what basically we did with that trial?

Nourhan El Ahmar: Yes. The HCRN GU16-260 trial, it's a prospective clinical trial that basically had patients with advanced renal cell carcinoma that were treatment-naive and basically gave them first-line anti PD-1, particularly nivolumab. And then patients who did not respond, responses were salvaged by ipilimumab as treatment. Dr. Atkins and his team, they concluded that, actually, patients who have advanced renal cell carcinoma and the treatment naive can actually have a good response and an active treatment for clear cell renal cell carcinoma.

Pedro Barata: Thank you for that. That's very helpful for some of us who are less familiar with the study. So thank you for reminding us of the design. Your lab actually is playing an important role investigating biomarkers of response to immunotherapy. You guys have been doing that in other trials, including CheckMate 025 to actually get the approval of nivolumab in the second line advanced RCC of several years ago. And to my understanding, you're kind of using some of the similar methodology and applying it to this HCRN study. So you got samples, the lab got samples from patients enrolled in this trial. Can you tell us a little bit about what were those samples' baseline, different time points, primary tumor metastatic sites, and what actually did you have to do with them?

Nourhan El Ahmar:
Yes. What we received from the HCRN GU16-260 trial was tumor tissue samples from the patients, and they were divided into three groups. First we got the pre-treatment samples and then we got the metastatic and then also we get the progression. Now in our study today, what we are presenting, we mainly focused on the pre-treatment samples.

Now, to talk about what our lab did and how we integrated the HCRN into our work. As you know, not all patients benefit from the nivolumab or anti-PD-1 treatment, and more clinically relevant biomarkers are required. Dr. Signoretti's lab has focused on finding predictive biomarkers of response and resistance to immune checkpoint inhibitors in general, and anti-PD-1 in specific. We have demonstrated before that high levels or high density of the CD8-positive tumor infiltrating lymphocytes that express the target of the treatment, which is, in our case, PD-1, but does not express other immune checkpoint markers such as TIM-3 and LAG-3 in this case. This is something that we named the IF biomarker. It's actually associated with improved clinical outcomes in patients that have metastatic RCC and failed the previous treatment. We did this in two independent clinical trial cohorts that are the CheckMate 010 and the CheckMate 025.

In addition to that, we combined the PD-L1 expression on tumor cells with this IF biomarker, and we had great results, in terms that patients that have high density of this IF biomarker and have positive PD-L1 expression on tumor cells had the most favorable outcomes. Our aim today in this study in HCRN is to validate these results, however, in treatment-naive patients who took first-line anti-PD-1 therapy.

Pedro Barata: Great. That's awesome you guys, you have done a great job validating that score that comes out of the lab, and it is my understanding, as you said, that you apply it to this study. Can you summarize what the findings of your analysis of applying the score to this trial court were that you presented at ASCO?

Nourhan El Ahmar: Yes. After correlating our results with the clinical outcomes, we were able to prove that patients that have higher density of this, what we call the IF biomarker, had better objective response rate and longer progression-free survival,

Pedro Barata: On nivolumab monotherapy.

Nourhan El Ahmar: On nivolumab monotherapy, exactly. In addition to that, when we combined the other biomarker, which is the PD-L1 expression on tumor cells, those patients that had high or high positive had the most vulnerable clinical outcomes. This validated our previous findings and had value of this biomarker.

Pedro Barata: That's so interesting in my opinion, because for a very long time, and I think we settled on that. We know that PD-L1 expression is not a good biomarker. Why? Because it doesn't have the ability to select the good actors or to predict good responses because we do miss responders among patients without any PD-L1. And you having PD-L1-positive cancer doesn't mean you will respond to immunotherapy.

Nourhan El Ahmar: Exactly.

Pedro Barata: But it sounds, based on the findings of your work, that when you combine it with the validated methodology that you used previously and you confirm in this study, it seems like the predictive value of them together is stronger than what we've seen thus far. Is that a fair summary?

Nourhan El Ahmar: This is exactly, you said it perfectly.

Pedro Barata: Okay. With that in mind, my question to you is some patients in the community are not getting ipilimumab-nivolumab combination. Some, or a lot of patients, are actually getting an immune therapy combined with a target therapy. So they don't get a CTLA-4 with a PD-1, they get a PD-1 with a TKI, anti VEGF, like Axi-Pembro or Cabo-Nivo or Lenv-Pembro. Can you tell us a little bit about what are your thoughts, whether or not it's possible that these results might seem or go in line with what we've seen in Ipi-Nivo if we were to apply the same methodology to patients treated with an IO-TKI? Is that something you guys are currently exploring? Is that something you have planned for the future? What can you tell us about that?

Nourhan El Ahmar: As you said, currently there's no approved biomarker for response to anti-PD-1, and it's very challenging to find a promising biomarker because we need to reproduce the results in many independent clinical trials. And as you said, our IF biomarker was proven or confirmed its value in three different independent clinical trials, however, in anti-PD-1 as a monotherapy.

So our next challenge and goal is to try to prove the usefulness of this biomarker in combination therapy that are approved for metastatic RCC, which is, as you said, IO plus IO or IO plus VEGF. It is very challenging, however, our lab is committing to try to find a solution to see how this biomarker is useful in this setting. It is challenging, however, we're working on it. I would like also to say that we are looking into other immune cell population in the tumor microenvironment and their spatial interaction in predicting clinical outcomes as well.

Pedro Barata: Right. No, that's amazing and thank you for that. By the way, I think it's only fair that to I bring it up that you let these work at the lab, but you actually have a team working with you, Dr. Mattel and others who are actually co-authors in this study. So, actually, kudos to all the entire team, of course led by your great mentor. But I think it's relevant to highlight that. Correct me if I'm wrong, but I do believe that it takes almost a village in the lab, if that's possible to say, to be able to process those samples and do those scores and actually put that data together. So great work from your team and to Brigham because that's really, really, really helpful and I'm looking forward to the manuscript.

Nourhan El Ahmar: Thank you.

Pedro Barata: Thank you. Thank you for taking the time to explain us and break down your study with us today.

Nourhan El Ahmar: Thank you so much for having me.

Pedro Barata: Thank you.