Pavlos Msaouel: Always a pleasure talking to you, Dr. Zhang.
Tian Zhang: So you're presenting what I think is a great trial and you've done so much work for renal medullary cancer. Can you talk us a little bit through the rationale for this trial, how it came to be?
Pavlos Msaouel: Yeah. So preclinically we had found that renal medical carcinoma defined always by the loss of the tumor suppressor SMARC-B1 expresses very high levels of EGFR, very, very high levels. And it appears that that has to do with the cell lineage. So other SMARC-B1 negative cancers do not express as high levels necessarily of EGFR, but renal medullary carcinoma, RMC does. And it's wild type EGFR. It's not mutant EGFR the way let's say lung cancer can have. It's more of the wild-type EGFR that head and neck cancer can have or sometimes colorectal cancer, et cetera.
But the levels of EGFR may actually be even higher than these common tumors. Almost every renal medullary carcinoma tissue is at least what we call three plus expression of wild-type EGFR. And we had found, and this is in the NCCN guidelines, that the use of the tyrosine kinase inhibitor erlotinib, that targets often is used or was used in the past for mutant EGFR, can have some efficacy against renal medullary carcinoma.
But our hypothesis was that similarly to the more common solid tumors where monoclonal antibodies tend to be more effective against wild type EGFR, cetuximab or panitumumab for head and neck cancers, et cetera. And the tyrosine kinase inhibitors are more effective for the mutant EGFR. Why? Because the tyrosine kinase inhibitors will target the constitutively active tyrosine kinase domain of the mutant EGFR, whereas the monoclonal antibodies will block the interaction between wild type EGFR and the EGF-like.
So that was our hypothesis, which panned out in our PDX and cell line derived xenograft models when we compared, let's say, the use of panitumumab versus erlotinib. These models, it was like night and day. And that we translated rapidly into the clinic and this is another novelty of the study, not by designing an actual trial that would take quite a long time. We made the discovery in May 2022 in the animal models and cell lines and we brought it to patients almost a couple of weeks later and we did it by repurposing a regimen that already existed for a rare form of EGFR wild type driven breast cancer called inflammatory breast cancer.
And the regimen uses panitumumab, the EGFR monoclonal antibody, plus Abraxane, nab-paclitaxel, That we knew from empirical experience in the past can have monotherapy activity, Abraxane, against treatment resistant RMC. So we said, "Okay, we have the regimen. Let's repurpose it and see what happens to patients." And we saw profound responses. The first patient we ever treated whom we took out of hospice responded for three years to that regimen, almost a near complete response.
Then there were others. And we shared, as you know, we shared these discoveries with all of our colleagues around the world and they started using them. It doesn't always work that profoundly. Always the first patient you ever try has the best response, but we started seeing responses. And so, what we then decided is, "Okay, let's create a prospective registry to gather the data together, analyze them as thoroughly as possible, and then have essentially a prospective study." A different way of doing a study for such a very, very rare cancer.
Tian Zhang: So I love that. The thoughtful rationale leading up to it, the proof of principle with a couple of patients. How many patients do you think you treated before you got to the prospective portion?
Pavlos Msaouel: So the prospective portion, we already had it for MD Anderson, for every patient with RMC. And so by the time, which was about four months later, that we started sharing it because we were convinced that this is working after we saw the first few patients at MD Anderson, we were convinced it's working. By the time we shared it with the rest of the world, we already were on it. We were ready to start gathering that prospective data. And that is the case with other regimens as well. This is something that's a living process that will hopefully allow us to come up with subsequent therapies.
Tian Zhang: That's great. And really taking and learning from the last patients and bringing an old regimen into a new space, those are all really great characteristics of the study. So how many patients did you treat on the study? What are the high level summary, if you can give our UroToday audience?
Pavlos Msaouel: Yeah. So in the abstract itself, and in the first study to hopefully be published, we include 26 patients because the data cutoff, because we had to do a data cutoff so that we can have radiologists and do the resist evaluation, et cetera, was about a year ago so that we can have the formal data. So this was '26, but honestly in practice, in subsequent works, we currently have more than 40 patients that we have treated with this regimen, which is huge numbers for this entity. And again, this is from all over the world. The first 26 patients are from around the United States, multiple centers, Canada and Germany, but there is now experience throughout the world in South America, multiple centers and countries in Europe, et cetera. So in the 26 patients high level with a median of two prior therapies, and I have to give some context for the audience that the best first-line therapy that we had for RMC was platinum-based chemotherapy, often carboplatin plus paclitaxel that would produce about a 29% to 30% objective response rate. This is our benchmark.
The median PFS in first-line therapy is less than four months. It's a very, very deadly disease, as you know very well. We've shared patients and you know how aggressive it is. This regimen with a median of two or three prior therapies produces a PFS of about six months, unheard of even in the first line setting, and an objective response rate between 50 to 60%, a complete response rate of about 10 to 15%. So this is very exciting. It has become the strongest therapy, the strongest regimen that we now have for renal medullary carcinoma.
And as you can imagine, a lot of folks are now saying, "Let's bring in more and more to the earlier lines." Now that it's proven it's merit in the later line setting. And these are in the upcoming 40 plus patients now that we have the experience, we're going to be exactly showing how it behaves in the first line setting, second-line setting, and later on.
Tian Zhang: Well, complete responses in renal medullary cancer is almost unheard of. So for context, will you describe the renal medullary carcinoma, those patients a little bit more for the community oncologists? What do they need to be looking out for to diagnose these and should they be thinking about sending them out to a specialty center or how do they approach treating those patients in their backyards?
Pavlos Msaouel: Exactly. I'm so glad you mentioned that because exactly to your point, renal medulla carcinoma, RMC, is very, very, very different from just about any other kidney cancer. So the anti-VEGF TKIs, for example, or other anti-VEGF therapies like bevacizumab that can work against clear cell kidney cancer and many other kidney cancers, they don't work at all against RMC. We're talking about almost 0% response rates.
The immune checkpoint therapies that, again, like nivolumab, ipilimumab, pembrolizumab that we may use for other kidney cancers in our prospective trials dedicated specifically for RMC, not only have we found evidence, clear evidence that their response rate is essentially 0%, we have some evidence that the RMC may grow even faster, hyper-progression, actual hyper-progression to immune checkpoint therapy. So it's a very, very, very different cancer that exactly, to your point, requires specialized care. Now, how would community oncologists think of RMC?
The classic patient, the typical patient that people will encounter will be young. So the vast, vast, vast majority of patients will be aged between 15 to 45 years old. It is very, very rare, although it can happen that patients will be older than 45. Usually the median age is around 25, 27 years old and they are predominantly in the US of African descent black African Americans, not because of the connection with race per se, but the connection with these otherwise benign blood disorder, the sickle cell trait. Many of them, about one third of them, don't know they have the sickle cell trait because it's otherwise asymptomatic. So people should think about RMC even if there is no history of sickle cell trait, and then they can send the electrophoresis to confirm whether there is or not. 90 plus percent of patients with RMC will end up having the sickle cell trait.
So young, mainly black, they will have the sickle cell trait if you check for it, and males, so two to one ratio, more commonly males, about 70% of cases. And amongst the kidney cancer, this is the only one that has the cleanest data that it prefers one side versus the other. So it happens in about 70% of cases in the right kidney. Why is it also so important to recognize this early? Because in addition to the systemic therapies being very, very different for this kidney cancer, as you know very well, this is the on kidney cancer where we almost never do upfront surgery. And the reason is because it's so aggressive, even if you think it's localized, it will end up not being localized. So we want to cool down the disease urgently with systemic therapies before we proceed with other considerations.
Tian Zhang: Absolutely. So really aggressive disease, involve the pathologist early and figure out what it is, send the electrophoresis, and then start them on some very active therapies. And I think your trial really improves that care for renal medullary cancer. So thank you so much for doing the study. Congratulations. Any last minute advice for the UroToday audience?
Pavlos Msaouel: Yeah. And thank you again for having me. It makes such a big difference raising awareness and I really appreciate your efforts in this. And I know that you personally as well have made a lot of work raising awareness about this disease. And as part of that, I want the audience to know that when they do encounter either a diagnosed renal medical carcinoma or something they suspect might be, get in touch. We are available 24/7, including on the weekends. They can get in touch. I can talk to them on the phone or through email and we can share our knowledge immediately on how best, what are our current best practices to manage this disease.
Tian Zhang: Fantastic. Thank you so much for joining us, Pavlos.
Pavlos Msaouel: Thank you for having me.