Pavlos Msaouel, MD, PhD – Leading the Way in Renal Medullary Carcinoma

Pavlos Msaouel, MD, PhD, is a clinician and cancer biologist in the departments of genitourinary medical oncology and translational molecular pathology at The University of Texas MD Anderson Cancer Center. He specializes in kidney cancers and is currently considered a top expert in treating renal medullary carcinoma (RMC)—an aggressive non-clear cell renal cell carcinoma (nccRCC) subtype.

GU Oncology Now spoke with Dr. Msaouel about his journey to becoming a world expert in this area, some of the landmark clinical trial work he has led to improve outcomes for patients with RMC, and the work he is involved with at the RMC Alliance.

Tell us about yourself. Why did you become a genitourinary medical oncologist? What was your inspiration to practice urologic oncology generally and to specialize in kidney cancers?

Dr. Msaouel: When I was a teenager, I was not interested in being a clinician. I wanted to be a biologist and was interested purely in the lab. I was living in Greece, and my mother advised me to go to medical school before deciding to be a lab-based scientist or work in some sort of hybrid role. Her rationale was that medical school would keep my options open. It was good advice, as I found out during my first clinical rotations in medical school that I actually enjoyed interacting with patients quite a bit. It was my first revelation that I wanted to be a clinician.

However, I still loved the lab, and so as soon as I finished my MD degree, I signed up for a PhD degree with the intention of following my interest in physiology and becoming an endocrinologist. As it happened, my PhD was focused on endocrine-related tumors, neoplasms such as fibroids, and then prostate cancer. While I was working toward my PhD in Greece in 2007, I went on a sabbatical that was supposed to last for a year, but it ended up lasting for a little bit more than 2 years, at the Mayo Clinic under Dr. Evanthia Galanis, an oncologist and physician-scientist herself, to research endocrine-related neoplasms like prostate cancer.

When I first started working with Dr. Galanis, she asked me what I wanted to be when I grew up. I said, “I want to be an endocrinologist,” to which she replied, “Oh no, you’re going to be an oncologist.” At the time, this declaration fell on deaf ears because the way I saw it, oncology was a depressing field where you lose so many patients you grow attached to. But over time, the more I looked at things from an oncology angle—the research, the excitement, the interesting developments across genitourinary malignancies—I started to see things differently. Instead of focusing on how many patients are lost, I became enamored with the very meaningful interactions and relationships built with the patients during our time together. No longer did I have such a depressing viewpoint of the field. Dr. Galanis was right, and in the end, it was a straightforward choice to become an oncologist.

I went back to Greece to finish my PhD, and then I returned to the United States in 2011, this time to the Bronx for my internal medicine residency, where I served as chief resident. I subsequently moved to Houston in 2015 to do my oncology fellowship at MD Anderson. The fellowship was a 3-year program, and in my third year I served as chief fellow of the MD Anderson program. Once I graduated, I stayed on as faculty in the genitourinary department and ultimately became an assistant professor and physician-scientist. I have become enthralled with kidney cancer, especially rare subtypes like RMC, and I operate a lab dedicated to these research and clinical trial interests.

You are highly regarded as a leading world expert in RMC. How did this happen? How did you become so interested in this rare non-clear cell kidney cancer?

Dr. Msaouel: While in the Bronx, I spent a lot of time around the population of people most susceptible to RMC—young individuals of African descent who have the sickle cell trait. But it was the countless hours spent with my mentor at MD Anderson, Dr. Nizar Tannir, who is a kidney cancer expert. Dr. Tannir genuinely infected me with his enthusiasm about RMC.

RMC had been invisible for so long, and it is a very deadly kidney cancer, one of the deadliest of kidney cancers. If left untreated, it can take your life within 2 or 3 months. Dr. Tannir was heartbroken to see these patients lose their lives at such a young age.

Once you start spending time with that population, it is hard not to become involved. You see all of the pain that this cruel disease inflicts upon patients and their families, and that motivates you to try and make a difference. In my case, I was struck with a moral imperative to utilize the resources and my position at MD Anderson to make a difference in this disease.

It is not as evident now, but at the time, there was a notion that this could have been a career suicide for a young faculty member like me going into a cancer that was not studied; there was no comprehensive molecular analysis, certainly no clinical trials, and very little understanding of the disease, not to mention it is very rare.

Nonetheless, I stuck with it, and over time, by raising awareness among physicians and in the general community, we learned that RMC is at least 10 times more common than we had thought in 2016 or 2017. By developing consensus guidelines on the diagnosis and management of RMC, clinicians now had guidance to accurately diagnose this disease. Furthermore, we harnessed the power of social media to make the world aware of the existence of RMC and its impact on actual people afflicted by this disease.

We are at a point where we have created a team of people here in Houston and around the world who are passionate about RMC and are significantly impacting the lives of patients with the disease. A key goal was to develop model systems as well as well-defined testable hypotheses that allow us to investigate the biological mechanisms driving RMC. In the past year alone, we have had patients, advocates, and researchers from other rare kidney cancers come to us and ask, “Okay, how were you able to build dedicated clinical trials and accelerate research and interest in RMC so fast? Was it a coincidence?” It was not a coincidence, especially when you start with something so difficult. You have to have a very structured approach. This kind of framework flips the narrative that progress is possible only for common diseases and can actually be used to make a difference, not just for RMC but for other rare kidney tumors.

Can you describe the clinical trial work you have led or been involved in that has had the most impact for patients with RMC?

Dr. Msaouel: In 2017, we were very proud to open the first clinical trial ever dedicated exclusively to RMC. At the time, many thought it was not possible to do a clinical trial in such a rare and specific kidney cancer. The dominant philosophy was that you can do a broad clinical trial that assesses a therapy in many different types of rare kidney cancers without distinguishing type from type. Such a trial might enroll 1 or 2 patients with RMC. But what can possibly be learned about RMC this way, or in any other rare disease type for that matter? Therefore, our trial in RMC represented a huge paradigm shift; we showed that not only can we open an investigator-initiated clinical trial in a specific rare kidney cancer subtype, but also successfully conduct and complete it at a single institution, under a reasonable budget, and with resource use tailored to maximize the amount of knowledge gained.

The trial took an immunotherapy approach of evaluating the efficacy of nivolumab plus ipilimumab, which was beginning to be used and approved across different histologies. We only enrolled 10 patients, and we had to stop the trial early because we were not seeing the efficacy for which we had hoped. Nonetheless, to this day, I receive messages from oncologists around the world, thanking me for the knowledge that was gained from this study; it prevents them from unnecessarily exposing their patients with RMC to these potentially toxic therapies. Instead, they can now prioritize the therapies that work. In addition, the tissue and blood samples collected from this trial are teaching us how to one day find a way to harness the immune system against RMC.

A year later, we opened our second clinical trial of standard RMC chemotherapy in combination with the proteasome inhibitor ixazomib. We carefully reviewed the efficacy data from this trial for evidence of futility with every 10 patients enrolled. These prespecified futility criteria were not met, and the trial enrolled its maximum sample of 30 patients with RMC. Despite the COVID-19 pandemic delaying this trial by more than 9 months, we completed the study last year, within the expected timeline. This experience again showed that dedicated trials for RMC are feasible and can make a difference for our patients.

Currently, we have a third clinical trial involving immunotherapy in RMC, and we’re working toward a fourth and a fifth one. Along with the efficacy results leading to significant improvement in patient outcomes, we have also demonstrated a path for similar studies to be conducted in other rare histologies, which is absolutely crucial to making progress for those patients as well.

One of your other responsibilities is being secretary of the RMC Alliance. Can you tell us about the Alliance, its goals, and your responsibilities on the board of directors?

Dr. Msaouel: The RMC Alliance is a nonprofit organization that brings together expert clinicians, researchers, and patient advocates to better understand how and why RMC occurs and to develop better strategies to screen, diagnose, and treat this deadly cancer. The Alliance has been tremendously helpful in both raising awareness and harmonizing our approach to how we manage these patients. Through the Alliance, we have established practical standards and created specific recommendations on how to tailor our approaches to this disease. RMC is managed very differently than most other kidney cancers, so having an international group of experts come together and provide consensus recommendations makes a significant difference in the management of this disease. The recommendations not only help with disease management, but also with accurate diagnosis. In years past, many people died of RMC without ever knowing they had the disease.

My responsibilities within the Alliance include updating the website with the latest scientific and clinical data. It is a good problem to have that we are generating data so fast that we cannot get them through peer review quickly enough. We very often know things about RMC even a year before we can get it published. So, we try a little bit with the RMC Alliance to stay ahead of the curve. Obviously, we want peer review; it is an especially important part of the academic process. However, we also want to make sure that clinicians and researchers all across the world have a good sense of where the RMC field is currently and where it is heading.

As you work to improve treatments and outcomes for these patients, how do you see the field evolving in the next 5 to 10 years?

Dr. Msaouel: The number one goal remains to improve the outcomes of patients with RMC. It is still a deadly cancer, but we have been able to render disease-free, essentially cure, up to 10% of patients, most of whom have metastatic disease. In years past, cure rates of up to 10% in metastatic RMC were thought to be completely impossible, particularly in patients whose disease has become resistant to platinum-based chemotherapy. Yet there are patients who have now achieved this goal using therapeutic strategies we have developed for RMC in the second- and third-line settings.

In 1995, when RMC was first described in medical literature, the average survival range was 3 to 4 months from diagnosis. Even in 2000 and 2010, the therapies that were available only translated to an average survival close to 7 months. In 2017, our analysis of RMC median survival in patients receiving the best available therapies at the time—both within MD Anderson and at other institutions—showed only 13 months. In other words, about half of patients would not survive for 13 months after diagnosis. Our upcoming analyses of our outcomes from 2020 to today suggest that the median survival trend continues to gradually improve.

But cure rates of up to 10% are still not enough. We continuously strive to get to 100%, and we need to have specific goals set to keep us on track. We know very well how challenging RMC is. There is no silver bullet, at least currently, that will cure the disease entirely across all patients. However, given the pace we are at, I believe we can increase that median survival to 5 years by 2030, and I am optimistic that we can essentially eradicate the disease by 2040.

Read our previous interview with Dr. Msaouel on molecular characteristics and management strategies of RMC.