Moving the Needle in Renal Medullary Carcinoma and Other Non-clear Cell Renal Cell Carcinomas

In an interview with GU Oncology Now, Pavlos Msaouel, MD, PhD, a clinician in the Department of Genitourinary Medical Oncology at The University of Texas MD Anderson Cancer Center, provides an overview of the molecular characteristics of non-clear cell renal cell carcinoma (nccRCC), with a particular focus on renal medullary carcinoma (RMC) and current treatment options that are improving survival for patients with this aggressive renal cell carcinoma (RCC) subtype.

Can you define nccRCC? What are the molecular characteristics of this diagnosis?

Dr. Msaouel: nccRCC encompasses all RCC subtypes that are not clear cell RCC, which is the most common kidney cancer in adults and comprises approximately 75% of all RCC cases. The name “clear cell” denotes how the cancer cells look under the microscope; they have a distinctively pale cytoplasm due to the lipid droplets and glycogen inside of them. Clear cell RCC is also characterized by certain molecular features, the key feature being they usually have mutations that inactivate the VHL gene.

The other 25% of RCC cases are deemed “non-clear cell RCC” or “variant histology RCC.” These are basket terms that include more than 20 different subtypes, each of which has different biology, is driven by different pathways, and requires different management. It is absolutely critical that patients know exactly what type of kidney cancer they have. In some cases, the therapies that we give for clear cell kidney cancer do not work at all against some non-clear cell subtypes; in fact, some of these therapies may even feed the disease. Conversely, the therapies that work against some non-clear cell subtypes may not work at all against clear cell RCC.

While we use “non-clear cell” as a basket term for convenience purposes, it is crucial that we think in a much more granular manner.

What are some of the most notable nccRCC molecular subtypes, and how are they characterized?

Dr. Msaouel: A notable subtype that is close to home for me is RMC, which is the focus of both my lab and my clinical trial research. It is one of the rarer types of nccRCC, yet it is the deadliest of all kidney cancer types. It predominantly afflicts young individuals who have the sickle cell trait. There are 3 million people who have the sickle cell trait in the United States, and the vast majority of those who do are African Americans. All are at risk for developing this rare but aggressive cancer. If RMC is not treated quickly and effectively, patients will succumb to the disease within 3 to 4 months of diagnosis.

We have the largest global referral center for RMC and regularly see at least 3 to 5 patients with RMC per week. I’m contacted regularly by offices in the United States and all over the world about these cases. I often advise on patient cases in Canada, South America, South Africa, Europe, Australia, and New Zealand.

It is important to highlight that the therapies used for clear cell RCC or for some of the other non-clear cell variants are completely ineffective for RMC. Generally speaking, the management of RMC is very different. That is why it is so important to make every effort to accurately diagnose RMC. Raising awareness of this cancer is one of the efforts we have been spearheading. We used to believe that RMC was rarer than other nccRCCs like collecting duct carcinoma, but we know now that RMC is at least 10 times more frequent than collecting duct carcinoma. By raising awareness, we get more accurate diagnoses and a better understanding of the true incidence of RMC in the population.

The most common nccRCC—far more common than RMC—is papillary RCC, which does tend to respond modestly to the therapies developed for clear cell RCC. Papillary RCC comprises 10% to 20% of kidney cancer cases. Chromophobe RCC is another nccRCC subtype, and it comprises close to 5% of all RCC cases. It is typically less aggressive than either papillary or clear cell RCC. However, when chromophobe RCC does spread to other organs, it tends to be resistant to many of the therapies developed for clear cell RCC. This fact again highlights the need to develop therapeutic strategies tailored to each nccRCC subtype.

What are some of the management strategies or available therapy options for patients with RMC? Can you summarize the data that support their use?

Dr. Msaouel: In contrast with other kidney cancers, RMC is almost always metastatic. Even when we initially believe it is at stage 3, if we wait for a few weeks, it will become evident that it is stage 4. For this reason, in the vast majority of cases, we do not start treatment by surgically removing the kidney tumor. Instead, to maximize the odds of curing these patients, we treat first with platinum-based cytotoxic chemotherapy. This type of chemotherapy can be effective in RMC but is not effective for clear cell RCC or many other nccRCC subtypes.

If the patient responds, then the chances of a cure increase drastically. We used to view a diagnosis of RMC as a death sentence, and it is important to note that it is still a highly aggressive cancer, but through our efforts over the past 10 years, we are now able to render up to 10% of patients with stage 4 RMC disease-free. Ten percent is still not a high number; we need to do much more, especially since many patients with RMC are so young. We aim to make further headway with our ongoing research.

Are there any ongoing efforts to look at long-term survival data with this treatment approach? What are some of the clinical trials you are running in RMC?

Dr. Msaouel: Our group is extracting and comparing current and previous long-term survival data as we speak. Based on our multicenter data from 2017, the median survival for patients with RMC after receiving optimal therapy available at that time was about 13 months. This means that approximately half of patients with RMC would not survive a year after their diagnosis. Nowadays, I’d venture to guess that the majority of patients with RMC who are treated immediately after diagnosis with the strategies we have developed survive for at least a year. We’re trying to see if the data support this assertion.

For RMC, we have successfully created a diverse portfolio of mouse models that recapitulate what we believe is the biology of the disease. We have also done a lot of research on analyzing tissues and blood samples from patients with RMC, and we are grateful to them for offering these samples to help future patients with RMC. It is a truly honorable legacy; because these patients donated their tissue, patients nowadays live much longer. Some are even cured.

I’m the principal investigator of the first and only trials to date designed and conducted specifically for RMC. We completed enrollment for the first 2 clinical trials (NCT03274258 and NCT03587662), and we opened the third one (NCT05347212) in September 2022. Due to funding constraints, these trials are open only at our center, but we have shown that we are quite capable of enrolling in high numbers and efficiently moving our knowledge forward for this disease. Investigator-initiated clinical trials dedicated to specific nccRCC subtypes such as RMC need to be championed by teams of people committed to those diseases. These trials are feasible and should be supported.

We plan to open our fourth clinical trial for RMC by 2024. A lot of stakeholders, including patient advocates across other non-clear cell subtypes, are noticing the efficient framework that we have utilized to achieve these numbers. As a result, there is a growing push to run similarly dedicated clinical trials for other subtypes and test therapy concepts developed specifically for each subtype.

This is the future. We should not just design basket trials enrolling patients with “nccRCC,” which end up enrolling 1 or 2 patients with RMC. We learn much more if, instead, we design and conduct trials dedicated to specific nccRCC subtypes. It is an exciting time for this field.