Select Kidney Tumors With Sarcomatoid Dedifferentiated RCC Still Challenging to Treat

Matthew T. Campbell, MD

Sarcomatoid dedifferentiation in patients with renal cell carcinoma (RCC) is associated with poor outcomes. However, response to immune checkpoint inhibitors (ICIs) have signaled hope for the patient population.

A retrospective single-institution study conducted by MD Anderson Cancer Center included information from 48 patients with RCC. Of the 48 patients, 41 had sarcomatoid dedifferentiated clear cell RCC (ccRCC) and 7 had sarcomatoid dedifferentiated non-clear cell RCC (nccRCC). Patients were assessed on treatment with ICIs to see if treatment led to improvement in overall survival progression-free survival and objective response rate. Survival outcomes were also compared in the ccRCC versus the nccRCC group using a prespecified multivariable Cox regression analysis.

The study revealed that although ICI therapy appeared to be effective in patients with sarcomatoid dedifferentiated ccRCC, treating patients with non-clear cell histology remains a challenge.

In an interview with Targeted Oncology™, Matthew T. Campbell, MD, assistant professor, Department of Genitourinary Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, discussed unmet needs for patients with RCC and sarcomatoid dedifferentiation. He also explained how to approach the treatment of patients with challenging non-clear cell tumors.

TARGETED ONCOLOGY ™: What are the key unmet needs for patients with metastatic RCC?

Campbell: There are a number of unmet needs. Currently, the most exploration has been done in clear cell kidney cancer, which is the most common kidney cancer, but we still have significant unmet needs in patients with non-clear cell kidney cancer. Far fewer trials have been done and far fewer trials are ongoing, and that's a patient population that we need to continue to focus on. We also struggle knowing optimal initial treatment for patients as well as optimal sequence for patients. And so, we still have a tremendous way to go even though we are making substantial improvements.

What disease characteristics tend to make treating these patients more challenging?

I think sites of disease and disease burden are large challenges. I'm particularly interested in bone metastasis. This is a site of disease that tends to cause a lot of pain and suffering, decreased response to treatment, oftentimes and increased risk of death. We also struggle with patients with extensive liver metastasis in brain metastasis, in addition to patients that are refractory to initial systemic treatment.

What do survival outcomes look like for patients with metastatic RCC and sarcomatoid de-differentiation?

I think that is evolving. These patients used to have the very worst prognosis of patients diagnosed with just about any histology. Clear cell with sarcomatoid did worse than the patients just with clear cell. Same with their counterparts with papillary sarcomatoid chromophobe sarcomatoid. They were, in a sense, more resistant to targeted therapy. However, we are seeing tremendous benefit with immunotherapy, and I would say that is the number one predictive biomarker of response to immune checkpoint therapy is the presence of sarcomatoid. So, my partner in his arch near at MD Anderson Cancer Center has presented data with how patients with sarcomatoid did with nivolumab and ipilimumab from the CheckMate 214 study. It was a subgroup, but the patients did extremely well. And the response rate of approximately 60% complete response rate pushing 20% was quite impressive. And we are seeing those patients with sarcomatoid features are living longer may not be reaching the same bar that the rest of the clear cell population but significantly improving.

What was the purpose of your analysis around outcomes of immune checkpoint therapy in patients with metastatic RCC and sarcomatoid de-differentiation?

The purpose of the analysis is always exploring how different subgroups do with different therapy at MD Anderson. We found again that there was substantial response, the median overall survival in our series was at 30 months, which is better than patients have historically done. We included patients that had non-clear cell RCC as part of that exploration which likely tamped down the numbers to some degree. But of interest, we are seeing patients benefit with papillary with sarcomatoid, and also chromophobe wth sarcomatoid, which we were worried early on may not be a group of patients that would respond to almost any type of systemic treatment.

Can you provide an overview of the results from this analysis published in Neurologic Oncology?

As I mentioned, the response rate for all patients that received immunotherapy with sarcomatoid differentiation was around 35%. The chance of benefit for most patients was much higher with fewer patients having progressive diseases best response, again, progression-free survival somewhere around 9 to 10 months and overall survival right around 30 months. It’s single institution experience but I think again, adds value from the fact that we are seeing more and more patients with sarcomatoid dedifferentiation with improved outcomes in this new era of immunotherapy.

What are the implications of these findings?

I think when I see patients in my clinic that have sarcomatoid dedifferentiation with metastatic disease, my preference is to use nivolumab and ipilimumab as initial therapy. I do this because I, again think that these patients are more likely to respond to immunotherapy and tend to be more resistant to targeted therapy. I think these are patients that the risk of potential toxicity with new nivolumab and ipilimumab is well warranted given the potential response and benefit.

_Reference:

_{Chahoud J, Msaouel P, Ross JA, et al. Outcomes of patients with metastatic renal cell carcinoma with sarcomatoid dedifferentiation to immune checkpoint inhibitors. Urol Oncol. 2021;39(2): 134.e9-134.e16. doi:10.1016/j.urolonc.2020.10.019}