Sarcomatoid Renal Cell Carcinoma: From Limited Options to a 'Game Changer'

CURE, Kidney Cancer Special Issue 2022,

FDA-approved immunotherapies offer patients with metastatic or recurrent sarcomatoid RCC more treatment choices and improved outcomes.

Advancements in the treatment of sarcomatoid renal cell carcinoma (RCC) have given patients more options, particularly those with metastatic or recurrent disease whose options were limited.

Approximately 10% of patients with RCC have a form of the disease with sarcomatoid features, such as cells shaped like ovals or spindles, said Dr. Mohit Gupta, a urologic oncologist and the director of clinical research for the department of urology at MedStar Georgetown University Hospital in Washington, D.C.

“Essentially (sarcomatoid cells look different) under the microscope,” Gupta explained. “What that means for the patient is that (it) is actually an aggressive type of cancer. ... Patients who have these types of features often present at very advanced stages or with what’s called metastatic disease, basically cancer that has spread to other parts of the body outside the kidney itself.”

Gupta noted that approximately 15% of patients who first present to a urologist with sarcomatoid RCC are diagnosed with stage 4 cancer. He emphasized the importance of reporting symptoms to oncologists, especially upon diagnosis of RCC, because bone pain and changes in mental status may indicate that the disease has spread to other areas of the body, most commonly the lungs, liver, bone or brain.

Improved Outcomes With Immunotherapy

If RCC has not spread, surgeons should aim to remove the cancer either with a partial nephrectomy (removal of part of a kidney) or a bilateral nephrectomy (removal of both kidneys).

“The most important thing, just like for any kidney cancer, is that 100% of the tumor is removed and that when the pathology doctors look under the microscope, they have something called nega- tive margins, which means 100% of the cancer was removed,” Gupta said.

If the pathology report indicates that the RCC has sarcomatoid features, the patient may be treated with immunotherapy. Keytruda (pembrolizumab) was approved by the Food and Drug Administration (FDA) in November 2021 for the treatment of patients with RCC, including patients with sarcomatoid RCC.

In the KEYNOTE-564 clinical trial that supported this FDA approval, patients with RCC, including those with RCC with sarcomatoid features, underwent nephrectomy and received once-weekly treatment with Keytruda every three weeks for one year. Treatment reduced the risk for disease recurrence by nearly 30%.

“What was most interesting was that for the patients who had sarcomatoid features on their pathology, this medication did even better,” Gupta said. “It actually helped those patients even more compared (with) patients who didn’t have sarcomatoid features. So there is luckily a treatment option in case a patient goes through surgery and they have this on their final pathology.”

Gupta noted that before this FDA approval, there wasn’t much in terms of treatment for patients with sarcomatoid RCC.

“We just prayed and hoped that the cancer didn’t come back,” he said. “There wasn’t much that we could do. And the problem was when (the cancer) did come back, we also had very limited options.”

Patients with metastatic sarcomatoid RCC or those with recurrent disease now have more treatment options thanks to immunotherapy. Metastatic or recurrent sarcomatoid RCC was previously treated with chemotherapies and vascular endothelial growth factor tyrosine kinase inhibitors (VEGF-TKIs), but these treatments had minimal effect on disease with sarcomatoid features. Now, however, patients with sarcomatoid RCC often respond well to the immunotherapy combination of Yervoy (ipilimumab) and Opdivo (nivolumab). Compared with VEGF-TKIs, Opdivo plus Yervoy significantly improves overall survival and progression-free survival in patients with sarcomatoid RCC.

“What we have found is that this immunotherapy works extremely well for these types of patients,” Gupta said. “That has really been a game changer for us, both for patients with metastatic cancer upfront and for patients whose cancer has come back.”

Addressing Unmet Needs

Even with all the progress made in treating patients with sarcomatoid RCC, not everyone responds to the current immunotherapy options, so more research is needed to find treatments to help these patients.

More research is also needed to determine how to best manage patients with metastatic disease. Gupta mentioned that before immunotherapy, patients with metastatic sarcomatoid RCC were treated with cytoreductive nephrectomy, which is a surgery to remove as many cancer cells as possible and may include surrounding organs.

Now researchers are wondering whether it might be beneficial to administer immunotherapy before potential surgery.

“For patients who have that sarcomatoid-type kidney cancer, because the immunotherapy works so well, what we’re doing now is giving them immunotherapy upfront because what we’re seeing is that if we operate on them first, oftentimes the cancer comes right back or it grows even faster while the patient is recovering from surgery,” Gupta said. “Instead of doing that, we are basically giving ... immunotherapy upfront for the patients that respond and are still healthy. And basically, all their other sites of disease shrink to just the kidney mass itself, (and then we) operate on them. But if (they don’t respond to therapy) or the cancer continues to grow, then we also spared patients from an unnecessary surgery.”


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