PD-1 and PD-L1 May Be Actionable Targets in Sarcomatoid Renal Cell Carcinoma

Renal cell carcinoma with sarcomatoid differentiation, a histology that is often resistant to targeted therapies and interleukin-2 immunotherapy (IL-2), may respond to anti–PD-1/PD-L1 therapies.

Thai H. Ho, MD, PhD

Renal cell carcinoma (RCC) with sarcomatoid differentiation, a histology that is often resistant to targeted therapies and interleukin-2 immunotherapy (IL-2), may respond to anti—PD-1/PD-L1 therapies, according to a new study published in Cancer Immunology Research.

The study directly compared two PD-L1 antibodies and found concordance of PD-L1 positivity in 89% tested in RCC with sarcomatoid differentiation. Coexpression of PD-L1 on neoplastic cells and the presence of PD-1—positive tumor-infiltrating lymphocytes was identified in 50% (13/26) of RCCs with sarcomatoid differentiation, while 3% of clear cell RCCs (1/29) had concurrent expression of PD-1 and PD-L1 (P = .002). Only 1 of 29 clear cell RCCs (3%) had concurrent expression of PD-1 and PD-L1 (P = .002).

While no PD-1 or PD-L1 agents are approved in RCC, nivolumab (Opdivo) recently received an FDA breakthrough therapy designation for the patient population. Anti—PD-1/PD-L1 agents approved in other settings can also be used under compassionate use for patients with RCC.

OncLive: How common is sarcomatoid RCC?

What role does PD-1 and PD-L1 play in sarcomatoid RCC?

Due to historical poor response, patients with sarcomatoid differentiation are often excluded from metastatic RCC clinical trials. A lack of understanding of best treatments, and the histology’s resistance to most standard RCC therapies, results in an average overall survival rate of <1 year in patients with sarcomatoid RCC, said study author Thai H. Ho, MD, PhD, assistant professor of Medicine, at Mayo Clinic. OncLive spoke with Ho to learn more about what impact these findings could have on the treatment of RCC with sarcomatoid differentiation. Dr Ho: Generally, it can arise in 5% to 15% of all kidney cancers. Most academic centers define it by the percentage of sarcomatoid differentiation. If a patient has more than 20% sarcomatoid differentiation, it will drive the prognosis of the patient. Now, when the sarcomatoid element is identified, oncologists have the opportunity to use these immunotherapies to treat a disease that is otherwise refractory to other treatments. Essentially, sarcomatoid differentiation occurs because the cells become more aggressive than the traditional epithelial component. This is usually associated with a much worse prognosis in patients, and it is generally associated with intransigence resistance to many of the drugs that are already approved for kidney cancer, including IL-2 immunotherapy, VEGF inhibitors, and mTOR inhibitors.

How does this study change the understanding of sarcomatoid kidney cancer?

What are the next steps in this research?

What kind of impact could this research have?

In this study, we took advantage of some of the new PD-L1 panels to stain for PD-L1 overexpression. Essentially, PD-L1 expression on the tumor acts as a “don’t-eat-me signal.” Basically, it tells the immune system to go away, allowing the tumor to escape the immune system. We compared two different PD-L1 antibodies and found that, in the sarcomatoid samples, they were overexpressed. This suggests that there may be benefit to targeting the PD-1 axis, which is the drug target already used in melanoma and lung cancer. To further support that, we had a patient with sarcomatoid differentiation kidney cancer who had already failed traditional chemotherapies and VEGF-directed therapies, and he actually showed a response in a lesion that was PD-L1 positive. Prior to this study, the traditional belief was that because these tumors were resistant to IL-2 immunotherapy, they were resistant to all immunotherapies. This study suggests that the PD-1 and PD-L1 axis is active in this particular type of cancer. The next step is to essentially do this in a clinical trial. Roche has allowed patients with this type of histology to enter their clinical trials. In the past, a lot of clinical trials would exclude sarcomatoid histology because it suggests such a poor prognosis. Researchers did not want those patients on the trial because it would skew the results. However, today, there are several clinical trials that have included the sarcomatoid histology. We could go back now and look specifically at the sarcomatoid patients and see how they performed. Eventually, the goal would be to do a trial with just sarcomatoid patients. These immunologic agents have not been tested in solely sarcomatoid patients to date. It would significantly increase the overall survival of patients with sarcomatoid kidney cancer. Currently, these patients live, on average, under 1 year. If you examine conventional clear cell kidney cancer, the average overall survival is anywhere from 2 to 3 years. If a patient has sarcomatoid histology of more than 20%, their prognosis is very poor to begin with.

What are the biggest challenges in understanding and treating sarcomatoid kidney cancer?

This gives oncologists another option to treat these patients. PD-1 and PD-L1 agents are not currently FDA approved for kidney cancer, but they are undergoing review. However, you can receive this drug on compassionate care so if an oncologist was interested in using it, they could apply for that. The hardest part has been that we have been going after sequencing, we have looked at RNA expression, and, to date, we have not really found many pathways we can target. This is the only study that found a pathway that we can act on. The current standard of care is cytotoxic chemotherapy or VEGF inhibitors upfront. Unfortunately, several reports have come out showing that if a patient has >20% sarcomatoid histology, it predicts for resistance against traditional therapy.

Joseph RW, Millis SZ, Carballido EM, et al. PD-1 and PD-L1 expression in renal cell carcinoma with sarcomatoid differentiation [published online August 25, 2015]. Cancer Immunol Res. pii: canimm.0150.2015.