When deciding on the best course of treatment for patients with metastatic renal cell carcinoma (mRCC), it’s difficult for oncologists to know which patients might respond to immunotherapy and who might not. A new study points to a combination of 2 potential biomarkers that may serve this purpose,1 but more research is needed to see if the findings could be applied in practice.

Researchers have previously investigated programmed death ligand-1 (PD-L1) as a potential predictive biomarker for immunotherapy, with mixed results.2 In renal cell carcinoma, it did not turn out to be an effective predictor of response.3 However, in the new study, pairing it with another measure — tumor cell proliferative status — yielded much more promising outcomes.

“In other words, a 1-variable predictor wasn’t enough, but when we put 2 variables together, we got a much better predictor of at least who would not respond, who would be resistant,” said study coauthor Razelle Kurzrock, MD, director of the Center for Personalized Cancer Therapy and Rare Tumor Clinic and distinguished professor of medicine at the University of California San Diego School of Medicine in La Jolla.

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In the study, the researchers looked at 56 patients with mRCC who had been treated with nivolumab across 7 different institutions. The median age of patients at diagnosis was 59 years. The authors evaluated the proliferative status of the tumor microenvironment, PD-L1 levels, and objective response rates.

Among the patients, there were 2 cases of complete response, 8 cases of partial response, 18 cases of stable disease, and 28 cases of progressive disease. The overall objective response rate equaled 17.9%.

After dividing cell proliferation into tertiles, the investigators found that 62.5% of all tumors were poorly proliferative, 30.4% were moderately proliferative, and 8.9% were highly proliferative. Although objective response was higher for moderately proliferative (29.4%) tumors compared with poorly (11.4%) proliferative ones, the result was not statistically significant (P =.11).

However, the investigators did achieve statistically significant results when they combined cell proliferation and negative PD-L1 tumor proportion scores (P =.048). Namely, they found that the response rate was significantly lower among patients with poorly proliferative and PD-L1–negative tumors (6.5%) than among those with moderately proliferative PD-L1–negative tumors (30%).

“The important thing here is that we could better estimate especially those patients who are very unlikely to respond,” Dr Kurzrock told Cancer Therapy Advisor. “And that’s actually important because not only do you want to know who should get the drugs, but you want to know who should not get the drugs. We don’t want to give patients drugs that won’t work for them.”

Thomas Bradley, MD, the system head of genitourinary oncology at Northwell Health Cancer Institute in Lake Success, NY, who was not involved in the study, noted that the findings were preliminary because the study included a small number of patients randomly selected from multiple institutions. “There were only 56 patients that were evaluated,” he said in a phone interview.  More research based on more extensive data from clinical trials should be conducted to determine whether the 2 measures could indeed be used as biomarkers in practice, he said.

Anas Al-Janadi, MD, the vice president of hematology and oncology for Spectrum Health in Grand Rapids, Michigan, agreed. “Unfortunately, the small sample size and the fact that all samples studied were obtained from patients who were treated with nivolumab alone limit the applicability of the paper to general practice,” he wrote in an email. “Currently, most patients receive combinations of 2 immunotherapy drugs or a tyrosine kinase inhibitor plus an immunotherapy drug, and we do not know what would be the effect of proliferative potential when combinations are used.”


  1. Zhang T, Pabla S, Lenzo FL, et al. Proliferative potential and response to nivolumab in clear cell renal cell carcinoma patients. Oncoimmunology. 2020;9(1):1773200.
  2. Davis, AA, Patel, VG. The role of PD-L1 expression as a predictive biomarker: an analysis of all US Food and Drug Administration (FDA) approvals of immune checkpoint inhibitors. J Immunother Cancer. 2019;7(278). doi: 10.1186/s40425-019-0768-9
  3. Motzer RJ, Escudier B, McDermott DF, et al. Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015;373(19):1803-1813.