Immune checkpoint inhibitor (IBI) therapies have quickly become a new standard of care for the treatment of metastatic clear cell renal cell carcinoma (CRC) based on several large-scale phase III clinical trials showing improvements in the survival. But these trials generally excluded kidney cancers with unclear cell histology, and there is limited data on the role of ICI in advanced unclear renal cell carcinoma (nccRCC). This pathologically and biologically diverse subset of RCC accounts for approximately 20% of cases.

A retrospective analysis of 1,181 patients, presented at the Virtual Symposium on Genitourinary Cancers, examined the actual effectiveness of first-line IBI therapy in advanced nccRCC.

In the following interview, lead author of the study, Jeffrey Graham, MD, of the University of Manitoba in Winnipeg, Canada, shared his perspective on the research.

What does the study add to the literature on the use of immune checkpoint inhibitors as a first-line treatment for advanced unclear renal cell carcinoma?

Graham: Our results suggest that ICI therapy appears to be active in treatment-naïve nccRCCs, with response rates consistent with previous prospective retrospective and single-arm studies.

To our knowledge, this is the first study to provide a comparison of ICI therapy with vascular endothelial growth factor (VEGF) and mammalian target rapamycin (mTOR) targeted therapy.

After controlling for prognostic confounding factors, IBI-based treatment appears to be associated with an improvement in overall survival (OS) in this population compared to treatment with VEGF or mTOR alone. The study population consisted primarily of papillary RCC, and the efficacy of IBI-based therapy in other less common histological subtypes remains inconclusive.

What are the highlights of the study?

Graham: In total, we identified 1,181 patients with advanced nccRCC who were classified into three groups according to the type of first-line treatment. Of this cohort, 78.2% received targeted VEGF therapy, 15.8% received mTOR inhibitors and 5.5% received IBI-based therapy (41.5% as ICI monotherapy, 30.8% in ICI-ICI doublet and 27.7% in ICI-VEGF doublet).

In the overall unclear cell population, the objective response rate for patients treated with ICI therapy was 25%, compared to 17.8% with VEGF therapy and 5.8% with mTOR therapy. The median OS in the ICI group was 28.6 months, compared to 19.2 and 12.6 months in the VEGF and mTOR groups, respectively. After adjusting for risk group, histologic subtype and age, the risk ratio (HR) for OS was 0.58 for ICI versus VEGF and 0.48 for ICI versus mTOR.

Interestingly, when we looked at responses within histological subtypes, we observed higher responses in the papillary subgroup (31.6%) and lower responses in the chromophobic subgroup (9, 1%). This is consistent with previous observations that chromophobic RCC appears to be an immunologically “cold” tumor and therefore may not respond as well to immune activation therapy.

What are the advantages of using IBI-based therapy over VEGF-targeted therapy or mTOR inhibitor monotherapy?

Graham: Due to the unique mechanism of action, IBI-based therapy may have a number of potential advantages over molecularly targeted single agent drugs. Based on clear cell population data, ICI therapy is generally well tolerated, with lower toxicity and, in some studies, improved health-related quality of life compared to targeted therapy.

ICI therapies are also associated with higher rates of complete responses and a longer duration of response. In clear cell RCC, ICI combination therapy produced complete responses (CR) in 8-16% of patients in phase III clinical trials compared with less than 5% in those receiving sunitinib. In our nccRCC study, the CR rate for ICI treatment was 4.2%, which is lower than reported in clear cell RCC.

Why do you think first-line IBI therapy appears to improve overall survival compared to VEGF and mTOR targeted therapy in advanced unclear cell RCC?

Graham: The advantage of OS observed in our study may be due to residual confusion and / or selection bias. For example, patients included in the ICI group may have been more likely to be enrolled in clinical trials. It is important to note that we found a reasonable balance of risk groups in the three treatment groups.

With these limitations in mind, it is possible that some nccRCC subtypes may demonstrate similar sensitivity to IBI-based therapies as seen in their clear cell counterparts. Our study population consisted primarily of papillary RCCs, and it is likely that the benefit in the general population was attributable to this subgroup.

What should be the next step in this research?

Graham: Our results need to be confirmed in prospective randomized trials. To date, there have been a number of prospective non-randomized trials exploring ICI therapy in unclear RCC using pembrolizumab and also exploring various combinations including cabozantinib with ICI therapy.

An ideal trial design would be a randomized trial of a tyrosine kinase inhibitor (TKI) – for example, cabozantinib, versus TKI plus ICI versus ICI alone. This design would hopefully be able to delineate the comparative advantage of combination therapy. In addition, more research on biomarker-selected assays is needed.

What is the message to practicing oncologists?

Graham: Based on the available data, there are a number of treatment options for advanced nccRCC. Our results support approaches integrating ICI therapy. We look forward to the results of prospective trials exploring the combined approaches HERE.

Given the pathological and biological diversity of nccRCC, it is difficult to make definitive recommendations without taking into account the differences between the various histological subtypes. Based on our results and data from prospective trials, IBI-based therapy appears to be active in papillary RCC, while chromophobic RCC appears to be less responsive to ICI therapies.

In view of these uncertainties, we encourage recruitment into clinical trials as the preferred option.

Read the study here and expert comments on the clinical implications here.


Graham reported financial relationships with Janssen Oncology and Pfizer.

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