Analyzing the Prognostic Potential of Biomarkers for ccRCC Treatment Stratification

Disease features such as sarcomatoid dedifferentiation, somatic mutations, and depth of response have been commonly used to classify patients with clear cell renal cell carcinoma (ccRCC) for PD-1-based combinations such as ipilimumab plus nivolumab or targeted tyrosine kinase inhibitor therapy plus immunotherapy (TKI/IO).

Data that validate this utilization are limited, however, so researchers evaluated several biomarkers to determine their predictive or prognostic potential for determining initial treatment modality for patients with ccRCC. They presented their findings at the 2023 International Kidney Cancer Symposium: North America.

Lead author Kelly N. Fitzgerald, MD, of the University of California, San Francisco, and colleagues examined data from patients with ccRCC who were treated at Memorial Sloan Kettering (MSK) Cancer Center with IO-based combination therapy between January 2014 and December 2020. Study cohorts were defined by first-line treatment received: IO/IO or TKI/IO.

A total of 173 patients were included in the study. Response Evaluation Criteria in Solid Tumors 1.1 was utilized to assess responses. Progression-free survival on next-line therapy (PFS-2) was analyzed and defined as time from start of first-line therapy to second progression or death. Deep response was also analyzed and defined as target lesion shrinkage of 80% or more. Sarcomatoid features were obtained through pathology reports, and tumor mutations were profiled using the MSK Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) test.

The restricted mean survival time (RMST) of up to 48 months was calculated for PFS-2 in each treatment group. In deep responders, PFS-2 was compared between treatment groups. To calculate for heterogeneity of treatment effect in subgroups, sarcomatoid features and genomic alterations were included in a linear model for RMST, and an interaction test was performed.

Of the full study group of 173 patients, 90 received IO/IO therapy and 83 received TKI/IO. MSK-IMPACT was used in 141 patients. Among altered genes, only BAP1 was significantly associated with PFS-2. The median PFS-2 for BAP1-altered versus BAP1-unaltered patients was 17 months (95% CI, 11-27) and 44 months (95% CI, 29-53; P=.006), respectively.

In the RMST model for PFS-2, the interaction between treatment groups and the presence or absence of sarcomatoid features or BAP1 alterations were not significant (P=.21 and P=.65, respectively). Among deep responders, PFS-2 events occurred in 2 of 17 patients in the IO/IO group and 4 of 23 patients in the TKI/IO group (log-rank P=.75).

The evaluated biomarkers did not demonstrate predictive or prognostic potential for patient stratification to initial treatment modality. TKI/IO and IO/IO remain acceptable standard of care, and clinical stratification should remain key for decision-making.