ASCO GU 2020: Challenging Clinical Scenarios in the Management of Renal Cell Carcinoma: Genomic Findings

The hypothetical case was that of a 65 year man who presented with gross hematuria. CT scan of the abdomen and pelvis revealed a 15 x 12 centimeter right renal mass with level 1 tumor thrombus and a 2.5 centimeter retrocaval lymph node. CT scan of the chest and bone scan were negative. He underwent surgical resection of a pT3bN1R0 clear cell renal cell RCC. The patient was started on active surveillance with CT imaging every 3 months. CT at one year showed multiple asymptomatic 3 centimeter metastases in both lungs. Biopsy confirmed metastatic RCC. Genomic profiling was performed, which showed alterations in the following genes: VHL, MET, TSC2.

Dr. Albiges began by discussing the impact of specific genomic alterations on response to VEGF tyrosine kinase inhibitors (TKI). Three genes (BAP1, TP53, and PBRM1) were identified as prognostic in patients with metastatic RCC. Loss of function alterations in BAP1 and TP53 were associated with decreased overall survival, while PBRM1 was associated with improved overall survival.¹ The positive prognostic impact of PRBM1 alterations was validated in the IMmotion150 Trial where patients with mutations had significantly longer progression-free survival than those who didn’t (Hazard Ratio [HR] = 0.38, 95% [CI] Confidence Interval 0.20-0.73; p = 0.003).² The presence of PBRM1 alterations was also found to have a positive prognostic factor in patients treated with PD-1 inhibitors.

Tumor mutational burden (TMB) has been identified as a predictive biomarker for response to immunotherapy in other solid tumors, however in RCC, it was not associated with pattern of response to immunotherapy, VEGF TKI, or combination therapy.² Similarly, there is no association between number of indels and response to immunotherapy in metastatic RCC.

Gene expression profiling of tumor biopsies from clinical trials has led to the development of signatures that predict response to VEGF TKI and/or immunotherapy in metastatic RCC. In the IMmotion150 Trial, a gene expression signature of angiogenesis was predictive of response to sunitinib, but not to atezolizumab plus bevacizumab or atezolizumab alone. Gene expression signatures reflecting the immune microenvironment were also found to be predictive: the “T-effector-High Myeloid-Low” signature was predictive of better response to an immunotherapy-based regimen than VEGF TKI alone. In contrast, “T-effector-High Myeloid-High” signature was associated with better response to combination anti-VEGF therapy plus immunotherapy.[2] A similar approach was performed in the JAVELIN Renal 101 Trial whereby an expression-based immune signature was found to be predictive of response to axitinib plus avelumab (HR = 0.60, 95% CI 0.44-0.83; p = 0.0019), but not sunitinib (HR = 0.89, 95% CI 0.67-1.17; p = 0.3973). The predictive value of this signature was validated in the independent JAVELIN Renal 100 cohort.

BIONNIK is an ongoing randomized clinical trial (NCT02960906) in France of patients with metastatic RCC where tumor gene-expression profiling is performed and patients receive immunotherapy or VEGF TKI based on their subtype.

Dr. Albiges concluded with the following take-home points:

• At this time, genomic alterations (eg PBRM1) provide prognostic information, but are not yet able to guide therapy
• Predictive gene-expression signatures in IMmotion150 and JAVELIN Renal 101 have paved the way for ongoing expression-based randomized clinical trials
• There is a current unmet need for molecular predictors to guide first-line treatment decisions in metastatic RCC (eg single agent versus combination and ipilimumab plus nivolumab versus axitinib plus pembrolizumab)

Presented by: Laurence Albiges, MD, PhD, Medical Oncologist at Institut Gustave Roussy

Moderated by: Sumanta Pal, MD, Medical Oncologist at City of Hope Comprehensive Cancer Center and Robert Uzzo, MD, MBA, Urologist at Fox Chase Cancer Center

References:

1. Voss MH, et al. Genomically annotated risk model for advanced renal-cell carcinoma: a retrospective cohort study. Lancet Oncol. 2018 Dec;19(12):1688-1698.
2. McDermott DF, et al. Clinical activity and molecular correlates of response to atezolizumab alone or in combination with bevacizumab versus sunitinib in renal cell carcinoma. Nat Med. 2018 Jun;24(6):749-757.