The 2022 American Society of Clinical Oncology Genitourinary Cancers Symposium (ASCO-GU22) was held February 17- 19, 2022, in San Francisco, California. This meeting gathered worldwide experts in genitourinary cancers across multiple specialties and was held both virtually and in-person. In this report, we highlight key kidney cancer research updates from oral presentations at the meeting. Slides from the meeting’s presentations are available on the ASCO-GU website.
Tumor Biology Highlights:Renal cell carcinomas (RCC) comprise a heterogeneous group of malignant neoplasms with broad clinical and biological behaviors.1,2 Furthermore, RCCs have distinct patterns of metastatic spread which are perceived to have therapeutic and prognostic implications.3,4 Dr. Rana McKay (University of California San Diego) presented a talk entitled, “Molecular alterations across sites of metastasis in patients with renal cell carcinoma”. In this study, the investigators utilized a commercial genomic database (CARIS) of RCC tumors from primary and metastatic sites to characterize molecular features across various metastatic sites including mutational landscape, gene expression profiles, and immunotherapy related markers. A total of 657 RCC samples from 653 patients who were subjected to molecular profiling were included in this analysis, of which clear cell RCC (77.3%) and lung metastasis (10%) presented the most predominant histology and metastatic site, respectively. When they examined the distribution of the commonly altered genes in RCC, they found that relative to the primary tumor, several genes were mutated at higher rates for select metastatic sites, including PBRM1 (59.5% bone, 59.1% endocrine organs, and 45.9% lung vs 33.8% kidney, p< 0.05) and KDM5C (27.8% endocrine, 29.2% lymph nodes, and 35.3% soft tissue vs 9.3% kidney, p< 0.05). Using the molecular subtypes previously reported by Motzer el al. based on the IMmotion 151 phase 3 clinical trial,5 bone metastases had a significantly higher proportion of tumors classified as ‘Angio/stromal’ (n = 1 9, 4 2.2%; v s n = 5 2, 1 5.4%; p< 0.0001). No notable differences were observed in PD-L1 expression, MSI status, and tumor mutational burden. These findings add to our understanding of the molecular heterogeneity of RCC organotropism. Dr. Joseph Jacob (Upstate Medical University, NY) presented data on comprehensive genomic profiling of chromophobe RCC (chRCC) and non-chromophobe RCC (non-chRCC) examining the impact of FLCN genomic alterations and molecular differences between these 2 RCC groups. FLCN is a tumor suppressor gene, and germline mutations in this gene are linked to inherited chromophobe RCC as part of the Birt-Hogg-Dubé (BHD) syndrome.6 In this study, 109 sporadic chRCC tumors and 5,862 non-chRCC tumors were subjected to hybrid capture comprehensive genomic profiling. Of note, none of the chRCC patients exhibited signs of BHD syndrome. FLCN genomic alterations were not associated with sporadic chRCC and were only identified in 1 out of 109 cases. Furthermore, chRCC tumors were significantly associated with lower tumor mutational burden and enriched in TP53, RB1, and PTEN gene alterations compared to nonchRCC tumors.
Systemic Therapy Biomarkers Highlights:With the established role of immunecheckpoint inhibitors (ICIs) in RCC, there is a critical unmet need to identify novel biomarkers predictive of response.7 TITAN-RCC is an adaptive phase 2 open label study of nivolumab induction monotherapy in patients with metastatic RCC with the addition of nivolumab plus ipilimumab boost cycles in non-responders (NCT02917772).8 The investigators reported on the characteristics of blood-circulating immune cell subsets within the population of the TITAN-RCC trial. Blood samples from 198 RCC patients were analyzed by multi-parametric flow cytometry for frequency and phenotype of T cell, monocyte, myeloid-derived suppressor cell (MDSC) and dendritic cell (DC) subsets. Blood samples for biomarker analyses were taken at baseline, during nivolumab induction and nivolumab plus ipilimumab boost cycles. A higher proportion of blood-circulating 4-1BB+ CD4+ T cells, 4-1BB+ CD8+ T cells, and LAG3+ CD4+ T cells were found in responders to nivolumab monotherapy induction compared to non-responders. In contrast, a higher proportion of PD-L1+ CD14+ monocytes, PDL1+ early-stage MDSC, and PDL1+ plasmacytoid DC were seen in nivolumab plus ipilimumab boost cycles responders. These intriguing findings may represent a novel predictive biomarker of ICI efficacy and merit further study.
Clinical trials Highlights:Patients with high risk localized RCC have a high risk of recurrence after undergoing nephrectomy, posing an unmet clinical need to reduce recurrence rates among these patients. The role for novel ICI therapies in reducing recurrence among patients with locally advanced RCC is currently under investigation in a variety of settings, including the neoadjuvant, perioperative and adjuvant spaces.9,10 The optimal therapeutic strategy in this setting is yet to be elucidated, although preclinical data supports neoadjuvant ICI use to enhance the antitumor T-cell response induced by the primary tumor while the tumor remains in situ.11
Dr. Axel Bex (Netherlands Cancer Institute) reported on the efficacy, safety, and biomarker analysis of a phase 2 open label single arm study of neoadjuvant avelumab plus axitinib in patients with localized risk RCC with high risk of relapse after nephrectomy (NeoAvAx) (NCT03341845). Avelumab plus axitinib is a combination of ICI plus vascular endothelial growth factor tyrosine kinase inhibitors (VEGF-TKI) which is approved as a frontline treatment for patients with metastatic clear cell RCC.12 However, no prior studies investigated the activity of ICI plus VEGF-TKI combination in the neoadjuvant or adjuvant setting in RCC. In this study, 40 patients with high risk localized clear cell RCC (cT1b-4cN0-1M0, Grades 3-4) were enrolled on the and received 12 weeks of neoadjuvant avelumab plus axitinib prior to nephrectomy. Twelve patients (30%) had a partial response of their primary tumor and at the time of analysis, ten of the twelve patients with response (83%) were disease free. After a median follow up of 23.5 months, 13 patients (32.5%) recurred, and 3 died of disease. Both the median diseasefree survival and overall survival were not reached. There were no grade 4-5 treatment related adverse events, and no concerning surgical safety signals were observed. Posttreatment samples from patients with recurrence were characterized by lower densities of total, intraepithelial and stromal CD8+, intraepithelial CD8+CD39+ (p<0.05) and total CD8+GZMB+ (p=0.1).
In the adjuvant setting, pembrolizumab was granted FDA approval in November 2021 as the first approved adjuvant immunotherapy for patients with intermediatehigh or high risk of recurrence after nephrectomy based on the phase 3 double-blind, multicenter, randomized KEYNOTE-564 study (NCT03142334).13 With a median follow-up time of 24.1 months, the study met its primary endpoint with significant disease-free survival benefit seen with adjuvant pembrolizumab compared to placebo (HR 0.68, 95% CI 0.53- 0.87, P = 0.001). Dr. Choueiri (Dana Farber Cancer Institute) reported on updated efficacy and safety results from KEYNOTE-564 after a median 30 months of follow-up. In the updated analysis, disease-free survival benefit with pembrolizumab was maintained (HR 0.63, 95% CI 0.50-0.80; P < 0.0001) and was consistent across subgroups. For patients with sarcomatoid tumors, the 24 months disease-free survival rate was 71.8% in patients treated with pembrolizumab compared to 52.0% in patients who received placebo. Overall survival data are still immature with the limited number of events thus far. With this prolonged follow up, no additional safety concerns were noted. These updated results further support the use of adjuvant pembrolizumab in selected patients with RCC.
In the metastatic setting, Dr. Zibelman (Fox Chase Cancer Center) reported on a multi-institutional investigator-initiated phase 1/2 open label single arm study of nivolumab plus axitinib in patients with metastatic ccRCC (NCT03172754). The primary endpoint of the phase 1 portion was to determine the recommended phase 2 dose (RP2D), and the primary endpoint for the phase 2 portion was the overall response rate (ORR) per RECIST v1.1 criteria. The RP2D was determined to be nivolumab 480 mg intravenously every 4 weeks and axitinib 5 mg twice daily orally. The study enrolled a total of 44 patients with 42 patients evaluable for efficacy. Using IMDC risk stratification, the patients’ risk distribution was 40.9% favorable risk, 52.3% intermediate risk, and 6.8% poor risk. The ORR of the combination was 59.5% with only 1 patient (2.4%) experiencing primary progressive disease and a disease control rate of 97.6%. After a median follow-up time of 11.5 months, the median progression-free survival of the combination was 16.4 months (95% CI, 10.2-21.2 months) and median overall survival was not reached. The combination safety profile favorably compared to other ICI-VEGF TKI combination with no grade 4-5 adverse events. The discontinuation rate of nivolumab and axitinib was 8.2% and 20.9%, respectively. The study is currently enrolling on a pretreated cohort of metastatic RCC patients who received prior ipilimumab plus nivolumab.