Barcelona, Spain (UroToday.com) Despite advances in clear cell renal cell carcinoma (RCC) treatment, patients with sarcomatoid RCC have a poor prognosis and are more resistant to VEGF-targeted therapy. Sarcomatoid RCC is characterized by immunologic infiltration and compared to other tumors has higher expression of PD-1 and PD-L1 on tumor infiltrating immune cells and tumor cells.1 In JAVELIN Renal 101, progression-free survival (PFS) was longer (median 13.8 vs 8.4 months; HR 0.69; p < 0.001) and objective response rate (ORR) was higher (51% vs 26%) with avelumab + axitinib versus sunitinib, and the benefit was observed in patients irrespective of PD-L1 expression and across all prognostic risk groups.2 At the ESMO 2019 annual congress, Dr. Toni Choueiri and colleagues presented results of their post hoc analysis of JAVELIN Renal 101 patients with sarcomatoid RCC.
There were 886 eligible patients with clear cell advanced RCC, no prior systemic therapy for advanced RCC, and ECOG performance status 0-1 that were randomized 1:1 to receive either avelumab + axitinib (n = 442) or sunitinib (n = 444) following a standard dose and schedule. PFS and ORR were assessed by an independent review committee in patients irrespective of PD-L1 expression. Patients whose pathology report indicated sarcomatoid features were included in this post hoc analysis. Biomarker analyses included expression of PD-L1, genes and signatures, and whole exome sequencing.
Among the 886 randomized patients, 108 (12.2%; 47 on avelumab + axitinib and 61 on sunitinib) had sarcomatoid RCC. Baseline characteristics were balanced between the 2 arms in this subgroup: 10.2% had favorable risk disease, 62.0% intermediate risk disease, and 27.8% poor IMDC risk disease. In patients with sarcomatoid RCC, avelumab + axitinib improved PFS: median 7.0 months, 95% CI 5.3-13.8 vs 4.0 months, 95% CI 2.7-5.7 compared to sunitinib (HR 0.57, 95% CI 0.325-1.003).
Avelumab + axitinib also improved ORR: 46.8%, 95% CI 32.1-61.9% vs 21.3%, 95% CI 11.9-33.7%, and complete response (4.3% vs 0%) compared to sunitinib. Among patients in with sarcomatoid RCC with a confirmed objective response, the median time to response was 1.6 months (range 1.2-9.8) in the combination arm and 3.1 months (range 1.2-11.1) in the sunitinib arm. Patients in the combination arm had 2.4 months longer median duration of response than those in the sunitinib arm:
The tumor microenvironment of samples from patients with sarcomatoid RCC demonstrated the presence of cancer-associated fibroblasts and increased regulatory T cells, as well as reduced VEGF signaling (FLT1 and KDR). Furthermore, patients with sarcomatoid RCC had increased markers of immune capacity and/or activation, including elevated gene expression of CD274 and CD8A.
Dr. Choueiri had the following take-home messages from this subgroup analysis of JAVELIN Renal 101 focusing on sarcomatoid RCC:
- Patients with sarcomatoid RCC in the avelumab + axitinib arm had improved efficacy outcomes compared with those on the sunitinib arm
- The results of the biomarker analysis suggest that patients with sarcomatoid RCC had an immunosuppressive tumor microenvironment and higher CD274 and CD8A gene expression
- These characteristics may contribute to the poorer prognosis of these patients when treated with single-agent VEGF/VEGFR inhibitors
- The combination of avelumab + axitinib may counteract the aggressive features of sarcomatoid RCC that hinder efficacy of standard of care RCC treatments
Clinical trial identification
Presented by: Toni K. Choueiri, MD, Jerome and Nancy Kohlberg Professor of Medicine, Harvard Medical School, Attending Physician, Solid Tumor Oncology, Dana-Farber Cancer Institute, Director, Genitourinary (GU) Oncology Disease, Center, Dana-Farber Cancer Institute, Director, Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Boston, MA
Written by: Zachary Klaassen, MD, MSc – Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia Twitter: @zklaassen_md at the 2019 European Society for Medical Oncology annual meeting, ESMO 2019 #ESMO19, 27 Sept – 1 Oct 2019 in Barcelona, Spain
1. Kawakami F, Sircar K, Rodriguez-Canales J, et al. Programmed cell death ligand 1 and tumor-infiltrating lymphocyte status in patietns with renal cell carcinoma and sarcomatoid dedifferentiation. Cancer 2017 Dec 15;123(24):4823-4831.
2. Motzer RJ, Penkov K, Haanen J, et al. Avelumab plus axitinib versus sunitinib for Advanced Renal-Cell Carcinoma. N Engl J Med 2019;380(12):1103-1115.