ASCO 2017: Integrated biomarker analysis for 412 renal cell cancer patients treated on the phase 3 COMPARZ trial

Chicago, IL (UroToday.com) Clear cell renal cell carcinoma (ccRCC) is a von Hippel-Lindau gene (VHL) – loss driven disease involving germline mutations at the VHL gene at chromosome 3p25. Chromatin modifying tumor suppressor genes in RCC including: PBRM1, BAP1, SETD2 AND KDM5C are located on chromosome 3p region, which is deleted in over 90% of ccRCC. PBRM1 is the second most frequently mutated gene after VHL. In RCC biology mutations in PBRM1 and BAP1 are largely non-overlapping and collectively affect >50% of pts, influencing disease kinetics.

Sunitinib and pazopanib result in inhibition of angiogenesis, which is a key driver in RCC. Dr. Voss presented a study (Clinical trial information: NCT00720941) analyzing mutation status and gene expression signatures in a large cohort of pts receiving first-line sunitinib or pazopanib on the COMPARZ trial. This was a large randomized, open label, phase 3 trial that confirmed disease progression free survival (PFS) noninferiority for pazopanib compared to Sunitinib in patients with treatment naïve advanced or metastatic ccRCC.

For this trial RNA and DNA were extracted from archived tissue of recruited patients. Consequently, PBRM1 and BAP1 mutation status was determined via a custom exon-targeted platform. Additionally, transcriptome analysis was performed. Overall, a 43 gene angiogenesis expression score was performed with previously reported dynamic response to VEGF-directed therapy in xenograft models.1 DNA and RNA findings were correlated with clinical outcomes.

Overall, 437 pts contributed tumor RNA, 377 pts contributed tumor DNA; and 352 pts contributed both. PBRM1 and BAP1 were mutated in 44% and 15% of pts, respectively. Presence of PBRM1 mutations correlated with superior PFS (11.04 months vs. 8.25 months, HR 0.71 [C.I. 95% 0.54-0.92], p=0.008) and overall survival (OS) (35.48 months vs. 26.12 months, HR 0.66 [0.49-0.84], p=0.004). PBRM1 mutation rate was higher in pts with objective response than those with progression (p=0.012). In contrast, pts with mutated BAP1 had inferior OS compared to those without mutations (p=0.012). In all pts angiogenesis score was associated favorably with outcome on univariate and multivariable analyses (Cox proportional hazard regression, OS p<0.001 and PFS p<0.005). Angiogenesis scores were higher in mutated PBRM1 MT vs non-mutated PBRM1 patients (p<0.001), but lower in mutated BAP1 vs. non-mutated (p<0.001).

In summary, PBRM1 and BAP1 mutations correlate inversely with cancer specific outcome on first line Tyrosine kinase inhibitor (TKI) therapy. Loss of PBRM1 enhances the pro-angiogenic microenvironment of RCC with favorable effects on response to TKI therapy. Conversely, loss of BAP1 is associated with decreased angiogenic signaling and adverse outcome in response to TKI therapy. The group of angiogenesis low/BAP1MT/PBRM1WT patients are of heightened interest for combination approaches, on which, the authors plan to investigate in independent datasets.

Presented By: Martin Henner Voss, Memorial Sloan Kettering Cancer Center, New York, NY

Written By: Hanan Goldberg, MD, Urologic Oncology Fellow (SUO), University of Toronto, Princess Margaret Cancer Centre
Twitter: @GoldbergHanan

at the 2017 ASCO Annual Meeting - June 2 - 6, 2017 – Chicago, Illinois, USA

Reference:
1.Masiero M, Simoes FC, Han HD, et al. A core human primary tumor angiogenesis signature identifies the endothelial orphan receptor ELTD1 as a key regulator of angiogenesis. Cancer cell 2013; 24(2): 229-41.
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