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. 2017 Mar;71(3):405-414.
doi: 10.1016/j.eururo.2016.10.007. Epub 2016 Oct 15.

Genomic Biomarkers of a Randomized Trial Comparing First-line Everolimus and Sunitinib in Patients with Metastatic Renal Cell Carcinoma

James J Hsieh  1 , David Chen  2 , Patricia I Wang  3 , Mahtab Marker  2 , Almedina Redzematovic  3 , Ying-Bei Chen  3 , S Duygu Selcuklu  3 , Nils Weinhold  3 , Nancy Bouvier  3 , Kety H Huberman  3 , Umesh Bhanot  3 , Michael S Chevinsky  4 , Parul Patel  2 , Patrizia Pinciroli  5 , Helen H Won  3 , Daoqi You  3 , Agnes Viale  3 , William Lee  3 , A Ari Hakimi  3 , Michael F Berger  3 , Nicholas D Socci  3 , Emily H Cheng  3 , Jennifer Knox  6 , Martin H Voss  3 , Maurizio Voi  2 , Robert J Motzer  3
Affiliations

Genomic Biomarkers of a Randomized Trial Comparing First-line Everolimus and Sunitinib in Patients with Metastatic Renal Cell Carcinoma

James J Hsieh et al. Eur Urol. 2017 Mar.

Abstract

Background: Metastatic renal cell carcinoma (RCC) patients are commonly treated with vascular endothelial growth factor (VEGF) inhibitors or mammalian target of rapamycin inhibitors. Correlations between somatic mutations and first-line targeted therapy outcomes have not been reported on a randomized trial.

Objective: To evaluate the relationship between tumor mutations and treatment outcomes in RECORD-3, a randomized trial comparing first-line everolimus (mTOR inhibitor) followed by sunitinib (VEGF inhibitor) at progression with the opposite sequence in 471 metastatic RCC patients.

Design, setting, and participants: Targeted sequencing of 341 cancer genes at ∼540× coverage was performed on available tumor samples from 258 patients; 220 with clear cell histology (ccRCC).

Outcome measurements and statistical analysis: Associations between somatic mutations and median first-line progression free survival (PFS1L) and overall survival were determined in metastatic ccRCC using Cox proportional hazards models and log-rank tests.

Results and limitations: Prevalent mutations (≥ 10%) were VHL (75%), PBRM1 (46%), SETD2 (30%), BAP1 (19%), KDM5C (15%), and PTEN (12%). With first-line everolimus, PBRM1 and BAP1 mutations were associated with longer (median [95% confidence interval {CI}] 12.8 [8.1, 18.4] vs 5.5 [3.1, 8.4] mo) and shorter (median [95% CI] 4.9 [2.9, 8.1] vs 10.5 [7.3, 12.9] mo) PFS1L, respectively. With first-line sunitinib, KDM5C mutations were associated with longer PFS1L (median [95% CI] of 20.6 [12.4, 27.3] vs 8.3 [7.8, 11.0] mo). Molecular subgroups of metastatic ccRCC based on PBRM1, BAP1, and KDM5C mutations could have predictive values for patients treated with VEGF or mTOR inhibitors. Most tumor DNA was obtained from primary nephrectomy samples (94%), which could impact correlation statistics.

Conclusions: PBRM1, BAP1, and KDM5C mutations impact outcomes of targeted therapies in metastatic ccRCC patients.

Patient summary: Large-scale genomic kidney cancer studies reported novel mutations and heterogeneous features among individual tumors, which could contribute to varied clinical outcomes. We demonstrated correlations between somatic mutations and treatment outcomes in clear cell renal cell carcinoma, supporting the value of genomic classification in prospective studies.

Keywords: BAP1; Everolimus; Genomic biomarker; KDM5C; Kidney cancer; PBRM1; SETD2; Sunitinib; Targeted therapy; Tumor suppressor gene.

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Conflict of interest statement

Financial disclosures: James J. Hsieh certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: Hsieh has received research grants from Novartis, Pfizer, and CGI and has served as a consultant for Novartis, Chugai, and Eisai. Chen is an employee of and a stockholder in Novartis Pharmaceuticals Corporation. Marker is an employee of and a stockholder in Novartis Pharmaceuticals Corporation. Patel is an employee of Novartis Pharmaceuticals Corporation. Lee is a stockholder in AbbVie, Abbott Laboratories, and Immunogen, Inc. Socci has received consulting or advisory fees from Champions Oncology. Voss has received research grants from BMS and Pfizer, consulting fees from Novartis and Bayer, and honoraria from Novartis. Voi is an employee of and a stockholder in Novartis Pharmaceuticals Corporation. Motzer has received research grants from Novartis, Pfizer, BMS, GlaxoSmithKline, Genentech, Exelixis, and Eisai, consulting or advisory compensation from Pfizer, and compensation for providing expert testimony for Pfizer.

Figures

Fig 1
Fig 1
RECORD-3 clear cell renal cell carcinoma next-generation sequencing cohort.
Fig. 2
Fig. 2
Mutation profiles of RECORD-3 clear cell renal cell carcinoma next-generation sequencing cohort. (A) Oncoprint of frequently mutated genes (≥ 5%) from RECORD-3 patients with clear cell metastatic renal cell carcinoma. (B) Frequently mutated genes from RECORD-3 and other published data. TCGA = The Cancer Genome Atlas.
Fig. 2
Fig. 2
Mutation profiles of RECORD-3 clear cell renal cell carcinoma next-generation sequencing cohort. (A) Oncoprint of frequently mutated genes (≥ 5%) from RECORD-3 patients with clear cell metastatic renal cell carcinoma. (B) Frequently mutated genes from RECORD-3 and other published data. TCGA = The Cancer Genome Atlas.
Fig. 3
Fig. 3
First-line progression-free survival (PFS) of RECORD-3 patients with metastatic clear cell renal cell carcinoma. First-line PFS of patients with (A) KDM5C, (B) PBRM1, and (C) BAP1 mutations. MT = mutant type; WT = wild type.
Fig. 3
Fig. 3
First-line progression-free survival (PFS) of RECORD-3 patients with metastatic clear cell renal cell carcinoma. First-line PFS of patients with (A) KDM5C, (B) PBRM1, and (C) BAP1 mutations. MT = mutant type; WT = wild type.
Fig. 3
Fig. 3
First-line progression-free survival (PFS) of RECORD-3 patients with metastatic clear cell renal cell carcinoma. First-line PFS of patients with (A) KDM5C, (B) PBRM1, and (C) BAP1 mutations. MT = mutant type; WT = wild type.
Fig. 4
Fig. 4
Overall survival (OS) of RECORD-3 patients with metastatic c clear cell renal cell carcinoma. (A) BAP1, PBRM1, and KDM5C mutation status. OS and BAP1/PBRM tumor mutations in the (B) everlimus-sunitinib (EVE-SUN) arm and the (C) SUN-EVE arm. (D) OS and KDM5C tumor mutation status. CI = confidence interval; Gr = group; MT = mutant type; WT = wild type
Fig. 4
Fig. 4
Overall survival (OS) of RECORD-3 patients with metastatic c clear cell renal cell carcinoma. (A) BAP1, PBRM1, and KDM5C mutation status. OS and BAP1/PBRM tumor mutations in the (B) everlimus-sunitinib (EVE-SUN) arm and the (C) SUN-EVE arm. (D) OS and KDM5C tumor mutation status. CI = confidence interval; Gr = group; MT = mutant type; WT = wild type
Fig. 4
Fig. 4
Overall survival (OS) of RECORD-3 patients with metastatic c clear cell renal cell carcinoma. (A) BAP1, PBRM1, and KDM5C mutation status. OS and BAP1/PBRM tumor mutations in the (B) everlimus-sunitinib (EVE-SUN) arm and the (C) SUN-EVE arm. (D) OS and KDM5C tumor mutation status. CI = confidence interval; Gr = group; MT = mutant type; WT = wild type
Fig. 4
Fig. 4
Overall survival (OS) of RECORD-3 patients with metastatic c clear cell renal cell carcinoma. (A) BAP1, PBRM1, and KDM5C mutation status. OS and BAP1/PBRM tumor mutations in the (B) everlimus-sunitinib (EVE-SUN) arm and the (C) SUN-EVE arm. (D) OS and KDM5C tumor mutation status. CI = confidence interval; Gr = group; MT = mutant type; WT = wild type
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