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Neoadjuvant pazopanib and molecular analysis of tissue response in renal cell carcinoma
Christopher G. Wood, … , Thomas Powles, W. Kimryn Rathmell
Christopher G. Wood, … , Thomas Powles, W. Kimryn Rathmell
Published November 19, 2020
Citation Information: JCI Insight. 2020;5(22):e132852. https://doi.org/10.1172/jci.insight.132852.
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Clinical Medicine Clinical trials Oncology

Neoadjuvant pazopanib and molecular analysis of tissue response in renal cell carcinoma

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Abstract

BACKGROUND Surgery remains the frontline therapy for patients with localized clear cell renal cell carcinoma (ccRCC); however, 20%–40% recur. Angiogenesis inhibitors have improved survival in metastatic patients and may result in responses in the neoadjuvant setting. The impact of these agents on the tumor genetic heterogeneity or the immune milieu is largely unknown. This phase II study was designed to evaluate safety, response, and effect on tumor tissue of neoadjuvant pazopanib.METHODS ccRCC patients with localized disease received pazopanib (800 mg daily; median 8 weeks), followed by nephrectomy. Five tumors were examined for mutations by whole exome sequencing from samples collected before therapy and at nephrectomy. These samples underwent RNA sequencing; 17 samples were available for posttreatment assessment.RESULTS Twenty-one patients were enrolled. The overall response rate was 8 of 21 (38%). No patients with progressive disease. At 1-year, response-free survival and overall survival was 83% and 89%, respectively. The most frequent grade 3 toxicity was hypertension (33%, 7 of 21). Sequencing revealed strong concordance between pre- and posttreatment samples within individual tumors, suggesting tumors harbor stable core profiles. However, a reduction in private mutations followed treatment, suggesting a selective process favoring enrichment of driver mutations.CONCLUSION Neoadjuvant pazopanib is safe and active in ccRCC. Future genomic analyses may enable the segregation of driver and passenger mutations. Furthermore, tumor infiltrating immune cells persist during therapy, suggesting that pazopanib can be combined with immune checkpoint inhibitors without dampening the immune response.FUNDING Support was provided by Novartis and GlaxoSmithKline as part of an investigator-initiated study.

Authors

Christopher G. Wood, James E. Ferguson III, Joel S. Parker, Dominic T. Moore, Jennifer G. Whisenant, Susan J. Maygarden, Eric M. Wallen, William Y. Kim, Mathew I. Milowsky, Kathryn E. Beckermann, Nancy B. Davis, Scott M. Haake, Jose A. Karam, Dante S. Bortone, Benjamin G. Vincent, Thomas Powles, W. Kimryn Rathmell

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Figure 5

Immune features pre and post neoadjuvant pazopanib therapy.

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Immune features pre and post neoadjuvant pazopanib therapy.
(A) Immune g...
(A) Immune gene signatures were made from log2 normalized gene counts. Two-tailed t test comparisons were made between matched patient pre- and posttreatment samples. No signatures were significant after Benjamini-Hochberg FDR correction. (B) Shannon entropy was calculated on TRB CDR3 counts. Points are colored by patient. Pre- and posttreatment results were not significantly different (paired t test, P = 0.18). (C) Public IgH CDR3 are represented on the y axis. Heatmap colors indicate the fraction of total counts a CDR3 represents out of the total IgH CDR3 counts for each a sample. (D) Morisita-Horn index was calculated on the fractional expression of all IgH CDR3 for each sample combination.
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