Evolution of circulating tumor DNA (ctDNA) profile from first-line (1L) to second-line (2L) therapy in metastatic renal cell carcinoma (mRCC).

Genitourinary Cancer
Session Type and Session Title: 
Oral Abstract Session C: Renal Cell Cancer
Poster Session C: Penile, Urethral, and Testicular Cancers; Renal Cell Cancer
Abstract Number: 


Poster Board Number: 
Poster Session C Board #B17
J Clin Oncol 35, 2017 (suppl 6S; abstract 434)
Sumanta K. Pal, Guru Sonpavde, Neeraj Agarwal, Nicholas J. Vogelzang, Sandy Srinivas, Naomi B. Haas, Sabina Signoretti, Richard B. Lanman, Kimberly Banks, Toni K. Choueiri; City of Hope, Duarte, CA; University of Alabama at Birmingham Comprehensive Cancer Center, Birmingham, AL; Huntsman Cancer Institute-University of Utah Health Care, Salt Lake City, UT; Comprehensive Cancer Centers of Nevada, Las Vegas, NV; Stanford University, Stanford, CA; Abramson Cancer Center of the University of Pennsylvania, Philadelphia, PA; Brigham and Women's Hospital, Boston, MA; Guardant Health, Inc., Redwood City, CA; Dana-Farber/Harvard Cancer Center, Boston, MA

Abstract Disclosures


Background: Treatment of mRCC typically entails mechanistically distinct agents across the 1L and 2L setting. Activity of these agents may be predicated on selective pressure that modulates RCC biology. ctDNA is a platform to conveniently ascertain temporal changes in genomic profile. Methods: Data was obtained from pts with mRCC who received ctDNA profiling as a part of routine clinical care at progression using a CLIAA-certified platform evaluating 70 genes. Genomic alterations (GAs) were pooled for the entire cohort. A comparison of 1L vs. 2L was performed, with grouping based on conventional practice patterns (1L regimens included sunitinib, pazopanib and bevacizumab, and 2L regimens included everolimus, axitinib, cabozantinib, and nivolumab). Results: ctDNA results from 224 pts with mRCC were assessed (gender: 149 M, 75 F; average age: 62; histology: 89 clear cell, 37 non-clear cell, 98 unknown). GAs were detected in 78.6% of pts. The most frequent GAs in the overall cohort included TP53 (35%), VHL (23%), EGFR (17%), NF1 (16%), and ARID1A (12%). 64 and 56 pts were coded as receiving 1L and 2L agents, respectively. The average number (range) of ctDNA alterations detected was 2.9 (1-14) in 1L and 3.7 (1-16) in 2L with median (range) ctDNA variant allele fractions of 0.23 (0.05-9.92) in 1L and 0.24 (0.04-47.14) in 2L. The highest disparity in GA frequencies in 2L vs. 1L were in TP53 (49% vs. 25%), VHL (29% vs. 25%), NF1 (20% vs. 15%), EGFR (17% vs. 21%), and PIK3CA (17% vs. 8%). Isolating 2L pts who specifically had 1L VEGF-therapy documented, these differences were even more prominent in comparison to 1L pts: TP53 (64% vs. 31%), PIK3CA (29% vs. 8%), and NF1 (29% vs. 4%). Conclusions: In the largest assessment of ctDNA in mRCC to date, the majority of pts demonstrated clinically relevant GAs. Increasing p53 and mTOR pathway (e.g, NF1, PIK3CA) alteration in 2L pts with 1L VEGF-directed therapy may underlie mechanisms of resistance. Increasing GA frequency from 1L to 2L pts may have implications for immunotherapeutic approaches.