sequencing and timing were assessed. The study identified 133 patients, of whom 28 received a CTLA-4 inhibitor alone, 88 received a PD-1 inhibitor alone, and 17 received both classes of inhibitors either sequentially (n=13) or concurrently (n=4). Fifty-six patients received radiation within 14 days of an immune checkpoint inhibitor. Forty-six patients experienced at least 1 ir-AE (34.6%). Patients receiving both CTLA-4 and PD-1 inhibitors experienced more any-grade ir-AEs as compared with either individually (71% vs 29%, P=.0008). Any-grade ir-AEs occurred in 39% of patients in whom radiation was administered within 14 days of immunotherapy, compared with 23% of other patients (P=.06) and more often in patients who received higher equivalent dose in 2-Gy fractions (EQD2) EQD2 (P=.01). However, most toxicities were mild. There were no associations between site irradiated and specific ir-AEs. Conclusion: The data suggest the combination of focal palliative radiation and CTLA-4 and/or PD-1 inhibitors is well tolerated, with manageable ir-AEs that did not seem to be associated with the particular site irradiated. Although conclusions are limited by the heterogeneity of patients and treatments, and future confirmatory studies are needed, this information can help guide clinical practice for patients receiving immune checkpoint therapy who require palliative radiation therapy. Correlation of genomic alterations assessed by nextgeneration sequencing (NGS) of tumor tissue DNA and circulating tumor DNA (ctDNA) in metastatic renal cell carcinoma (mRCC): potential clinical implications. Hahn AW, Gill DM, Maughan B, et al. Oncotarget. 2017 May 16;8(20):33614-33620. Summary: Tumor tissue and circulating tumor DNA (ctDNA) next-generation sequencing (NGS) testing are frequently performed to detect genomic alterations (GAs) to help guide treatment in metastatic renal cell carcinoma (mRCC), especially after progression on standard systemic therapy. This report assessed whether GAs detected by ctDNA NGS are different from those detected by tumor tissue NGS, specifically in patients with mRCC, and if these platforms are interchangeable or complimentary. When controlling for genes tested by both platforms, the median mutation rate for ctDNA was similar to tissue (median 3.0 vs. 1.0, p = 0.14). However, the concordance rate between the two platforms was only 8.6%. When the study compared GAs by molecular pathway, GAs in tumor tissue were more common for the DNA repair and epigenetic pathways. Results of NGS testing from tumor tissue and ctDNA from 19 sequential mRCC patients were compared. GAs in each were statistically evaluated using 52 Kidney Cancer Journal the Wilcoxon signed-rank test. The Fischer’s exact test was used to compare the incidence of mutations in selected molecular pathways. Conclusion: When controlling for genes tested by both platforms, similar number of GAs were detected by both tissue and ctDNA based NGS. However, there was discordance in the type of GAs detected suggesting that ctDNA NGS may be more reflective of dynamic tumor genomic heterogeneity. Hence, these two platforms may be considered complementary to each other, rather than interchangeable, for assessment of tumor GAs to guide selection of targeted clinical trial therapies. Evolution of circulating tumor DNA profile from first-line to subsequent therapy in metastatic renal cell carcinoma. Pal SK, Sonpavde G, Agarwal N, et al. Eur Urol. 2017 Apr 13. pii: S0302-2838(17)30277-4. Summary: Circulating tumor DNA (ctDNA) is a platform to noninvasively ascertain temporal changes in genomic profile. The ctDNA profile was obtained in mRCC patients who received ctDNA profiling as part of routine clinical care at progression using a 73-gene Clinical Laboratory Improvement Amendments-certified ctDNA platform. Genomic alterations (GAs) were pooled for the entire cohort. A comparison of first- and post first-line was performed with grouping based on conventional practice patterns (first-line regimens included sunitinib, pazopanib, and bevacizumab, and postfirst-line regimens included everolimus, axitinib, cabozantinib, and nivolumab). ctDNA clinical results from a nationwide cohort of 220 consecutive patients with mRCC were assessed (145 men, 75 women; median age: 63 yr, interquartile range: 57-70). GAs were detected in 78.6% of patients. The most frequent GAs in the overall cohort included TP53 (35%), VHL (23%), EGFR (17%), NF1 (16%), and ARID1A (12%). Thirty-eight and 64 patients were coded as receiving first-line and later line agents, respectively. The highest disparity in GA frequencies in postfirst-line versus first-line were in TP53 (49% vs 24%), VHL (29% vs 18%), NF1 (20% vs 3%), EGFR (15% vs 8%), and PIK3CA (17% vs 8%) while ARID1A was equivalent (13% vs 11%). Restricting the analysis to later lines versus first-line vascular endothelial growth factor inhibitors, these differences were even more prominent, particularly for TP53 (64% vs 31%) and NF1 (29% vs 4%). Conclusion: In the largest assessment of ctDNA-detected GAs prevalence in mRCC to date, the majority of patients demonstrated clinically and biologically relevant GAs. Increasing p53 and mechanistic target of rapamycin pathway (eg, NF1, PIK3CA) alterations in post first-line patients with first-line vascular endothelial growth factor-directed therapy may underlie mechanisms of resistance. Routine ctDNA assessment during the clinical course of mRCC patients may have therapeutic implications. KCJ JOURNAL CLUB (continued from page 36)
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