Circulating tumor DNA (ctDNA) analysis in participants (pts) with advanced clear cell renal cell carcinoma (ccRCC) treated with first-line pembrolizumab (pembro) monotherapy from the phase 2 KEYNOTE-427 study.

541 Background: First-line pembro showed durable antitumor activity in pts with advanced ccRCC (cohort A) and non-ccRCC (cohort B) in the phase 2 KEYNOTE-427 study. We present an exploratory analysis of the association of ctDNA status with clinical outcomes from cohort A of KEYNOTE-427. Methods: Pts with advanced ccRCC and no prior systemic therapy received pembro 200 mg IV Q3W for ≤2 years. Whole exome sequencing (WES) of tumor tissue and plasma ctDNA were evaluated using Natera’s Signatera RUO 16-plex personalized ctDNA assay. Plasma samples with ≥2 variants (of 16 tested tumor-specific variants) detected above Signatera calling threshold were considered ctDNA positive. Continuous metrics of ctDNA burden (maximum somatic allele frequency [MSAF]) were explored. Primary objectives were to descriptively evaluate the association of baseline ctDNA status and ctDNA status change from baseline to cycle 2 day 1 (C2D1) with clinical outcomes (ORR, PFS, and OS). Secondary objectives included the association of MSAF and clinical outcomes and the association between ctDNA change at C2D1 with change in tumor size. No hypothesis testing was performed. Results: Of 110 pts with ccRCC, 72 had tumor tissue and plasma samples available for ctDNA testing; 58 had evaluable baseline ctDNA data, of whom 56 also had evaluable postbaseline ctDNA data. ctDNA was detected (ctDNA positive) at baseline in 39 pts (67%). At baseline, MSAF was not associated with ORR or change in tumor size (Spearman correlation -0.023). Pts with ctDNA positive status at baseline had shorter OS than those with negative status at baseline (median 30.5 mo [95% CI, 18.1-56.4] vs 53.7 mo [95% CI, 28.7-not reached (NR)]). ORR (28% vs 26%) and PFS (median 4.1 mo [95% CI, 2.7-12.6] vs 8.3 mo [95% CI, 6.9-NR]) were similar between pts with or without detectable ctDNA at baseline. ORR was higher in pts whose ctDNA status changed from positive at baseline to negative (pos-neg) at C2D1 (4/6; 67%) compared with pts who remained positive (pos-pos; 7/32; 22%), remained negative (neg-neg; 4/14; 29%), or changed from negative to positive (neg-pos; 1/4; 25%). Compared with the pos-pos group, pts in the pos-neg group had longer PFS (median 13.9 mo [95% CI, 12.4-NR] vs 2.8 mo [95% CI, 2.7-9.7]) and OS (median NR [95% CI, 28.2 mo-NR] vs 25.2 mo [95% CI, 14.2-40.7]). Larger C2D1 decrease in ctDNA burden relative to baseline was associated with improved ORR (AUC, 0.72 [95% CI, 0.52-0.92]). Conclusions: In pts with advanced ccRCC treated with pembro, ctDNA positivity at baseline may be associated with shorter OS and change from positive ctDNA status at baseline to negative during treatment may be associated with better ORR, PFS, and OS. Larger decreases in ctDNA burden at C2D1 were also associated with improved ORR. ctDNA as a treatment biomarker should be investigated in larger cohorts. Clinical trial information: NCT02853344 .