Early plasma circulating tumor DNA (ctDNA) changes to predict response to first-line pembrolizumab +/- chemotherapy in non-small cell lung cancer (NSCLC).

Abstract

3518 Background: ctDNA shedding into plasma can be prognostic in lung cancer, and changes in plasma ctDNA levels correlate with response to systemic therapy. However, is unknown whether early detection of ctDNA levels change predicts response to first-line pembrolizumab +/- chemotherapy. We hypothesized that serial assessment of plasma ctDNA by next generation sequencing would enable early detection of response to immunotherapy in NSCLC prior to radiological assessment. Methods: Patients (pts) with advanced NSCLC who received first-line treatment with pembrolizumab +/- platinum doublet chemotherapy at the Dana-Farber Cancer Institute were enrolled in this study. Plasma collected from pts prior to starting therapy and serially after starting therapy was analyzed by NGS using enhanced tagged-amplicon sequencing (eTAm-Seq) of hotspots and coding regions from 36 genes (InVisionFirst-Lung). ctDNA allele fractions (AF) change was correlated with treatment responses. Results: Among 38 pts who received first-line pembrolizumab +/- platinum/pemetrexed, 9 (23.7%) had no ctDNA detected at baseline while 29 had alterations detected. Pembrolizumab was administered as monotherapy in 19 of the 29 pts (65.5%) and in combination with chemotherapy in 10 (34.5%). The median time to the first ctDNA assessment was 21 days (IQR:21-24). Pts who had a decrease in the max AF at the first blood drawn compared to pre-treatment AF had a significantly higher response rate to treatment with pembrolizumab +/- platinum doublet chemotherapy than those with an AF increase (64.5% vs 7.7%, P < 0.01). The median PFS (mPFS) and median OS (mOS) were significantly longer among pts with early AF decrease compared to those with an AF increase mPFS: 13.7 vs 3.4 months, HR:0.20, P < 0.01; mOS: 32.8 vs 14.7 months, HR:0.06, P < 0.01). The median change in allele fraction at the first on-treatment blood draw was -90% (range: -100 to +65), -71% (range: -100 to +100) and +35% (range: +17 to +100) in pts with subsequent radiological response (N = 11), stable disease (N = 11) and progressive disease (N = 7), respectively (P < 0.01). Among the 9 cases with no detected ctDNA at baseline, 2 pts with emergence of cfDNA within 8 weeks developed progressive disease. In the other 7 cases, ctDNA remained undetected. Conclusions: In pts with advanced NSCLC, rapid decreases in ctDNA prior to radiological assessment correlated with clinical benefit. These results suggest a potential role for ctDNA as an early pharmacodynamic biomarker of response or resistance to immunotherapies.