1193P Clinical validity of FoundationOne liquid CDx (F1L CDx) assay as an aid in selecting patients for treatment with entrectinib

Abstract

F1L CDx is a next generation sequencing-based in vitro diagnostic for detecting genetic alterations in circulating cell-free DNA. We studied concordance between gene rearrangement status (NTRK and ROS1 fusion and non-fusion rearrangements) determined by F1L CDx and clinical trial assays (CTAs), and clinical efficacy of the TRK/ROS1 kinase inhibitor, entrectinib, in patients (pts) with NTRK rearrangement-positive (rp) or ROS1 rp tumours according to F1L CDx (FL1 CDx+). A total of 107 frozen pre-treatment plasma samples were obtained from pts with NTRK-rp solid tumours (n=49) and ROS1-rp NSCLC (n=37), according to CTAs, enrolled in the entrectinib phase II STARTRK-2 trial (NCT02568267), and pts with NTRK/ROS1 rearrangement-negative (rn) non-NSCLC tumours (n=21; external vendor). Positive and negative percentage agreements (PPA; NPA) between F1L CDx and CTA results were calculated. Positive and negative predictive values (PPV; NPV) were computed after adjustment for fusion prevalence (NTRK, 0.32%; ROS1, 1%). Clinical efficacy in F1L CDx+ cohorts was calculated by clinical bridging and compared with primary efficacy populations from pivotal entrectinib clinical trials. A total of 98 samples were evaluable by F1L CDx, of which 85 were included in primary analyses (NTRK-rp, 38; ROS1-rp, 31; NTRK/ROS1-rn, 16). Clinical efficacy of entrectinib according to CTA and F1L CDx results are presented (Table). Clinical bridging from CTAs to F1L CDx estimated the objective response rate (ORR) as 72.2% (95% CI 50.0–88.9) in both the F1L CDx NTRK-rp and ROS1-rp cohorts; greater than the CTA+ NTRK-rp subset and similar to the CTA+ ROS1-rp subset (Table). Observed PPA (Table) likely reflects comparison vs multiple tissue DNA/RNA based CTAs and is in line with plasma vs tissue PPA of FDA-approved plasma CDx. We show the clinical validity of using F1L CDx to identify pts with NTRK-rp tumours and ROS1-rp NSCLC who may benefit from entrectinib treatment.Table: 1193PNTRK-rpROS1-rpORR, % (95% CI) in primary efficacy population subsetsCTA+†57.4 (43.2–70.8), n=5478.4 (64.8–88.7), n=51*CTA+ FL1 CDx+72.2 (46.5–90.3), n=1872.2 (46.5–90.3), n=18CTA+ F1L CDx-55.0 (31.5–76.9), n=2072.7 (39.0–94.0), n=11CTA+ F1L CDx unknown43.8 (19.8–70.1), n=1686.4 (65.1–97.1), n=22Performance, % (95% CI); n/NPPA F1L CDx vs CTA47.4 (31.0–64.2); 18/3864.5 (45.4–80.8); 20/31NPA F1L CDx vs CTA100 (92.5–100.0); 47/47100 (93.4–100); 54/54PPV F1L CDx‡100 (82.4–100.0)100 (83.9–100)NPV F1L CDx§99.8 (98.8–99.9)99.6 (99.4–99.8)*2 ROS1-rp pts removed per FDA request†ORR in ALKA/STARTRK-1/STARTRK-2 integrated analysis‡95% CI Wilson score method§95% CI 5000 bootstraps Open table in a new tab