Abstract 1193P
Background
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+).
Methods
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.
Results
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.
Conclusions
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: 1193P
| NTRK-rp | ROS1-rp | |
| ORR, % (95% CI) in primary efficacy population subsets | ||
| CTA+† | 57.4 (43.2–70.8), n=54 | 78.4 (64.8–88.7), n=51* |
| CTA+ FL1 CDx+ | 72.2 (46.5–90.3), n=18 | 72.2 (46.5–90.3), n=18 |
| CTA+ F1L CDx- | 55.0 (31.5–76.9), n=20 | 72.7 (39.0–94.0), n=11 |
| CTA+ F1L CDx unknown | 43.8 (19.8–70.1), n=16 | 86.4 (65.1–97.1), n=22 |
| Performance, % (95% CI); n/N | ||
| PPA F1L CDx vs CTA | 47.4 (31.0–64.2); 18/38 | 64.5 (45.4–80.8); 20/31 |
| NPA F1L CDx vs CTA | 100 (92.5–100.0); 47/47 | 100 (93.4–100); 54/54 |
| PPV 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
Clinical trial identification
ALKA-372-001 (EudraCT 2012-000148-88); STARTRK-1 (NCT02097810); STARTRK-2 (NCT02568267).
Editorial acknowledgement
Third-party medical writing assistance, under the direction of the authors, was provided by Lewis Cawkwell, PhD, of Gardiner-Caldwell Communications, and was funded by F. Hoffmann-La Roche Ltd.
Legal entity responsible for the study
F. Hoffmann-La Roche Ltd.
Funding
F. Hoffmann-La Roche Ltd.
Disclosure
R. Dziadziuszko: Advisory/Consultancy: F. Hoffmann-La Roche, Foundation Medicine, Pfizer, AstraZeneca, Celon Pharma, Merck, MSD, Takeda, Seattle Genetics, Novartis; Travel/Accommodation/Expenses: F. Hoffmann-La Roche, AstraZeneca. F. André: Research grant/Funding (institution): AstraZeneca, Novartis, Pfizer, Lilly, F. Hoffmann-La Roche. W-K. Yip: Shareholder/Stockholder/Stock options, Long term incentive from FMI: F. Hoffmann-La Roche; Full/Part-time employment: Foundation Medicine Incorporated, a subsidiary of Roche Holdings. X. Wu: Shareholder/Stockholder/Stock options: F. Hoffmann-La Roche; Full/Part-time employment: Genentech. J. Skoletsky: Shareholder/Stockholder/Stock options: F. Hoffmann-La Roche; Full/Part-time employment: Foundation Medicine. R. Woodhouse: Shareholder/Stockholder/Stock options: F. Hoffmann-La Roche; Full/Part-time employment: FoundationMedicine, Inc. T. Hung: Full/Part-time employment: Genentech. T.R. Wilson: Shareholder/Stockholder/Stock options: F. Hoffmann-La Roche; Full/Part-time employment: Genentech. T. Riehl: Shareholder/Stockholder/Stock options: F. Hoffmann-La Roche; Full/Part-time employment: Genentech/F. Hoffmann-La Roche. L. Dennis: Shareholder/Stockholder/Stock options: F. Hoffmann-La Roche. All other authors have declared no conflicts of interest.