Circulating tumor DNA (ctDNA) analyses in patients with HER2-positive biliary tract cancer (BTC) treated with trastuzumab deruxtecan (T-DXd): Exploratory results from the HERB trial.
Authors: Ohba Akihiro , Morizane Chigusa , Kawamoto Yasuyuki , Komatsu Yoshito , Ueno Makoto , Kobayashi Satoshi , Ikeda Masafumi , Sasaki Mitsuhito , Furuse Junji , Okano Naohiro , Hiraoka Nobuyoshi , Yoshida Hiroshi , Kuchiba Aya , Sadachi Ryo , Nakamura Kenichi , Matsui Naoko , Nakamura Yoshiaki , Okamoto Wataru , Yoshino Takayuki , Okusaka Takuji 
Published: June 2023

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Background: In the phase 2 HERB trial (NCCH1805; JMA-IIA00423), T-DXd exhibited promising activity among patients with HER2-positive BTC (ASCO 2022 ab 4006). HER2 positivity was defined as tumor tissue immunohistochemistry (IHC) 3+ or IHC 2+ with in situ hybridization (ISH) positivity. HER2 gene amplification (HER2-amp) can also be detected in ctDNA, which may be an alternative when tumor tissue is not available. ctDNA may also detect tumor molecular changes during treatment and at disease progression. Methods: In this ancillary study, we collected plasma samples for ctDNA analysis (Guardant360) at baseline (BL), day 1 of cycle 2 (C2D1; ie, day 22 of treatment), and end of treatment (EOT). The relationships between clinical outcomes and ctDNA genomic profiles were evaluated. Results: Among the 30 patients in the full analysis set of HERB (22 with HER2-positive and 8 with HER2-low BTC), plasma samples for ctDNA were obtained from 30, 29, and 24 at BL, C2D1, and EOT, respectively. HER2-amp was found in ctDNA of 8 BL samples, all of which were from tissue HER2-positive patients. This included 50% (5 of 10) of the IHC 3+ tumors and 25% (3 of 12) of the IHC 2+/ISH + tumors. Comparing clinical outcomes for patients with HER2-amp in ctDNA (n=8) to those with HER2-positive in tissue (n=22), the confirmed objective response rate (cORR) was 50.0% (95% CI, 15.7–84.3), including all 2 CR cases, vs 36.4% (95% CI, 17.2–59.3); median duration of response was 7.9 (95% CI, 2.8–11.5) vs 7.4 months (95% CI, 2.8–NA), median progression-free survival (PFS) was 6.1 (95% CI, 2.8–20.3) vs 5.1 months (95% CI, 3.0–7.3), and median overall survival was 10.8 (95% CI, 4.7–NA) vs 7.1 months (95% CI, 4.7–14.6). Plasma copy number (median 5.1, range 2.3–9.9) was not associated with response or survival, even after adjusting for maximum variant allele frequency (MAF). Common BL genomic mutations found in ctDNA were in TP53 (n=19, 63%), PIK3CA (n=8, 27%), and TERT (n=7, 23%). No mutation was associated with treatment efficacy. Median MAF decreased from 7.3% at BL to 1.6% at C2D1. Decreased MAF was associated with better response (CR, PR, and SD) and longer PFS. Among 24 EOT samples, including 7 from patients with BL HER2-amp in ctDNA, 10 (42%) acquired potential resistance alterations, most related to receptor tyrosine kinase, MAPK, and PI3K pathways. HER2-amp was lost at EOT in 4 of the 7 patients with HER2-amp detected in BL ctDNA. Conclusions: Using a ctDNA assay, HER2-amp was detected in 36% of patients with tissue HER2-positive BTC. Those with HER2-amp in ctDNA than HER2-positive in tissue had potentially higher cORR and longer survival with TDXd. Clinical trial information: JMA-IIA00423 .