HER2 over-expression/amplification, which accounts for roughly 15% of total biliary tract cancer (BTC) patients, has been identified as a druggable molecular target by recent genomic profilings, Trastuzumab is a humanized monoclonal antibody against HER2 that has been shown to be effective in patients with HER2-positive breast and gastric cancer, but it has not been studied prospectively in HER2-positive BTC. In the phase III ABC-06 trial, the FOLFOX regimen showed survival benefit as a second-line therapy of BTC. We report the result of a multi-institutional phase II trial of Trastuzumab plus modified-FOLFOX as a second- or third-line treatment for HER2-positive BTC (KCSG-HB19-14; NCT04722133).
HER2-positive (defined as IHC3+ or IHC2+/ISH+ or ERBB2 gene copy number ≥6.0 by NGS) BTC (intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, gallbladder cancer and ampulla of vater cancer) patients who progressed on gemcitabine/cisplatin containing chemotherapy (1 or 2 previous chemotherapy lines permitted) were enrolled. Pts received trastuzumab 4mg/kg (after 6mg/kg load) D1, oxaliplatin 85mg/m2 D1, Leucovorin 200mg/m2 D1, 5-FU 400mg/m2 bolus D1, and 5-FU 2400mg/m2 infusion D1-2 every 2 weeks until unacceptable toxicities or disease progression. The primary endpoint was ORR per RECIST v1.1. Secondary endpoints included PFS, DCR, OS, safety, QOL and correlative biomarker exploration.
Total of 34 pts were treated with median follow up of 9.9 months, and 6 pts remained on treatment (treatment duration range: 1.0 to 14.7 months). The primary endpoint was met, with 29.4% (95%CI 15.1-47.5) ORR (PR n=10), and 79.4% DCR. Median PFS was 5.1 months (95%CI 3.6-6.7) and median OS was not reached (95%CI 7.1-NR; 12-months OS rate 50.6%, 95%CI 29.3-63.6). Pts with HER2 IHC3+ (n=23, 67.6%) showed tendency for better PFS compared to pts with HER2 IHC 2+/ISH+ (median 5.5 vs 4.9 months, HR 0.52, 95%CI 0.23-1.16). Pts with HER2 3+ tumor cell proportion ≥30% (n=10) by an artificial intelligence-powered automated HER2 IHC analyzer (Lunit SCOPE HER2) showed significantly better PFS compared to pts without (median 6.67 vs 4.87 months, HR 0.33 95%CI 0.13-0.88). Targeted-panel sequencings were done with tumor tissues from 32 pts and tissue HER2-amplification by NGS did not confer better survival. Treatment-related AE (≥G3) occurred in 29 pts (85.3%) including 19 pts (55.9%) with neutropenia G3-4 and 4 pts (11.8%) with peripheral neuropathy G3-4. No pt showed cardiac AE nor treatment-related study discontinuation.
For HER2-positive BTC, 2nd- or 3rd-line trastuzumab plus FOLFOX exhibited a promising efficacy with acceptable toxicity, warranting further investigations. Targeted NGS analyses with ctDNAs from pre-treatment and post-progression liquid biopsies are ongoing.
Choong-kun Lee1, Hong Jae Chon2, Jaekyung Cheon2,3, Myung Ah Lee4, Hyeon-Su Im3, Joung-Soon Jang9, Min Hwan Kim1, Chan-Young Ock6, Jin Won Kim7, Hyung Soon Park8, Myoung Joo Kang9, Hye Jin Choi1.
1Division of Medical Oncology, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul. 2Medical Oncology, Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam. 3Department of Hematology and Oncology, Ulsan University Hospital, Ulsan University College of Medicine, Ulsan. 4Division of Medical Oncology, Department of Internal Medicine, The Catholic University of Korea, Seoul St. Mary’s Hospital, Seoul. 5Department of Internal Medicine, Chung-Ang University College of Medicine, Seoul. 6Lunit Inc., Seoul.
7Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam. 8Division of Medical Oncology, St. Vincent's Hospital, The Catholic University of Korea, Suwon. 9Department of Oncology, Inje University Haeundae Paik Hospital, Busan; Republic of Korea.
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