OD2-2 Trastuzumab plus FOLFOX for gemcitabine/cisplatin refractory HER2-positive biliary tract cancer: A multi-institutional phase II trial of the Korean Cancer Study Group (KCSG-HB19-14)

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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 updated 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, and gallbladder 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. As of May 01, 2022, total of 34 pts were treated with median follow up of 13.0 months, and 3 pts remained on treatment (treatment duration range: 1.0 to 18.4 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 10.7 months (95%CI 7.1-NR; 12-months OS rate 49.2%). 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). Targeted-panel sequencings were done with tumor tissues from 32 pts and tissue HER2-amplification by NGS did not confer better survival (HER2 amplified vs non-amplified, median 5.3 months vs 5.5 months). 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.

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