Efficacy and safety of HER2-targeted therapies in biliary tract cancer: A systematic review and meta-analysis of early phase clinical trials.

599 Background: Biliary tract cancers (BTC) are a rare type of gastrointestinal malignancy, often presenting in advanced stages and associated with a dismal prognosis. BTC are frequently resistant to conventional chemotherapy, with novel targeted therapies playing a pivotal role in overcoming this challenge. HER2 has recently emerged as an important actionable target in patients with BTC. We aim to evaluate the efficacy and safety of HER2 -directed monoclonal antibodies (MOAs), bispecific antibodies, antibody-drug conjugates (ADCs), and their combinations in BTC. Methods: A systematic literature search was conducted on PubMed, Embase, and Cochrane Central Register of Controlled Trials for clinical trials investigating HER2 -directed MOAs, bispecific antibodies, ADCs, and their combinations in BTC. The study was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Guidelines. A random effects model was used to pool the outcomes along with 95% confidence intervals (CI). Statistical analyses were performed using program R version 4.4.1. Results: We included 12 clinical trials with three Phase I and nine Phase II trials. The pooled ORR (objective/overall response rate) was 35.5% (95% CI: 26.2-45.3, I 2 : 69%), and the DCR (disease control rate) was 72.2% (95% CI: 65.3-78.8, I 2 : 37%). The median follow-up period for DCR was four months. Trastuzumab, in combination with gemcitabine-cisplatin as first-line therapy, had the highest median progression-free survival of 7 months (95% CI: 6.2-7.8), whereas the combination of trastuzumab and tucatinib had the longest median overall survival 15.5 months (90% CI: 6.5-16.7) reported. The most common treatment-related ≥grade 3 adverse events reported across the cohort were anemia and neutropenia. Three cases of confirmed grade 5 interstitial lung disease were reported in patients who received trastuzumab deruxtecan. Clinical trials included in this study are summarized in the table. Conclusions: Advances in precision oncology and the emergence of novel targeted therapies have revolutionized cancer management. HER2 -directed therapies have shown promising results for patients inflicted with BTC having HER2 alterations in the early phase clinical trials. Further larger studies are awaited to explore the efficacy of HER2 -directed therapies in BTC. Clinical trials of HER2 -directed therapies in BTC. HER2-directed therapy Number of clinical trials Total number of BTC participants ORR, in % (95% CI) DCR, in % (95% CI) Trastuzumab + chemo 2 124 43.2 (19.4-68.8) 80 (72.3-86.7) Trastuzumab + pertuzumab 2 45 20.9 (9.1-35.3) 53.4 (37.8-68.8) Trastuzumab deruxtecan 4 84 27.2 (6.9-52.6) 71.9 (58.4-84) Trastuzumab + tucatinib 1 30 46.7 (28.5-65.5) 76.7 (57.7-89.7) Zanidatamab 2 101 40.5 (30.9-50.4) 67.6 (57.9-76.6) SHR-A1811 1 16 56.3 (29.9-80.2) 81.3 (54.4-96)