A phase Ib/II trial of first-line trastuzumab, nivolumab, gemcitabine, and cisplatin in HER2-positive biliary tract cancer (HERBOT): A multi-institutional study from the Korean Cancer Study Group

초록

Background: Several phase II trials support HER2 as a promising actionable target in advanced biliary tract cancers (BTCs). However, the efficacy of adding anti-HER2 therapy to the current first-line standard-of-care (ICI plus gemcitabine/cisplatin [GemCis]) remains unknown. We report the results of the HERBOT trial evaluating this quadruplet combination. Methods: This multi-institutional, open-label, phase Ib/II study (KCSG-HB23-05; NCT05749900) enrolled treatment-na¨ıve pts with locally advanced/unresectable or metastatic, HER2-positive BTC (defined as centrally confirmed HER2 IHC3+, or IHC2+/ISH+, or ERBB2 gene copy number $6.0byNGS).Ptsreceivedtrastuzumab6mg/kg(after8mg/kgload)D1,nivolumab360mgD1,cisplatin25mg/m2D1,8,andgemcitabine1000mg/m2(doselevel0)or800mg/m2(doselevel-1)D1,8every3weeks.TheprimaryendpointswererecommendedphaseIIdose(RP2D,phaseIb)andORRperRECISTv1.1(phaseII).SecondaryendpointsincludedPFS,DCR,OS,safety.ExploratorybiomarkeranalysesincludedAI-poweredwhole-slideimage(WSI)profilingofHER2expressionandimmunephenotypeassessment.Results:Doselevel0wasestablishedasRP2DwithnoDLT.Amongtotalof40pts,29(72.5$3 treatmentrelated adverse events (TRAEs) included neutropenia (57.5%), anemia (30.0%), and thrombocytopenia (22.5 %). A grade 2 decreased ejection fraction occurred in 1 pt (2.5%); no grade $3immune-relatedAEswereobserved.AI-basedWSIanalysesrevealedthat$10% HER2 3+ tumor cells proportion was associated with higher ORR (80% vs 36.4%, P = 0.009) and numerically superior PFS (17.4 vs 9.1 months; HR 0.54, 95%CI: 0.23 – 1.28). Pts with inflamed immune phenotype (n = 4) showed durable responses (ORR 75%; mPFS and mOS NR). Conclusions: The HERBOT trial demonstrates that adding trastuzumab to first-line ICI plus GemCis provides robust antitumor activity and manageable safety in HER2-positive BTC. This study is the first to report the efficacy of a HER2-targeted quadruplet regimen in the first-line setting, providing strong clinical rationale for integrating HER2-targeted strategies into first-line treatment and complementing ongoing global phase III trials in this molecularly defined subgroup. Clinical trial information: NCT05749900. Research Sponsor: Korean Cancer Study Group; Boryung Corp; ONO/BMS.