Targeting HER2 in BTCs

For patients with locally advanced/metastatic biliary tract cancers (BTCs), standard second-line therapies offer limited clinical benefit, highlighting the need for novel therapies in this setting. Given that HER2 amplification/overexpression is observed in a subset of BTCs, HER2-targeted therapies are being evaluated in gastrointestinal cancers including BTCs.¹ These include dual HER2 inhibition with anti-HER2 antibodies pertuzumab and trastuzumab; antibody-drug conjugate trastuzumab deruxtecan (T-DXd); the bispecific antibody zanidatamab, which targets 2 distinct HER2 epitopes; and trastuzumab plus gemcitabine/cisplatin. At the 5th annual CCA Summit meeting, Shubham Pant, MD, provided an overview of clinical data relating to these HER2-targeted therapies in BTC.¹

In the MyPathway trial, which evaluated the combination of pertuzumab and rastuzumab in patients with HER2-positive metastatic BTC, an overall response rate (ORR) of 23% was achieved; median progression-free survival (PFS) was 4 months, and overall survival was 10.9 months.²

In the HERB trial, T-DXd showed promising antitumor activity in patients with HER2-expressing BTCs; ORR of 36.4% was achieved in HER2-positive patients including 2 complete responses.³ Treatment-emergent adverse events grade ≥3 were mostly hematologic including anemia, decreased neutrophil and white blood cell counts, and interstitial lung disease/pneumonitis.³

In the phase 2b HERIZON-BTC-01 study, zanidatamab monotherapy demonstrated meaningful clinical benefit (ORR was 41.3% with a manageable safety profile in patients with HER2-amplified, unresectable, locally advanced, or metastatic BTC; median PFS was 5.5 months).⁴ No grade 4 treatment-related adverse events (TRAEs) and no treatment-related deaths occurred; grade 3 TRAEs were reported in 18% of patients, including diarrhea and decreased ejection fraction.⁴

In the TAB study, which evaluated the clinical activity of trastuzumab plus gemcitabine/cisplatin combination therapy as initial treatment in HER2-positive BTC, a 12-month overall survival (OS) rate of 39.1% and median OS of 9.95 months were achieved; 12-month PFS rate was 17.6% and median PFS was 7.95 months.⁵

These data support HER2-targeted therapies having meaningful clinical benefit and potential as a future treatment option in HER2-positive BTC.¹ Other HER2-targeted combination regimens such as tucatinib and trastuzumab are being investigated in BTC; it is anticipated that data from such studies will define the role of HER2-directed therapies in BTCs.

Sources:

1. Pant S. Her 2 in BTC. Presented at: 5th Annual CCA Summit Meeting, October 19-21, 2023; Scottsdale, AZ.
2. Javle M, Borad MJ, Azad NS, et al. Pertuzumab and trastuzumab for HER2-positive, metastatic biliary tract cancer (MyPathway): a multicentre, open-label, phase 2a, multiple basket study. Lancet Oncol. 2021;22:1290-1300.
3. Ohba A, Morizane C, Kawamoto Y, et al. Trastuzumab deruxtecan (T-DXd; DS-8201) in patients (pts) with HER2-expressing unresectable or recurrent biliary tract cancer (BTC): an investigator-initiated multicenter phase 2 study (HERB trial). J Clin Oncol. 2022;40(suppl 16):abstr 4006.
4. Harding JJ, Fan J, Oh D-Y, et al. Zanidatamab for HER2-amplified, unresectable, locally advanced or metastatic biliary tract cancer (HERIZON-BTC-01): a multicentre, single-arm, phase 2b study. Lancet Onc. 2023;24(7):P772-P782.
5. Ostwal VS, Mandavkar S, Bhargava PG, et al. Trastuzumab (T) plus gemcitabine-cisplatin (GC) for treatment naïve HER2 positive biliary tract adenocarcinomas (BTC): a multicentre open-label, phase II study (TAB). J Clin Oncol. 2023;41(suppl 16):abstr 4089.