HER2 is a target we should be considering in BTC’s starting in the first line. The overall response rates were 80% with 55% having a CR/PR. Interestingly it seems HER2 is much more prevalent in GBC compared to cholangio’s, at least in this study.
Human epidermal growth factor receptor 2 (HER2) overexpression is seen in 4%-16% of biliary tract cancers (BTCs). We aimed to evaluate the clinical activity of gemcitabine-cisplatin (GC) plus anti-HER2 antibody trastuzumab as initial treatment in HER2-positive BTCs.
This study was an investigator-initiated, open-label, single-arm, multi-institutional, phase II trial in adult patients with HER2-positive (defined as immunohistochemistry [IHC] 3+ or IHC 2+ and fluorescent in situ hybridization–positive), treatment-naïve BTCs. The primary end point of the study was 6-month progression-free survival (PFS). Next-generation sequencing was performed on tissue samples to evaluate mutational status.
From March 2020 to August 2022, of the 876 screened patients, 118 (13.4%) were found to have HER2-positive status, of whom 90 were enrolled in the study. Most patients had GBC (n = 96; 96%) with two or more sites of metastatic disease (n = 70; 78%). With a median follow-up of 17.3 (95% CI, 15.22 to 19.32) months, 72 patients had disease progression with a median PFS of 7 (95% CI, 6.2 to 7.8) months. The diagnosis to event 6-month PFS rate was 75.6% (95% CI, 66.6 to 84.6). A complete or partial response was seen in 50 (55.5%) patients and 22 (24.4%) patients had stable disease as the best response to treatment, for an overall disease control rate of 80%. The presence of isolated TP53 mutations was associated with inferior PFS compared with other mutations (TERT promoter, HER2, PIK3CA, etc) or no detected mutations (6.51 v 12.02 v 10.58 months; P < .001).
The combination of GC and trastuzumab achieved its primary end point of improving PFS compared with historical data in the treatment-naïve HER2-positive BTC. Evaluating additional mutations such as TP53 and PIK3CA along with HER2 testing may help to preferentially select patients for anti-HER2 therapy in the future (Clinical Trial Registry India number: CTRI/2019/11/021955).
Enhertu shows promising activity in met-BTC’s that are HER2-pos but also in HER2-low. Using this in HER2-low would be off label but something to consider after SOC therapy.
A Phase II basket study looking at tucatinib + trastuzumab in mBTC, only 30 patients were studied as this is a small subpopulation. However, the results were compelling, with an ORR of 47%. For a 3L patient who has failed gem/cis and FOLFONI, this would be a targeted option to consider.
A South Korean study showing the superiority of 5FU/LV + liposomal irinotecan vs. 5FU/LV alone. This is an attractive option after gemcitabine + cisplatin, particularly in patients who may not tolerate oxaliplatin due to peripheral neuropathy.
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