A multi-institutional, investigator-initiated, open label, single-arm, phase II TAB study evaluated the combination of trastuzumab with gemcitabine and cisplatin in patients with treatment-naïve HER2-positive advanced biliary tract cancer. The study met the primary objective of an improvement in progression-free survival (PFS) with no new safety signals and improved patient-reported outcomes.
This is the first prospective study to report the outcomes of trastuzumab combined with chemotherapy in this population. The findings are published by Dr. Anant Ramaswamy of the Department of Medical Oncology, Tata Memorial Hospital, Homi Bhabha National Institute in Mumbai, India, and colleagues on 9 November 2023 in the JCO.
The standard first-line treatment, for over a decade, in patients with biliary tract cancer has remained a combination of gemcitabine and platinum (cisplatin or oxaliplatin), although recent evidence has suggested a marginal overall survival benefit of adding either durvalumab or pembrolizumab to the gemcitabine-cisplatin combination.
Specific molecularly defined subsets of biliary tract cancer with FGFR fusions, IDH1 mutations, NTRK fusions, and MSI-high tumour have been identified with approved targeted treatment options available. HER2 overexpression or amplification has also been identified as a druggable molecular target in biliary tract cancer. HER2 mutations are also considered poor prognostic markers with emerging data on the correlation between HER2 mutations and response to anti-HER2 therapy in biliary tract cancer.
The authors wrote in the background that several studies have shown the feasibility of targeting HER2, and these include early-phase studies such as MyPathway, KCSG-HB19-14, and the recently published HERIZON-BTC-01. Although early-phase studies have shown that targeting HER2 is feasible in advanced biliary tract cancer, this has not been prospectively evaluated in treatment-naïve patients in combination with first-line chemotherapeutic regimens.
TAB investigators hypothesised that the addition of an anti-HER2 antibody, trastuzumab, to gemcitabine-cisplatin may improve clinical outcomes in comparison with historical controls treated with chemotherapy alone. They performed a single-arm multicentre phase II study to evaluate the efficacy and safety of trastuzumab plus gemcitabine-cisplatin in treatment-naïve patients with advanced biliary tract cancer.
HER2 overexpression is seen in 4-16% of biliary tract cancers. In this study HER2-positive status was defined as immunohistochemistry [IHC] 3+ or IHC 2+ and fluorescent in situ hybridisation–positive. Next-generation sequencing was performed on tissue samples to evaluate mutational status. The primary endpoint of the study was 6-month PFS.
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 gallbladder carcinoma (96%) with two or more sites of metastatic disease (78%). With a median follow-up of 17.3 months, 72 patients had disease progression with a median PFS of 7 months (95% confidence interval [CI] 6.2 to 7.8). 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 55.5% patients and 24.4% patients had stable disease as the best response to treatment, for an overall disease control rate of 80%.
The authors commented that slightly higher diagnosis to event PFS rate is primarily because of deferment in initiation of therapy from diagnosis of advanced disease because of reasons such as baseline obstructive jaundice and the fact that not all patients in the study had an immediately preceding radiologic assessment before the start of systemic treatment.
One of the major features of this study was that 96% of patients had advanced gallbladder carcinoma. Reasons for this are the high prevalence of gallbladder carcinoma in certain regions of India, recruiting institutions are high-volume centres for the management of gallbladder carcinoma, and HER2 overexpression/amplification is more common in gallbladder carcinoma compared with other subsets of biliary tract cancers.
The adverse event rate and need for dose modifications were not increased compared with previously published data with gemcitabine-cisplatin alone; only two patients required temporary cessation of trastuzumab because of fall in cardiac ejection fraction. Trastuzumab, besides expected cardiac toxicity, did not add additional toxicity to that observed with chemotherapy alone in this dtudy. In fact, the patient-reported outcomes assessed by EORTC QLQ-C30 showed improvement in all the domains in 64% patients correlating with the 6-month PFS improvement seen in 67% patients.
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 versus 12.02 versus 10.58 months; p < 0.001). Evaluating mutations such as TP53 and PIK3CA along with HER2 testing may help to preferentially select patients for anti-HER2 treatment in the future.
The authors wrote that further randomised phase III studies are required to evaluate whether the combination of trastuzumab and chemotherapy will improve survival when compared with chemotherapy alone in this subset of patients.
The study was presented in part at ASCO 2023 Annual Meeting (2-5 June 2023, Chicago, IL, US).
Ostwal V, Mandavkar S, Bhargava P, et al. Trastuzumab Plus Gemcitabine-Cisplatin for Treatment-Naïve Human Epidermal Growth Factor Receptor 2–Positive Biliary Tract Adenocarcinoma: A Multicenter, Open-Label, Phase II Study (TAB). JCO; Published online 9 November 2023. DOI:10.1200/JCO.23.01193