In a multicentre, single-arm, phase II HERB study of trastuzumab deruxtecan, conducted in patients with HER2-positive biliary tract cancer (BTC) refractory or intolerant to treatment including gemcitabine and additionally performed exploratory evaluation in the HER2-low BTC cohort, the primary cohort of patients with HER2-positive BTC achieved a confirmed objective response rate (ORR) of 36.4%, resulting in the primary endpoint being met, while confirmed ORR in patients with HER2-low disease was 12.5%. Median progression-free survival (PFS) in the HER2-positive and HER2-low BTC was 5.1 months and 3.5 months, respectively.
Although the safety profile was generally manageable, in terms of interstitial lung disease (ILD), there is a probability that their frequency and severity may be high in patients with BTC. The results of the HERB, NCCH1805 study are reported by Dr. Chigusa Morizane of the Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital in Tokyo, Japan, and colleagues on 5 August 2024 in the JCO.
The authors wrote in the background that further investigations are needed to develop more effective second- or later-line treatment options for patients with progressive BTC. HER2 overexpression, gene amplification, or both have been reported in 15-30% of gallbladder cancers, 10-20% of extrahepatic cholangiocarcinomas and cancer of the ampulla of Vater, and 3-5% of intrahepatic cholangiocarcinomas. In HER2-positive BTC, the antitumour activity of several agents has been reported in case reports or case series, and pertuzumab plus trastuzumab showed an ORR of 23% in the HER2-positive BTC cohort of 39 patients in a phase II basket study.
In HERB study, the researchers aimed to investigate the efficacy and safety of trastuzumab deruxtecan in patients with HER2-positive refractory BTC or intolerant to treatment. They also performed an exploratory evaluation of the HER2-low BTC cohort. Patients from five institutions in Japan were enrolled. Eligible patients had pathologically confirmed unresectable or recurrent BTC with centrally confirmed HER2-positive (immunohistochemistry [IHC]3+ or IHC2+ and in situ hybridisation [ISH]+) or HER2-low (IHC2+ and ISH-, IHC1+, and IHC0 and ISH+) and were refractory or intolerant to a gemcitabine-containing regimen.
The patients received 5.4 mg/kg trastuzumab deruxtecan once every 3 weeks until disease progression or unacceptable toxicity. The primary endpoint was the confirmed ORR in HER2-positive BTC by an independent central review with threshold ORR of 15% and expected ORR of 40%. A total of 32 patients were enrolled and treated.
Among these patients, 22 with HER2-positive disease comprised the primary efficacy population and had a confirmed ORR of 36.4% (90% confidence interval 19.6 to 56.1; p = 0.01), meeting the primary endpoint. Eight patients with HER2-low disease comprised the exploratory population and had a confirmed ORR of 12.5%.
The most common ≥grade 3 treatment-related adverse events were anaemia (53.1%) and neutropenia (31.3%). Eight patients (25.0%) had ILD, including two with grade 5 events. Although the safety profile was generally manageable, ILD requires careful monitoring and early intervention.
In an accompanied Oncology Grand Rounds article, Dr. Katherine Van Loon of the University of California San Francisco (UCSF) Helen Diller Family Comprehensive Cancer Center and Division of Hematology/Oncology, Department of Medicine, UCSF in San Francisco, CA, US, and colleagues commented the unanswered questions and future directions in development of anti-HER2 therapies for patients with BTC.
They wrote that the mechanisms that drive clinical resistance to HER2-directed therapy in BTC remain uncertain and commented on an intriguing possibility that regimens targeting both the ECD2 and ECD4 epitopes of HER2 may delay resistance by blocking both signalling mechanisms and impeding HER2-HER3 heterodimerisation-mediated resistance to ECD4 targeting in BTC.
The Cancer Genome Atlas shows that >5% of patients with ERBB2 amplification also have ERBB2-activating mutations, although clinical data on this population are limited. ERBB2 (S310F) is the most common ERBB2 mutation and disrupts the ECD2 epitope, blocking pertuzumab, but not trastuzumab binding. This would limit the benefit to patients of regimens targeting ECD2 and raises the possibility that tumours harbouring ERBB2 (S310F) mutations may be better served by trastuzumab plus tucatinib, trastuzumab deruxtecan, or trastuzumab plus FOLFOX.
Additional open questions remain around the optimal sequencing of anti-HER2 therapies in BTC. Furthermore, although current evidence supports the use of anti-HER2 therapies as second-line therapy for BTC, studies are ongoing to investigate the role for anti-HER2 agents in first-line treatment, when patients might potentially derive more benefit.
Besides trastuzumab deruxtecan, other anti-HER2 antibody-drug conjugates with novel mechanisms are being studied in patients with BTC and have shown promising early results. Additionally, bispecific antibodies, chimeric antigen receptor natural killer cells, and chimeric antigen receptor monocytes, are tested in phase I basket trials for which patients with BTC would be eligible. However, many of these studies exclude patients with high risk for infection, such as patients with indwelling biliary stents or percutaneous drains because of high risk for cholangitis or other biliary infections.
Future anti-HER2 regimens in BTC may look to address more mechanistic categories with demonstrated efficacy, for instance, adding pertuzumab to or substituting zanidatamab into trastuzumab-containing regimens. They conclude that the results from the HERB study, focused on a rare population of HER2-positive BTCs, are particularly timely in the context of recent first-ever tissue-agnostic approval of a targeted anti-HER2 agent.
The HERB study was supported in part by grants from the Japan Agency for Medical Research and Development, and funded by Daiichi Sankyo Co, Ltd. The study drug was donated by Daiichi Sankyo Co, Ltd.
References
- Ohba A, Morizane C, Kawamoto Y, et al. Trastuzumab Deruxtecan in Human Epidermal Growth Factor Receptor 2–Expressing Biliary Tract Cancer (HERB; NCCH1805): A Multicenter, Single-Arm, Phase II Trial. JCO; Published online 5 August 2024. DOI: https://doi.org/10.1200/JCO.23.02010
- Zeme EL, Van Loon K, Kelley RK, Gordan JD. Emerging Therapies for the Management of Human Epidermal Growth Factor Receptor 2–/ERBB2-Altered Advanced Biliary Tract Cancers. JCO; Published online 5 August 2024. DOI: https://doi.org/10.1200/JCO.24.00868