Trastuzumab Deruxtecan in Human Epidermal Growth Factor Receptor 2–Expressing Biliary Tract Cancer (HERB; NCCH1805): A Multicenter, Single-Arm, Phase II Trial

Author(s): Akihiro Ohba, MD¹; Chigusa Morizane, MD, PhD¹; Yasuyuki Kawamoto, MD, PhD²; Yoshito Komatsu, MD, PhD²; Makoto Ueno, MD, PhD³; Satoshi Kobayashi, MD³; Masafumi Ikeda, MD, PhD⁴; Mitsuhito Sasaki, MD⁴; Junji Furuse, MD, PhD^3,5; Naohiro Okano, MD, PhD⁵; Nobuyoshi Hiraoka, MD, PhD⁶; Hiroshi Yoshida, MD, PhD⁶; Aya Kuchiba, PhD⁷; Ryo Sadachi, PhD⁷; Kenichi Nakamura, MD, PhD, MBA⁸; Naoko Matsui, BS⁸; Yoshiaki Nakamura, MD, PhD⁹; Wataru Okamoto, MD, PhD¹⁰; Takayuki Yoshino, MD, PhD⁹; Takuji Okusaka, MD, PhD¹

Source: https://doi.org/10.1200/JCO.23.02010

Dr. Anjan Patel's Thoughts

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.

PURPOSE

Treatment options for patients with unresectable or recurrent biliary tract cancer (BTC) who progress on a gemcitabine-containing regimen are limited. In addition, the significance of anti–human epidermal growth factor receptor 2 (HER2) therapy in HER2-expressing BTC has not been sufficiently investigated.

METHODS

In this phase II trial, participants 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 hybridization [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 (T-DXd) once every 3 weeks until disease progression or unacceptable toxicity. The primary end point was the confirmed objective response rate (ORR) in HER2-positive BTC by an independent central review (threshold ORR, 15%; expected ORR, 40%).

RESULTS

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% CI, 19.6 to 56.1; P = .01), meeting the primary end point. Eight 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 anemia (53.1%) and neutropenia (31.3%). Eight patients (25.0%) had interstitial lung disease (ILD), including two grade 5 events.

CONCLUSION

T-DXd showed promising activity in patients with HER2-positive BTC and a signal of efficacy in patients with HER2-low BTC. Although the safety profile was generally manageable, ILD requires careful monitoring and early intervention.

Author Affiliations

¹Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Tokyo, Japan; ²Division of Cancer Center, Hokkaido University Hospital, Sapporo, Japan; ³Department of Gastroenterology, Kanagawa Cancer Center, Yokohama, Japan; ⁴Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital East, Kashiwa, Japan; ⁵Department of Medical Oncology, Kyorin University Faculty of Medicine, Tokyo, Japan; ⁶Division of Pathology and Clinical Laboratories, National Cancer Center Hospital, Tokyo, Japan; ⁷Biostatistics Section, Clinical Research Support Office, National Cancer Center Hospital/Biostatistics Division, Center for Research Administration and Support, National Cancer Center, Tokyo, Japan; ⁸Clinical Research Support Office, National Cancer Center Hospital, Tokyo, Japan; ⁹Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan; ¹⁰Cancer Treatment Center, Hiroshima University Hospital, Hiroshima, Japan

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)

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.

Tucatinib and Trastuzumab for Previously Treated Human Epidermal Growth Factor Receptor 2–Positive Metastatic Biliary Tract Cancer (SGNTUC-019): A Phase II Basket Study

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.

Treatment With Liposomal Irinotecan Plus Fluorouracil and Leucovorin for Patients With Previously Treated Metastatic Biliary Tract Cancer

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.