Trastuzumab Deruxtecan Demonstrates Activity in HER2-Expressing Biliary Tract Cancer

Akihiro Ohba, MD

Fam-trastuzumab deruxtecan-nxki (Enhertu; T-DXd) elicited a confirmed objective response rate (ORR) of 36.4% (90% CI, 19.6%-56.1%) by blinded independent central review (BICR) in Japanese patients with HER2-positive biliary tract cancer (BTC), meeting the primary end point of the single-arm, phase 2 HERB study (NCCH1805; JMA-IIA00423).1 Data have been published in the Journal of Clinical Oncology.

Among those in the HER2-positive subgroup (n = 22) who responded to treatment with the antibody-drug conjugate (ADC), 9.1% achieved a complete response (CR), 27.3% experienced a partial response (PR), and 45.5% had stable disease (SD); 13.6% experienced disease progression and 4.5% were not evaluable for response. The disease control rate (DCR) in this group was 81.8% (95% CI, 59.7%-94.8%).

The ADC also demonstrated an efficacy signal in the subset of patients with HER2-low BTC (n = 8), with an ORR of 12.5% (95% CI, 0.3%-52.7%) by BICR. No CRs were achieved; 1 patient had a PR and 5 patients had SD. One patient progressed and another patient was not evaluable for response. In this group, the DCR was 75.0% (95% CI, 34.9%-96.8%).

“In this trial, T-DXd showed promising activity among patients with HER2-positive BTC and signal of efficacy among patients with HER2-low BTC,” Akihiro Ohba, MD, of Japan’s National Cancer Center Hospital, and colleagues, wrote in the paper. “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 open-label, multicenter study, which was conducted in Japan, enrolled patients aged 20 years and older with unresectable or recurrent BTC, including intrahepatic and extrahepatic cholangiocarcinoma, gallbladder cancer, and cancer of the ampulla of Vater. They were required to have adenocarcinoma or adenosquamous carcinoma; confirmed HER2 expression; refractoriness or intolerance to treatment, including gemcitabine; and an ECOG performance status of 0 or 1. Moreover, they needed to have at least 1 measurable lesion, acceptable organ function, and a left ventricular ejection fraction above 50%. Those with steroid-requiring ILD or lung disease that could not be ruled out by imaging at the time of screening were excluded. Patients could have previously received HER2-targeted therapy.

In addition to the primary end point of confirmed ORR by BICR in the HER2-positive BTC group, secondary end points included confirmed ORR by BICR in those with HER2-low BTC and all patients enrolled with BTC, confirmed ORR by local investigator review (LIR) in each cohort, DCR by BICR and LIR in each cohort, progression-free survival (PFS) by BICR and LIR, overall survival (OS) in each cohort, and safety. In a post-hoc analysis, investigators also examined duration of response (DOR).

Exploratory analyses focused on pharmacokinetics of the ADC, total antibody, and MAAA-1181a in serum concentrations, and estimating the HAHA incidence.

In the full analysis set (n = 30), the median patient age was 68 years (range, 39-80). Most patients were male (60.0%), had an ECOG performance status of 0 (70.0%), unresectable (56.7%) and metastatic (90.0%) disease. The most common primary tumor was gallbladder cancer (43.3%), followed by extrahepatic cholangiocarcinoma (26.7%), intrahepatic cholangiocarcinoma (20.0%), and cancer of the ampulla of Vater (10.0%). Seventy percent of patients previously received 2 or more regimens.

Regarding HER2 expression, 40.0% of patients had immunohistochemistry (IHC)2+/in situ hybridization (ISH)+ status, 33.3% had IHC3+/ISH+ status, 20.0% had IHC2+/ISH­– status, 3.3% had IHC1+/ISH– status, and 3.3% had IHC0/ISH+ status.

Additional efficacy data indicated that in the full analysis set, the BICR-assessed ORR was 30.0% (95% CI, 14.7%-49.4%), which comprised a CR rate of 6.7%, a PR rate of 23.3%, and a SD rate of 50.0%; 13.3% of patients experienced disease progression and 6.7% were not evaluable for response. The DCR was 80.0% (95% CI, 61.4%-92.3%). The LIR-assessed confirmed ORR was 30.0% (95% CI, 14.7%-49.4%) and DCR was 80.0% (95% CI, 61.4%-92.3%), respectively.

In the HER2-positive subset, the LIR-assessed ORR was 36.4% (95% CI, 17.2%-59.3%) and DCR was 86.4% (95% CI, 65.1%-97.1%). The estimated median DOR by LIR in this group was 7.4 months (95% CI, 2.8-not applicable). Moreover, the median PFS and OS by LIR was 5.1 months (95% CI, 3.0-7.3) and 7.1 months (95% CI, 4.7-14.6), respectively. In the HER2-low subset, the respective ORR and DCR rates by LIR assessment were 12.5% (95% CI, 0.3%-52.7%) and 62.5% (95% CI, 24.5%-91.5%). The respective median PFS and OS was 3.5 months (95% CI, 1.2-5.5) and 8.9 months (95% CI, 3.0-12.8).

Further subgroup analyses of confirmed ORR by BICR in the HER2-positive subgroup were performed. The confirmed ORR by BICR in those aged 65 years or older (n = 13) was 38.5% (95% CI, 13.9%-68.4%); in those younger than 65 years (n = 9), this rate was 33.3% (95% CI, 7.5%-70.1%). The ORR in male participants (n = 13) was 23.1% (95% CI, 5.0%-53.8%); this rate was 55.6% (95% CI, 21.2%-86.3%) in female participants (n = 9). ORRs achieved by those with a performance status of 0 (n = 15) or 1 (n = 7) were 40.0% (95% CI, 16.3%-67.7%) and 28.6% (95% CI, 3.7%-71.0%), respectively.

Broken down by primary tumor location, ORRs were 33.3% (95% CI, 0.8%-90.6%), 33.3% (95% CI, 4.3%-77.7%), 36.4% (95% CI, 10.9%-69.2%), and 50.0% (95% CI, 1.3%-98.7%) for those with intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, gallbladder cancer, or Ampulla of Vater cancer, respectively. The ORR with the ADC in those with unresectable disease (n = 13) was 38.5% (95% CI, 13.9%-68.4%) and was 33.3% (95% CI, 7.5%-70.1%) in those with recurrent disease (n = 9). Those with locally advanced (n = 2) or metastatic (n = 20) disease experienced respective ORRs of 50.0% (95% CI, 1.3%-98.7%) and 35.0% (95% CI, 15.4%-59.2%). Lastly, those with HER2 expression of IHC3+ and IHC2+ experienced respective ORRs of 40.0% (95% CI, 12.2%-73.8%) and 33.3% (95% CI, 9.9%-65.1%).

Safety data (n = 32) revealed that all patients experienced treatment-related adverse effects (TRAEs), and for 81.3% of patients, they were grade 3 or higher. Serious TRAEs occurred in 18.8% of patients. TRAEs resulted in dose reduction, treatment interruption, or discontinuation for 18.8%, 37.5%, and 25.0% of patients, respectively. Two TRAE-associated deaths were reported.

The most common TRAEs occurring in 10% or more of patients included anemia (any grade, 68.8%; grade ≥3, 53.1%), decreased neutrophil count (56.3%; 31.3%), decreased white blood cell count (56.3%; 31.3%), decreased platelet count (43.8%; 9.4%), nausea (43.8%; 0%), alopecia (40.6%; 0%), anorexia (37.5%; 3.1%), decreased lymphocyte count (34.4%; 21.9%), fatigue or malaise (34.4%; 21.9%), ILD or pneumonitis (25.0%; 12.5%), hypoalbuminemia (21.9%; 3.1%), vomiting (21.9%; 0%), and oral mucositis (15.6%; 0%).

Of the 8 patients who experienced ILD or pneumonitis, 3 experienced a grade 1 event, 1 patient experienced a grade 2 event, 2 had a grade 3 event, and 2 had grade 5 events. The median time to onset was 124 days (range, 35-247).

The study authors noted that although the toxicity profile of T-DXd was generally manageable, ILD needs to be carefully monitored.

“The main limitations of this study were that it included a small number of Japanese patients and was conducted in a single country,” the authors concluded. “Although our findings may have limited generalizability, previous trials of chemotherapy and targeted therapy for BTC have consistently demonstrated efficacy across different regions and races.”

Reference

1. 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. J Clin Oncol. Published online August 5, 2024. doi:10.1200/JCO.23.02010