Disitamab Vedotin Shows Early Efficacy in HER2-Expressing Breast Cancer With PAM Pathway Abnormalities

Disitamab vedotin (RC48) demonstrated early efficacy signals with an acceptable toxicity profile in patients with HER2-positive and HER2-low pretreated metastatic breast cancer and abnormal activation of the PAM pathway, according to data from a phase 2 study (NCT05331326) presented at the 2024 ESMO Congress.¹

In all patients with HER2-expressing metastatic breast cancer (n = 62), the objective response rate (ORR) with disitamab vedotin was 34.40% (95% CI, 22.7%-44.7%), with a disease control rate (DCR) of 81.97% (95% CI, 72.3%-91.6%). In the HER2-positive subgroup (n = 26), the ORR with the agent was 34.60% (95% CI, 17.2%-55.7%) and the DCR was 73.10% (95% CI, 52.2%-88.4%). In the HER2-low subgroup (n = 36), the ORR was 34.30% (95% CI, 19.1%-52.2%) and the DCR was 88.60% (95% CI, 73.3%-96.8%).

The median follow-up was 13.2 months. The median progression-free survival (PFS) was 3.5 months (95% CI, 2.4-4.6) in all patients. In the HER2-positive subgroup, the median PFS was 4.5 months (95% CI, 2.9-6.1); in the HER2-low subgroup, the median PFS was 3.4 months (95% CI, 2.8-4.0). Notably, no statistically significant difference in PFS was observed between the HER2- and HER2-low subgroups (HR = 0.67; 95% CI, 0.37-1.22; P = 0.18). At the data cutoff date of March 15, 2024, 3 patients had died, and the secondary end point of overall survival (OS) had not been met.

“RC48 demonstrated certain efficacy with a manageable safety profile in [patients with] HER2-positive and HER2-low pretreated metastatic breast cancer with abnormal activation of the PI3k/Akt/mTOR pathway,” lead study investigator, Yun Wu, MD, and colleagues, wrote in the poster featuring the data. “RC48 may be a therapeutic option for patients with HER2-expressing MBC with PAM pathway abnormal activation.” Wu is a medical oncologist at the National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, in Beijing, China.

Delving Into the Inspiration for the Research and the Study Design

Approximately 50% of HER2-positive breast tumors and 40% of hormone receptor–positive/HER2-low tumors have PAM mutations, underscoring the need for more effective therapeutic options in these populations. The HER2-targeted antibody-drug conjugate is comprised of a humanized HER2 antibody covalently linked with the MMAE payload through a plasma stable linker.

Preliminary data from the C001 CANCER (NCT02881138) and C003 CANCER, (NCT03052634) trials demonstrated efficacy with disitamab vedotin in patients with HER2-positive (ORR, 42.9%; DCR, 90.5%; median PFS, 5.7 months) and HER2-low (ORR, 33.3%; DCR, 81.8%; median PFS, 5.1 months) metastatic breast cancer, supporting the drug’s evaluation in the current study.²

This prospective, single-arm phase 2 trial (NCT05331326) enrolled patients aged 18 years or older with confirmed invasive locally advanced or metastatic breast cancer with abnormal activation of the PAM pathway and progression after at least 1 line of systemic chemotherapy.¹ Patients were required to have an ECOG performance status of up to 2 and HER2 expression defined as either HER2 positive (immunohistochemistry [IHC] 3+ or IHC 2+/fluorescence in situ hybridization [FISH]+) or HER2 low (IHC 2+/FISH– or IHC 1+).

A total of 62 patients were enrolled between September 2022 and December 2023 and received disitamab vedotin at a dose of 2 mg/kg via intravenous infusion once every 2 weeks. The study’s primary end point was ORR, and secondary end points included DCR, PFS, OS, and safety. Patients were stratified by whether they had HER2-positive or HER2-low expression.

Breaking Down Baseline Characteristics

As of the data cutoff, the study enrolled a total of 62 patients with metastatic breast cancer with confirmed PAM pathway activation. In all patients, the median age was 53.0 years, with 54.8% younger than 55 years. The majority of patients were female (98.4%) and postmenopausal (63.9%). Hormone receptor status was positive in 83.9% of patients. Most patients presented with visceral metastases (82.3%), and the most common disease sites were the bone (62.9%), liver (50.5%), and lung (45.2%). Additionally, 83.9% of patients underwent prior surgical treatment, and 22.6% had been initially diagnosed with stage IV disease. With regard to HER2 status, 25.8% were HER2 IHC 3+, 16.1% were HER2 IHC 2+/FISH+, and 43.5% were HER2 IHC 2+/FISH–; 3.2% were IHC 1+.

Patients received a median of 2 prior lines of chemotherapy (range, 1-9), the most common of which being taxanes (98.4%) and anthracyclines (75.8%). The median lines of prior endocrine therapy were 2 (range, 0-7). Patients with HER2-low disease were more likely to have received CDK4/6 inhibitors (87.5%) and fulvestrant (Faslodex; 84.4%), compared with 20.0% and 45.0%, respectively, of patients with HER2-positive disease. Prior targeted therapies included trastuzumab (Herceptin; 96.2%), pyrotinib (96.2%), and trastuzumab plus pertuzumab (Perjeta; 30.8%). Trastuzumab and trastuzumab/pertuzumab were exclusively received by patients with HER2-positive disease.

Safety Spotlight

Adverse effects (AEs) were predominantly grade 1 or 2. The most common AEs included aspartate aminotransferase (AST) elevation (77.4%), leukopenia (46.8%), alanine aminotransferase (ALT) elevation (40.3%), neurotoxicity (35.5%), anemia (24.2%), increased bilirubin (21.0%), increased alkaline phosphatase (19.4%), albumin decline (6.5%), decreased appetite (6.5%), fatigue (4.8%), alopecia (4.8%), nausea (4.8%), abdominal distension (4.8%), thrombocytopenia (3.2%), renal function damage (3.2%), diarrhea (1.6%), cutaneous pruritus (1.6%), and myosalgia (1.6%). Grade 3 or higher AEs included neurotoxicity (11.3%), neutropenia (8.1%), increased AST (3.2%), leukopenia (3.2%), increased ALT (1.6%), anemia (1.6%), and increased bilirubin (1.6%).

Importantly, no treatment-related deaths were reported.

References

1. Wu Y, Mo H, Sun X, et al. Disitamab vedotin (RC48) for previously treated HER2-expressing metastatic breast cancer with abnormal activation of PAM pathway: Results from a single-arm, prospective phase II clinical trial. Annals of Oncology. 2024;35(suppl 2):S379. doi:10.1016/j.annonc.2024.08.332
2. Wang J, Liu Y, Zhang Q, et al. Disitamab vedotin, a HER2-directed antibody-drug conjugate, in patients with HER2-overexpression and HER2-low advanced breast cancer: a phase I/Ib study. Cancer Commun (Lond). 2024;44(7):833-851. doi:10.1002/cac2.12577