Disitamab vedotin (RC48) has shown early efficacy signals and an acceptable safety profile in patients with HER2-positive and HER2-low pretreated metastatic breast cancer and abnormal activation of the PAM pathway. These findings come from a phase 2 study (NCT05331326) presented at the 2024 ESMO Congress.
In the study involving 62 patients with HER2-expressing metastatic breast cancer, disitamab vedotin achieved an objective response rate (ORR) of 34.40% (95% CI, 22.7%-44.7%), and a disease control rate (DCR) of 81.97% (95% CI, 72.3%-91.6%).
Efficacy Across HER2 Subgroups
When broken down by HER2 expression levels, the HER2-positive subgroup (n = 26) had an ORR of 34.60% (95% CI, 17.2%-55.7%) and a DCR of 73.10% (95% CI, 52.2%-88.4%). The HER2-low subgroup (n = 36) showed an ORR of 34.30% (95% CI, 19.1%-52.2%) and a DCR of 88.60% (95% CI, 73.3%-96.8%).
With a median follow-up of 13.2 months, the median progression-free survival (PFS) was 3.5 months (95% CI, 2.4-4.6) for all patients. The HER2-positive subgroup had a median PFS of 4.5 months (95% CI, 2.9-6.1), while the HER2-low subgroup had a median PFS of 3.4 months (95% CI, 2.8-4.0). Notably, there was no statistically significant difference in PFS between the HER2- and HER2-low subgroups (HR = 0.67; 95% CI, 0.37-1.22; P = 0.18).
Rationale and Study Design
Approximately 50% of HER2-positive breast tumors and 40% of hormone receptor–positive/HER2-low tumors have PAM mutations, highlighting the need for more effective treatments in these populations. Disitamab vedotin, a HER2-targeted antibody-drug conjugate, comprises a humanized HER2 antibody covalently linked with the MMAE payload.
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. Patients received disitamab vedotin at 2 mg/kg via intravenous infusion every 2 weeks. The primary endpoint was ORR, and secondary endpoints included DCR, PFS, OS, and safety.
Patient Characteristics
The study enrolled 62 patients with metastatic breast cancer and confirmed PAM pathway activation. The median age was 53.0 years, with 54.8% younger than 55 years. Most patients were female (98.4%) and postmenopausal (63.9%). Hormone receptor status was positive in 83.9% of patients. Common disease sites included the bone (62.9%), liver (50.5%), and lung (45.2%).
Patients had received a median of 2 prior lines of chemotherapy (range, 1-9), most commonly taxanes (98.4%) and anthracyclines (75.8%). Patients with HER2-low disease were more likely to have received CDK4/6 inhibitors (87.5%) and fulvestrant (84.4%), compared with those with HER2-positive disease (20.0% and 45.0%, respectively).
Safety Profile
Adverse events (AEs) were predominantly grade 1 or 2. The most common AEs included elevated aspartate aminotransferase (AST) (77.4%), leukopenia (46.8%), and elevated alanine aminotransferase (ALT) (40.3%). Grade 3 or higher AEs included neurotoxicity (11.3%) and neutropenia (8.1%). No treatment-related deaths were reported.
"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," wrote lead study investigator Yun Wu, MD, and colleagues. "RC48 may be a therapeutic option for patients with HER2-expressing MBC with PAM pathway abnormal activation."
