IBI354, an anti-HER2 antibody-drug conjugate (ADC), has demonstrated promising efficacy and a favorable safety profile in patients with advanced HER2-positive and HER2-low breast cancer. These findings, from a phase 1 study (NCT05636215) presented at the 2024 ESMO Congress, suggest that IBI354 could offer a new treatment option for these patient populations. The study, which evaluated various solid tumors, showed notable responses in breast cancer cohorts, warranting further investigation.
Efficacy in HER2-Positive Breast Cancer
In the HER2-positive breast cancer cohort (n = 59), IBI354 achieved an overall response rate (ORR) of 67.8% (95% CI, 54.4%-79.4%) and a disease control rate (DCR) of 88.1% (95% CI, 71.1%-95.1%). The best overall responses included a complete response (CR) rate of 3.4%, a partial response (PR) rate of 64.4%, a stable disease (SD) rate of 20.3%, and a progressive disease (PD) rate of 11.9%. These results indicate a strong antitumor effect in patients with HER2-positive disease.
Efficacy in HER2-Low Breast Cancer
For patients with HER2-low breast cancer (n = 67), the ORR was 41.8% (95% CI, 29.8%-54.5%), with a DCR of 82.1% (95% CI, 70.8%-90.4%). This included a CR rate of 1.5%, a PR rate of 40.3%, an SD rate of 40.3%, and a PD rate of 17.9%. Notably, when excluding patients with HER2 IHC 0, the ORR reached 65%. These data suggest that IBI354 may provide clinical benefit for patients with HER2-low expressing tumors, an area of increasing therapeutic interest.
Study Design and Patient Population
The open-label, multicenter, multinational, dose-escalation, phase 1 study enrolled patients with locally advanced unresectable or metastatic solid tumors refractory or intolerant to standard treatments. Eligible patients had histologically confirmed HER2-positive tumors, defined by HER2 IHC 1+, 2+, or 3+ and/or ISH+ positivity, and/or a next-generation sequencing (NGS)-confirmed HER2 mutation or amplification. The study consisted of dose-escalation and dose-expansion phases, with IBI354 administered intravenously once every 3 weeks at doses ranging from 0.8 mg/kg to 18 mg/kg. The primary objective was to assess safety and dose-limiting toxicities (DLTs), while secondary objectives included evaluating pharmacokinetics (PK) and preliminary antitumor activity. A total of 368 patients were enrolled, with a median age of 56 years. The most common tumor types included breast cancer (48.4%), ovarian cancer (25.0%), and colorectal cancer (10.3%).
Safety and Tolerability
IBI354 was well-tolerated, with no DLTs observed up to 18 mg/kg. The incidence of dose interruptions (19.8%), reductions (2.4%), or discontinuations (1.9%) due to treatment-emergent adverse events (TEAEs) was low. Interstitial lung disease (ILD) occurred in 1.6% of patients, all at grade 1 severity. The most common treatment-related AEs (TRAEs) included nausea (43.3%), decreased white blood cell count (36.7%), anemia (37.2%), and decreased neutrophil count (24.4%).
Expert Commentary
According to lead study author Christina Teng, BMed, MMed, FRACP, PhD, of Scientia Clinical Research, IBI354 demonstrated a favorable safety profile, even at higher doses, and showed promising efficacy in both HER2-positive and HER2-low breast cancer. These findings support further clinical development of IBI354 as a potential treatment option for patients with advanced HER2-expressing breast cancers.
