IBI354 Shows Efficacy and Safety in HER2+ and HER2-Low Advanced Breast Cancer

IBI354, a novel anti-HER2 antibody-drug conjugate, demonstrated efficacy and was well tolerated in patients with advanced HER2-positive and HER2-low breast cancer, according to findings from a phase 1 study (NCT05636215) presented at the 2024 ESMO Congress.

Findings showed that evaluable patients with HER2-positive breast cancer (n = 59) 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%, partial response (PR) rate of 64.4%, stable disease (SD) rate of 20.3%, and progressive disease (PD) rate of 11.9%.

In the HER2-low breast cancer cohort (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%, PR rate of 40.3%, SD rate of 40.3%, and PD rate of 17.9%.

For patients in the HER2-positive group who had HER2 immunohistochemistry (IHC) 3+ or 2+/in situ hybridization (ISH)+ disease, the ORR was 69.1%; In the HER2-low group, excluding patients with HER2 IHC 0, the ORR reached 65%.

“IBI354 was well tolerated with [a] favorable safety profile, including at higher doses up to 18 mg/kg every 3 weeks and showed promising efficacy in both HER2-positive and HER2-low breast cancer,” lead study author Christina Teng, BMed , MMed, FRACP, PhD, of Scientia Clinical Research in Randwick, Australia, said in the presentation.

Study Design

The open-label, multicenter, multinational, dose-escalation, phase 1 study of IBI354 enrolled patients with locally advanced unresectable, or metastatic solid tumors that were refractory or intolerant to standard treatment options. Eligible patients were required to have 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.

Patients needed to be at least 18 years of age, have at least 1 measurable lesion, and have an ECOG performance status of 0 or 1.

The study consisted of 2 parts. The dose-escalation phase used a modified continuous reassessment model guided by Bayesian logistic regression with overdose control, applying a 3+3 design. IBI354 was administered intravenously once every 3 weeks at doses ranging from 0.8 mg/kg to 18 mg/kg. The primary objective of this phase was to assess the safety and dose-limiting toxicities (DLTs) associated with IBI354; secondary objectives included evaluating pharmacokinetics (PK) and the preliminary antitumor activity.

The dose-expansion phase enrolled patients across specific cancer cohorts, including breast cancer, platinum-resistant ovarian cancer, endometrial cancer, cervical cancer, colorectal cancer, biliary tract cancer, and other solid tumors. Based on the PK, safety, and efficacy data from the escalation phase, patients received IBI354 at the recommended doses of 6 mg/kg, 9 mg/kg, or 12 mg/kg once every 3 weeks. Treatment continued until disease progression, unacceptable toxicity, or withdrawal from the study. Safety assessments were based on the incidence of adverse effects (AEs) and DLTs.

At the data cutoff of July 24th, 2024, the dose-escalation phase had progressed through multiple dose levels without reaching the maximum tolerated dose (MTD). Subsequent analyses from the dose-expansion cohorts will provide further insight into the efficacy and safety profile of IBI354 in a diverse range of HER2-positive solid tumors.

Patient Characteristics

Accounting for all tumor types, the study enrolled a total of 368 patients who had a median age of 56 years (range, 27-82). Most patients were female (89.4%) and had an ECOG performance status of 1 (75.0%).

The cohort primarily included patients with advanced-stage disease; 93.0% had stage IV tumors. The most common tumor types included breast cancer (48.4%), ovarian cancer (25.0%), and colorectal cancer (10.3%).

HER2 expression was distributed as follows: IHC 1+ (32.9%), IHC 2+ (33.7%), IHC 3+ (32.3%), IHC 0 (0.3%), ISH+ (0.5%), and NGS amplification and/or mutation (0.3%). As a heavily pretreated population, 77.4% of patients had received 3 or more prior treatment regimens.

Safety Overview of IBI354

No DLTs were observed up to 18 mg/kg. At all dose levels in the overall population, there was a low incidence of dose interruptions (19.8%), reductions (2.4%), or discontinuations (1.9%) due to treatment-emergent AE (TEAEs). Interstitial lung disease (ILD) occurred in 1.6% of patients, all at grade 1 severity.

The most common treatment-related AEs (TRAEs) reported in at least 10% of patients included nausea (grade 1/2, 43.3%; grade ≥3, 0.5%), decreased white blood cell count (36.7%; 5.4%), anemia (37.2%; 4.1%), decreased neutrophil count (24.4%; 8.2%), vomiting (22.3%; 0.8%), and decreased platelet count decrease (15.5%; 1.9%).

Reference

Lemech C, Sun Y, Nagrial A, et al. IBI354 (anti-HER2 antibody-drug conjugate [ADC]) in patients (PTS) with advanced solid tumors and breast cancer (BC): Results from a phase I study. Ann Oncol. 2024;35(suppl 2):S360. doi:10.1016/j.annonc.2024.08.293