SHR-A1811 Showed Promise Among Patients With HER2-Expressing Solid Tumors

According to results from a first-in-human, phase 1 study, novel antibody drug conjugate [ADC] SHR-A1811 demonstrated promising antitumor activity with acceptable safety and tolerability among heavily pretreated patients with human epidermal growth factor receptor 2 (HER2)-expressing or mutated advanced solid tumors. 

“HER2–targeted therapies have revolutionized the management of HER2-overexpressing or mutated tumors, leading to a significant improvement in survival,” stated Herui Yao, MD, Sun Yat-sen Memorial Hospital, Guangzhou, China, and coauthors. “SHR-A1811 is a novel ADC composed of anti-HER2 antibody trastuzumab, a cleavable linker, and the topoisomerase I inhibitor payload SHR169265.” 

In this multicenter dose escalation and expansion study, researchers enrolled 307 patients with HER2-expressing or mutated unresectable advanced or metastatic solid tumors who were refractory or intolerant to standard therapies. Types of cancer included gastric/gastroesophageal junction adenocarcinoma, breast cancer, non-small cell lung cancer, and others. Patients received at least 1 dose of intravenous SHR-A1811 (1 mg/kg to 8 mg/kg) once every 3 weeks until disease progression or unacceptable toxicity. In the dose escalation cohort, 35 patients were enrolled to receive either 1 mg/kg, 2 mg/kg, 3.2 mg/kg, or 4.8 mg/kg (n = 6 in each group), 6.4 mg/kg (n = 8), or 8 mg/kg (n = 3). In the expansion cohort, 96 patients received one of the selected doses of 4.8 mg/kg (n = 28), 5.6 mg/kg (n = 25), 6.4 mg/kg (n = 27) or 8 mg/kg (n = 16). Primary end points included dose-limiting toxicity and safety. A key secondary end point was objective response rate (ORR). 

At analysis, dose-limiting toxicities were experienced by 1 patient in the 6.4 mg/kg arm (pancytopenia and colitis). Grade ≥3 treatment-related adverse events were experienced by 54.1% of patients and serious grade ≥3 treatment-related adverse events were experienced by 13% of patients. The most common events included decreased neutrophil count, decreased white blood cell count, and anemia. Grade ≥3 treatment-related interstitial lung disease was experienced by 2 patients in the 4.8 mg/kg and 8 mg/kg arms. There were 21.8% of patients who experienced dose redutions and 40.7% who experienced treatment interruptions. Thirteen patients discontinued treatment due to a treatment-related adverse event and 4 treatment-related deaths occurred due to pneumonia (n = 1 in the 4.8 mg/kg arm), colitis and pancytopenia (n = 1 in the 6.4 mg/kg arm), unknown reason (n = 1 in the 6.4 mg/kg arm), and ILD and bacterial pneumonia (n = 1 in the 8 mg/kg arm). 

At a median follow-up of 4.1 months, the ORR was 59.9% in the intention-to-treat population. At a median follow-up of 8.9 months, in a breast cancer specific cohort (n = 209), the ORR was 76.3% (90/118) in HER2-positive patients and 60.4% (55/91) in HER2-low patients. 

Dr Yao et al, concluded, “This phase I study had paved the way for further development of SHR-A1811 as a new treatment option for patients with HER2-expressing or mutated advanced solid tumors.”

Journal of Clinical Oncology Associate Editor Robert G. Maki, MD, PhD, Memorial Sloan Kettering Cancer Center, New York, New York, added, “SHR-A1811…may have a different toxicity profile than existing agents, but such determination, as with response end points, will require a head-to-head clinical trial.” 

Source:

Yao H, Yan M, Tong Z, et al. Safety, efficacy, and pharmacokinetics of SHR-A1811, a human epidermal growth factor receptor 2–directed antibody-drug conjugate, in human epidermal growth factor receptor 2–expressing or mutated advanced solid tumors: A global phase I trial. J Clin Oncol. Published online: June 20, 2024. doi: 0.1200/JCO.23.02044