SHR-A1811 Maintains Efficacy, Safety in Pretreated HER2-Expressing/-Mutated Breast Cancer, Other Solid Tumors

SHR-A1811, a third-generation antibody-drug conjugate, demonstrated antitumor activity and manageable safety in the treatment of heavily pretreated patients with HER2-positive and HER2-low breast cancer, as well as other HER2-expressing or -mutated solid tumors, according to results from the phase 1 SHR-A1811-I-101 trial (NCT04446260) presented during the 2024 San Antonio Breast Cancer Symposium.1

At a median follow-up of 13.4 months, among response-evaluable patients with HER2-positive breast cancer (n = 136), the objective response rate (ORR) was 79.1% (95% CI, 71.2%-85.6%). The complete response (CR) rate was 3.0%, and the partial response (PR) rate was 76.1%. In patients with HER2-low breast cancer (n = 110), the ORR was 62.0% (95% CI, 52.2%-71.2%) at a median follow-up of 9.5 months; the CR rate was 1.9%, and the PR rate was 60.2%. In patients with non-breast solid tumors (n = 145), the ORR was 40.0% (95% CI, 31.5%-49.0%) at a median follow-up of 6.3 months.

The median progression-free survival (PFS) was 20.0 months (95% CI, 15.1-not evaluable [NE]) in the HER2-positive breast cancer cohort, 11.0 months (95% CI, 8.2-13.7) in the HER2-low breast cancer cohort, and ranged from 3.4 months to 8.5 months in the non–breast cancer cohorts.

The median duration of response (DOR) was 23.6 months (95% CI, 15.6-NE) for HER2-positive breast cancer, 12.2 months (95% CI, 7.3-NE) for HER2-low breast cancer, and 15.2 months (95% CI, 9.9-20.9) for non-breast tumors. PFS and DOR outcomes in patients with breast cancer and liver or visceral metastases were consistent with those for the overall breast cancer patient population. Moreover, a trend towards improved ORR (45.1%), median DOR (15.2 months), and median PFS (7.9 months) was observed for patients with HER2-positive non-breast cancers compared with the overall breast cancer cohort.

“This updated analysis reaffirms the manageable safety profile and promising efficacy of SHR-A1811 in heavily pretreated multiple solid tumors with HER2 expression or mutations,” Herui Yao, MD, PhD, of Sun Yat-Sen University in Guangzhou, China, and colleagues wrote in a poster presentation of the data. “Pivotal study results are expected in HER2-positive breast cancer, HER2-low breast cancer, colorectal cancer [CRC], gastric cancer, gastroesophageal junction [GEJ] cancer, and non–small cell lung cancer [NSCLC].”

Study Overview

SHR-A1811 consists of the HER2-directed antibody trastuzumab (Herceptin), a cleavable linker, and a topoisomerase I inhibitor payload. The agent has an optimized drug-antibody ratio of 6 and has displayed both a strong bystander killing effect and an acceptable toxicity profile.

This global, multicenter, first-in-human study enrolled patients with advanced, unresectable, or metastatic HER2-expressing or -mutant solid tumors. Patients were refractory or intolerant to standard therapy, had an ECOG performance status (PS) of 0 or 1, and had 1 or more measurable target lesions.

In the dose-escalation portion of the study, SHR-A1811 was administered intravenously every 3 weeks at 1 of 6 doses escalating from 1.0 mg/kg to 8.0 mg/kg. Doses selected in the ensuing pharmacokinetic expansion phase were 4.8 mg/kg, 5.6 mg/kg, 6.4 mg/kg, and 8.0 mg/kg; 15 patients were included in each group. Patients in the indication expansion phase received either 4.8 mg/kg or 6.4 mg/kg of SHR-A1811 and were evaluated in 1 of 5 cohorts according to whether they had HER2-positive breast cancer (cohort A), HER2-positive gastric or GEJ cancer (cohort B), HER2-low–expressing breast cancer (cohort C), HER2-expressing or -mutated NSCLC (cohort D), or another HER2-expressing or -mutated solid tumor (cohort E).

The study’s primary end points were dose-limiting toxicities, safety, and identification of the recommended phase 2 dose.

A total of 391 patients received SHR-A1811 between September 7, 2020, and January 12, 2024. In the overall patient population, the median age was 55.0 years (range, 48.0-62.0). Most patients were female (79.0%), had an ECOG PS of 1 (66.8%), and had received fewer than 3 prior lines of therapy in the metastatic setting (57.0%). Regarding tumor type, 34.8% and 28.1% of patients had HER2-positive and HER2-low breast cancer, respectively. The remaining patients had HER2-expressing non-breast cancers, including biliary tract cancer (10.7%), urothelial cancer (10.0%), gynecologic cancers (5.6%), CRC (3.3%), gastric or GEJ cancer (3.3%), NSCLC (1.0%), and other solid tumors (2.8%).

The current analysis comprised novel PFS results and updated safety data with an additional 1 year of follow-up in an expanded cohort.

Safety Findings

The frequency, severity, and specificity of toxicities with SHR-A1811 were consistent with observations from prior findings, and no new safety signals were identified. Most patients experience any-grade adverse effects (AEs; 98.2%). Grade 3 or higher treatment-related AEs (TRAEs) were reported in 63.2% of patients, 6.6% of whom discontinued treatment due to TRAEs.

The most common TRAEs included decreased neutrophil counts (any-grade, 73.9%; grades 3-5, 47.3%), anemia (70.6%; 25.8%), decreased white blood cell counts (64.7%; 32.0%), nausea (61.6%; 1.3%), decreased platelet counts (44.2%; 15.9%), alopecia (40.2%; 0.0%), decreased appetite (39.4%; 1.5%), vomiting (39.4%; 0.8%), increased aspartate aminotransferase levels (36.6%; 0.5%), increased alanine aminotransferase levels (32.2%; 0.8%), hypoalbuminemia (27.6%; 0.3%), and weight decrease (25.1%; 0.5%).

Notably, interstitial lung disease (ILD) occurred in 2.6% of patients and was primarily grade 1 (0.8%) or 2 (1.0%). Three patients had grade 3 ILD.

Reference

Yao H, Yan M, Tong Z. Efficacy and safety of SHR-A1811, an anti-HER2 antibody-drug conjugate (ADC), in 391 heavily pretreated multiple solid tumors with HER2-expression or mutations: a global, multi-center, first-in-human, phase 1 study. Presented at: 2024 San Antonio Breast Conference Symposium; December 10-13, 2024; San Antonio, TX. PS8-08.