B7-H4, a transmembrane glycoprotein belonging to the B7 superfamily, is minimally expressed in normal tissues but exhibits significant overexpression in a variety of cancer types. HS-20089 is an innovative antibody-drug conjugate (ADC) that targets B7-H4, composed of a humanized anti-B7-H4 IgG1 monoclonal antibody linked to a small molecule toxin, a topoisomerase I inhibitor, via a protease-cleavable linker. Preclinical studies have demonstrated that HS-20089 possesses a strong binding affinity for human B7-H4 and exhibits potent anti-tumor activity. In a groundbreaking Phase I clinical trial, the company investigated HS-20089 in its first use in humans. The trial aimed to assess dose-limiting toxicity (DLT), safety, tolerability, pharmacokinetics, and efficacy in patients with advanced solid tumors unresponsive to standard therapies.

As of April 11, 2023, 44 patients diagnosed with advanced solid tumors, including 41 with breast cancers, 2 with ovarian cancers, and 1 with endometrial cancer, were treated with HS-20089. Notably, three dose-limiting toxicities were observed, all occurring at the 7.2 mg/kg dose. The most common treatment-related adverse events included issues like low white blood cell counts, nausea, anemia, and changes in platelet counts, liver enzymes, and sodium levels. Importantly, no cases of lung problems or infusion reactions were reported. Among the 33 patients evaluated for their response to treatment, 8 achieved partial responses, resulting in a 24.2% response rate, including 3 confirmed responses and 5 awaiting confirmation. The overall disease control rate was robust at 63.6%. In the subset of 16 triple-negative breast cancer patients, 6 experienced partial responses, with a response rate of 37.5%, including 2 confirmed responses and 4 awaiting confirmation. Notably, at the target therapeutic doses of 4.8 and 5.8 mg/kg, 5 out of 12 triple-negative breast cancer patients achieved partial responses, resulting in a response rate of 41.7%. One patient who had a significant response, with a treatment duration of 403 days, continued treatment in the 0.7 mg/kg cohort. These findings highlight the potential of HS-20089 in treating advanced solid tumors, particularly in the context of triple-negative breast cancer.

The data presented at ESMO 2023, with a cutoff date in August 2023, reinforces the highly promising anti-tumor potential of HS-20089, particularly in the challenging landscape of triple-negative breast cancer (TNBC). Notably, at the target therapeutic doses of 4.8 and 5.8 mg/kg, the observed objective response rates (ORR) were 33.3% and 27.3%, respectively. Even more impressively, HS-20089 demonstrated notable anti-tumor activity in TNBC patients who had previously been treated with PARP inhibitors or PD-1/PD-L1 inhibitors, signifying its potential as a therapeutic option for these patients. Furthermore, this groundbreaking treatment showcased remarkable anti-tumor effects in ovarian cancer (OC), boasting an extraordinary ORR of 66.7% in platinum-resistant OC cases. These findings underscore the substantial clinical promise and potential impact of HS-20089 in combating these challenging malignancies. 

 

 

 

Preclinical experiments demonstrated the inhibition of tumor cell growth expressing B7-H4 both in vitro and in vivo. Numerous solid cancers, including breast and ovarian cancer, exhibit elevated B7-H4 expression. The promising clinical efficacy of HS-20089 in treating triple-negative breast cancer (TNBC) underscores its potential as a groundbreaking therapy for advanced breast cancer.

KOL insights

“While the novel, distinct tumour-associated target, B7-H4, which is related both to immune escape and to tumour cell proliferation and invasion, presents a new approach for directing treatment, the mechanism of action of HS-20089 remains somewhat of a mystery because the payload has not yet been disclosed”– Professor from Institute Gustave Roussy, Villejuif, France.

Conclusion: The novel tumor-associated target B7-H4, which has implications for both immune evasion and tumor progression, offers a promising avenue for treatment. HS-20089 demonstrated dose-dependent serum exposure within a specific dose range and exhibited good stability in patient serum. Importantly, there were no instances of patients developing anti-drug antibodies (ADA). Among the patients with advanced solid tumors, including a majority with breast cancer, three experienced dose-limiting toxicities. Common treatment-related adverse events included decreases in white blood cell, neutrophil, and platelet counts, anemia, and nausea, vomiting, and elevated liver function test results. Fortunately, there were no cases of interstitial lung disease (ILD) or infusion reactions reported.

Regarding efficacy, in a subset of triple-negative breast cancer (TNBC) patients, an overall response rate of 28.6% and a disease control rate of 75.0% were observed. At the potentially effective therapeutic doses, HS-20089 demonstrated response rates of 33.3% and 27.3% in TNBC patients. Furthermore, HS-20089 displayed anti-tumor activity in TNBC patients who had previously received PARP inhibitors or PD-1/PD-L1 inhibitors. Additionally, in platinum-resistant ovarian cancer, the overall response rate was as high as 66.7%. Taken together, these findings suggest that HS-20089 is well-tolerated and exhibits promising anti-tumor effects in advanced solid tumors, particularly in the context of triple-negative breast cancer, thereby offering encouraging clinical prospects for this novel therapeutic approach.

For more insight into the patient’s burden/epidemiology, treatment, and changing market landscape-related advancements, refer to the following reports such as Triple Negative Breast Cancer (TNBC) Market Report and Ovarian Cancer Market Report