pertuzumab zuvotolimod (SBT6050)

P1, N=58, Active, not recruiting, Silverback Therapeutics | Recruiting --> Active, not recruiting | N=344 --> 58 | Trial completion date: Aug 2024 --> Dec 2022 | Trial primary completion date: Aug 2023 --> Dec 2022

A third HER2-directed ADC, disitamab vedotin (RC48), has been approved for locally advanced or metastatic gastric or gastroesophageal junction cancer by the NMPA (National Medical Products Administration) of China in 2021. In this review article, we summarize the three approved ADCs (T-DM1, DS-8201a and RC48), together with the investigational EGFR-directed ADCs (ABT-414, MRG003 and M1231), HER2-directed ADCs (SYD985, ARX-788, A166, MRG002, ALT-P7, GQ1001 and SBT6050) and HER3-directed ADC (U3-1402). Lastly, we discuss the major challenges associated with the development of ADCs, and highlight the possible future directions to tackle these challenges.

Background SBT6050 is a novel therapeutic comprising a selective small molecule toll-like receptor 8 (TLR8) agonist linked to the HER2-directed monoclonal antibody pertuzumab, allowing for combination with trastuzumab-based agents and regimens. Pharmacodynamic markers of myeloid and NK/T cell activation will be assessed in peripheral blood and on-treatment tumor biopsies. Circulating tumor DNA will be evaluated as an exploratory assessment.

Based on preliminary safety data, SBT6050 given alone or in combination with pembrolizumab has a manageable safety profile. Related TEAEs are consistent with immune activation. A single-agent dose of 0.6 mg/kg administered Q2 weeks had a tolerable safety profile, drug exposure that reflects evidence of target saturation, and pharmacodynamics indicative of myeloid, NK and T cell activation.

P1, N=294, Recruiting, Silverback Therapeutics | N=210 --> 294

SBT6050 is designed to activate human myeloid cells only in the presence of moderate-to-high HER2 expression (immunohistochemistry [IHC] 2+ or 3+) and binds to the same epitope as pertuzumab...Preclinical studies also support combinations with checkpoint inhibitors and with trastuzumab to further enhance antitumor activity...Pharmacokinetics, immunogenicity, and antitumor activity will be evaluated and pharmacodynamic markers of myeloid cell activation will be assessed in peripheral blood and on-treatment tumor biopsies. Results N/A Conclusions N/A

SBT6050 is designed to activate human myeloid cells only in the presence of moderate-to-high HER2 expression (immunohistochemistry [IHC] 2+ or 3+) and binds to the same epitope as pertuzumab...Preclinical studies also support combinations with checkpoint inhibitors and with trastuzumab to further enhance antitumor activity...Pharmacokinetics, immunogenicity, and antitumor activity will be evaluated and pharmacodynamic markers of myeloid cell activation will be assessed in peripheral blood and on-treatment tumor biopsies. Results N/A Conclusions N/A

P1, N=210, Recruiting, Silverback Therapeutics | Not yet recruiting --> Recruiting

P1, N=210, Not yet recruiting, Silverback Therapeutics

SBT6050, a novel therapeutic comprised of a potent toll-like receptor (TLR) 8 agonist conjugated to a HER2-directed monoclonal antibody that binds an epitope distinct from trastuzumab, is designed for systemic delivery and tumor-localized activation of human myeloid cells in the presence of moderate and high HER2-expressing tumor cells. These data also highlight the potential for SBT6050 to be clinically active as a monotherapy. SBT6050 is projected to enter the clinic in 2020 for patients with moderate or high HER2-expressing tumors.

Trastuzumab and SBT6050 bind to distinct epitopes on HER2 and enhanced activity is observed when the two agents are combined. SBT6050 is a systemically administered, tumor-targeted myeloid cell agonist that demonstrates single agent efficacy in multiple mouse tumor models without peripheral cytokine production. A first-in-human study with SBT6050 is expected to begin this year for patients with HER2-expressing solid tumors. Research Funding: Silverback Therapeutics