Interim clinical results from a Phase 1/1b clinical study of SBT6050 as a monotherapy and in combination with pembrolizumab in patients with advanced or metastatic HER2-expressing or amplified solid tumors, at the 2021 European Society for Medical Oncology Congress (ESMO), being held September 16 – 21, 2021.

SBT6050, being developed by Silverback Therapeutics, targets the pertuzumab binding domain of HER2 and is designed to be used in combination with standard of care agents, including trastuzumab-containing regimens.

The drug leverages Silverback’s proprietary ImmunoTAC™ technology platform and comprises a TLR8 agonist linker-payload conjugated to a HER2-directed antibody.

TLR8 agonism directly activates myeloid cells and secondarily activates NK and T cells, inducing a broad spectrum of anti-tumor immune mechanisms.

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“Over this past year, we have gathered compelling data with clear signals of SBT6050’s pharmacological activity, marked by the activation of both the innate and adaptive immune response in patients,” said Laura Shawver, Ph.D., Chief Executive Officer of Silverback.

“We look forward to moving into expansion cohorts and to expanding our clinical development plan to include combination with standard-of-care trastuzumab-containing regimens,” Shawver added.

Study design
As of August 1, 2021, 40 patients with advanced or metastatic HER2-expressing or amplified solid tumors were enrolled in the SBT6050-101 trial (NCT04460456).

SBT6050 dose levels ranged from 0.3 to 1.2 mg/kg in the monotherapy dose-escalation arm (Part 1), and 0.15 and 0.3 mg/kg in the pembrolizumab combination arm (Part 3). Patients received between 1 and 17 doses of SBT6050.

As a monotherapy and in combination with pembrolizumab, SBT6050 was generally well-tolerated, with an adverse event profile that is consistent with immune system activation and considered on-mechanism.

“The adverse event profile thus far has been very manageable and importantly, suggests the potential to combine with another standard of care agents,” said Samuel Klempner, MD, Medical Oncologist at the Massachusetts General Hospital.

“The signals of anti-tumor activity are encouraging and its complementary mechanism of action with standard-of-care agents makes SBT6050 attractive for combination regimens.”

Initial Safety
The most frequent treatment-related adverse events observed by the investigators were consistent with immune activation and included injection site reactions, fever and chills, hypotension, nausea, vomiting, and fatigue. These were mostly Grade 1 or 2 in nature, and no Grade 4 or higher related adverse events were reported. At higher dose levels, dose-limiting toxicities (DLTs) were observed and included Grade 3 hypotension, injection site reaction, fever, and hypoxia. These DLTs were resolved with supportive care. Cytokine release syndrome (CRS) > Grade 2 was not observed at any dose level.

Pharmacokinetic and Pharmacodynamic
Exposure with SBT6050 increased with dose and exhibited a linear PK profile at 0.6 mg/kg and higher. Linear exposure is evidence of saturation of receptor-mediated clearance. The stability of the conjugate was assessed using a highly sensitive assay. The investigators did not observe active levels of SBT6050’s free payload were detected in the blood and any amount of free payload was absent in 98% of all blood samples tested. The investigational agent induces pharmacologic activity indicative of myeloid and NK/T cell activation at all dose levels, with effects plateauing at 0.6 mg/kg. Pharmacodynamic activity is maintained with repeat dosing of SBT6050.

Anti-Tumor Activity
In the phase I/Ib study, the investigators observed early signals of anti-tumor activity were observed in a heavily pre-treated, heterogeneous population. Among 18 evaluable patients for tumor types of interest, one patient with HER2 IHC 2+ NSCLC had a confirmed partial response (-55% per RECIST 1.1 criteria), maintained at the most recently available scan obtained at 36 weeks post-enrollment, and 8 weeks after discontinuing the study treatment. In addition, stable disease was reported in seven patients.

Clinical trials
A Study of SBT6050 Alone and in Combination With PD-1 Inhibitors in Subjects With Advanced HER2 Expressing Solid Tumors – NCT04460456 

Highlights of prescribing information
Pembrolizumab (Keytruda®; Merck & Co., Inc.). [Prescribing Information]

Klempner SJ, Beeram M, Sabanathan D, Chan A, Hamilton E, Loi S, Oh D, Emens LA, Patnaik A, Kim JE, Park YH, Odegard V, Hamke S, Jang G, Jacquemont C, Hunder N, Piha-Paul SA. Interim results of a phase I/Ib study of SBT6050 monotherapy and pembrolizumab combination in patients with advanced HER2-expressing or amplified solid tumors. Annals of Oncology (2021) 32 (suppl_5): S447-S456. 10.1016/annonc/annonc688 [Poster]

Featured Image: General images of ESMO 2019 Congress being held in Barcelona, Spain, September 27 – October 1, 2019. Courtesy ® 2019 – 2021 European Society for Medical Oncology (ESMO). Used with Permission.

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