linavonkibart (SRK-181)

P1, N=112, Active, not recruiting, Scholar Rock, Inc. | Recruiting --> Active, not recruiting | N=74 --> 112 | Trial primary completion date: Dec 2023 --> Dec 2024

Conclusions As of 26 May 2023, combination treatment of SRK-181 and anti-PD-1 (pembrolizumab) was generally well tolerated with an ORR of 25% and clinical benefit rate of 69% in heavily pre-treated, anti-PD-1-refractory ccRCC patients. Enrollment is ongoing for all cohorts.

P1, N=74, Recruiting, Scholar Rock, Inc. | N=200 --> 74

No DLTs were observed up to 3000mg q3w/2000mg q2w as monotherapy and up to 2400mg q3w as combination treatment. Early signs of efficacy were observed with 3 cPR in pts with anti-PD-1 resistant ccRCC.

No DLT was observed up to 3000mg q3w/2000mg q2w as monotherapy and up to 2400mg q3w as combination treatment. Early evidence of efficacy was observed with prolonged stable disease and a confirmed PR.

Currently, a limited number of small molecular inhibitor and monoclonal antibody candidates that target TGF-β are in clinical development in combination with the following immune checkpoint inhibitors: SRK 181, an antibody inhibiting the activation of latent TGF-β1; NIS 793, a monoclonal antibody targeting TGF-β; and SHR 1701, a fusion protein consisting of an anti-PD-L1 monoclonal antibody fused with the extracellular domain of human TGF-β receptor II. Several small molecular inhibitors are also in development and are briefly reviewed: LY364947, a pyrazole-based small molecular inhibitor of the serine-threonine kinase activity of TGFβRI; SB-431542, an inhibitor targeting several TGF-β superfamily Type I activin receptor-like kinases as well as TGF-β1-induced nuclear Smad3 localization; and galunisertib, an oral small molecular inhibitor of the TGFβRI kinase. One of the most advanced agents in this area is bintrafusp alfa, a bifunctional fusion protein composed of the extracellular domain of TGF-β receptor II fused to a human IgG1 mAb blocking PD-L1. Bintrafusp alfa is currently in advanced clinical development and as an agent in this space with the most clinical experience, is a focused highlight of this review.

P1, N=200, Recruiting, Scholar Rock, Inc. | Trial completion date: Jul 2022 --> Dec 2024 | Trial primary completion date: Dec 2021 --> Dec 2023

In Part A2, 10 patients were treated with SRK-181 at doses of 240, 800 and 1600mg Q3W+pembrolizumab. Next planned dose in Part A2 will be 2400mg Q3W. Trial Registration DRAGON trial (NCT04291079)

As of Feb 01 2021, dose escalation has proceeded to the highest planned dose of 2400 mg Q3W in Part A1 (monotherapy) and to 800 mg Q3W in Part A2 (anti-PD-(L)1 combination) . Additional planned doses in Part A2 are 1600 mg and 2400 mg Q3W.

In summary, the nonclinical pharmacology, pharmacokinetic, and toxicology data demonstrate that SRK-181 is a selective inhibitor of latent TGFβ1 that does not produce the nonclinical toxicities associated with nonselective TGFβ inhibition. These data support the initiation and safe conduct of a phase 1 trial with SRK-181 in patients with advanced cancer.

A companion assay to exclude blood samples with nonspecific background signals has been characterized and will be performed in parallel when evaluating circulatory TGFβ1 in clinic. In summary, we present several novel, tailored biomarker readouts that are part of a broader biomarker strategy aimed at maximizing detection of relevant clinical data to both support the ongoing clinical trial and provide further insight into the mechanism of action of SRK-181.

PD effects will be assessed by measuring modulation of tumor immune cells and TGFb pathway within the tumor microenvironment. Results N/A Conclusions An enrollment update will be provided

PD effects will be assessed by measuring modulation of tumor immune cells and TGFb pathway within the tumor microenvironment. Results N/A Conclusions An enrollment update will be provided

P1, N=183, Recruiting, Scholar Rock, Inc. | Not yet recruiting --> Recruiting

P1, N=183, Not yet recruiting, Scholar Rock, Inc.