1O - Safety, pharmacokinetics, efficacy, and biomarker results of SRK-181 (a latent TGFβ1 inhibitor) from a phase I trial (DRAGON trial)

Background

SRK-181 is an investigational, fully human, IgG4 monoclonal antibody that selectively binds to latent transforming growth factor-beta 1 (TGFβ1). TGFβ1 activation has been associated with primary resistance to PD-1/PD-L1 [PD-(L)1] blockade. Compared to broad TGFβ inhibitors, SRK-181 was observed to have an improved safety profile (no cardiotoxicities) in 4-week GLP toxicology studies.

Methods

NCT04291079 is a multicenter ongoing phase I study with a 3+3 dose escalation design to evaluate SRK-181 in patients (pts) with advanced solid tumors at 80-3000mg q3w and 2000mg q2w (Part A1), and SRK-181 + anti-PD-(L)1 in pts with no response to prior anti-PD-(L)1 therapy at 240-2400mg q3w (Part A2). In Part B, SRK-181 (1500mg q3w or 1000mg q2w) + anti-PD-(L)1 are expanded in anti-PD-(L)1-resistant pts with non-small cell lung cancer, urothelial carcinoma, melanoma, clear cell renal cell carcinoma (ccRCC), or other advanced solid tumors.

Results

As of Dec 2, 2022, the study enrolled 19 pts in Part A1 and 15 in Part A2 with no DLTs observed. The median prior lines of therapies were 4 (range 1-10). In Part A1, the most common treatment-related AEs (TRAEs, >10%) of any grade were fatigue (16%, n=3), decreased appetite and nausea (each 11%, n=2). Best response of stable disease (SD) was observed in 8 pts. All 3 ovarian cancer pts were stable for 25 to 42 weeks. In Part A2, the TRAEs (>10%) of any grade were rash maculo-papular (33%, n=5), pruritus (27%, n=4), rash (20%, n=3), diarrhea and pemphigoid (each 13%, n=2). One confirmed RECIST 1.1 partial response (cPR) was observed at 800mg in a pt with anti-PD-1 resistant ccRCC who stayed on study for 30 weeks. Of 9 pts with best response of SD, 5 were stable >16 weeks. SRK-181 treatment resulted in increased levels of circulatory TGFβ1, indicating target engagement. Part B enrollment is ongoing (N=9 in ccRCC cohort); two cPR were observed in pts with anti-PD-1 resistant ccRCC.

Conclusions

SRK-181 has been tolerated as monotherapy and in combination with anti-PD-(L)1. 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.

Clinical trial identification

NCT04291079.

Editorial acknowledgement

Legal entity responsible for the study

Scholar Rock, Inc.

Funding

Scholar Rock, Inc.

Disclosure

All authors have declared no conflicts of interest.