1O Safety, pharmacokinetics, efficacy, and biomarker results of SRK-181 (a latent TGFβ1 inhibitor) from a phase I trial (DRAGON trial)
Yap TA, Gainor J, McKean M, Bockorny B, Barve M, Sweis R, Vaishampayan UN, Tarhini A, Kilari D, Chand A, Abdul-Karim R, Park D, Babu S, Ju Y, Dewall S, Liu L, Kennedy AM, Marantz J, and Gan L. 1O Safety, pharmacokinetics, efficacy, and biomarker results of SRK-181 (a latent TGFβ1 inhibitor) from a phase I trial (DRAGON trial). ESMO Open 2023; 8(1).
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.