The combination of SRK-181 and pembrolizumab demonstrated improvements in objective response rate among patients with clear cell renal cell carcinoma in a phase 1 proof-of-concept study.
SRK-181, a selective latent TGFβ1 inhibitor, continues to show promise as a treatment option for patients with clear cell renal cell carcinoma (ccRCC) resistant to anti-PD-1 therapy, according to findings from the phase 1 proof-of-concept DRAGON trial (NCT04291079) presented at the Society for Immunotherapy of Cancer Annual Meeting.1
As of the data cutoff date of August 29, 2023, 6 of 28 evaluable patients treated with SRK-181 and pembrolizumab (Keytruda) who were heavily pretreated had confirmed partial responses and best tumor reduction of 33% to 93%. Stable disease was observed in 10 patients, the disease control rate was 57%, and the objective response rate (ORR) was 21.4%. In the difficult-to-treat ccRCC population, anti-PD-1 retreatment generally results in single-digit ORR or no response, according to Scholar Rock.
Safety was evaluable in 30 patients, and SRK-181 appeared to be well-tolerated in combination with pembrolizumab. There were no observed dose-limiting toxicities (DLTs). One grade 4 treatment-related adverse event (TRAE) of dermatitis exfoliative generalized was seen, and no grade 5 TRAEs were observed. Pemphigoid and rash were observed in 1 patient, immune-related hepatitis was observed in 1 patient, and diarrhea, nausea, and vomiting were all observed in 1 patient.
“The DRAGON trial has successfully delivered on its objective of demonstrating proof of concept for SRK-181 by showing promising anti-tumor activity. These data, along with biomarker results that support proof of mechanism, highlight the immunosuppressive role of TGFβ as a mechanism of anti-PD-1 resistance in patients,” said Jay Backstrom, MD, MPH, president and chief executive officer of Scholar Rock, SRK-181’s manufacturer, in a press release.1
The phase 1, open-label, dose-escalation, and dose-expansion DRAGON trial has an estimated enrollment of 74 patients and an estimated study completion date of December 2024. The primary end points are safety and tolerability of SRK-181 as a monotherapy and in combination with an anti-PD-(L)1 antibody therapy as evaluated by DLTs assessed by investigators. Secondary end points include pharmacokinetics of SRK-181 alone and in combination with anti-PD(L)1 antibody therapy as measured by maximum drug concentration (Cmax), time to Cmax, last validated plasma concentration (Clast), time to Clast, half-life, and objective response.2
SRK-181 is also being investigated in other solid tumor types, including non–small cell lung cancer, urothelial carcinoma, and head and neck squamous cell carcinoma.1