SRK-181/Pembro Combination Shows Promise in ccRCC


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.

Renal cell carcinoma: © -

Renal cell carcinoma: © -

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.

Human kidney cross section on scientific background: ©Crystal Light -

Human kidney cross section on scientific background: ©Crystal Light -

“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

About the DRAGON Trial

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

1. Scholar Rock presents new data from phase 1 DRAGON trial showing promising anti-tumor activity in anti-PD-1 resistant metastatic ccRCC patients and supporting SRK-181 continued tolerability. News release. Scholar Rock. November 3, 2023. Accessed November 7, 2023.
2. SRK-181 alone or in combination with anti-PD-(L)1 antibody therapy in patients with locally advanced or metastatic solid tumors (DRAGON). Updated September 5, 2023. Accessed November 7, 2023.
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