Recent Phase 1 DRAGON Data Show SRK-181 Continues to be Well Tolerated with Early Indications of Efficacy
- All doses were generally well tolerated, no dose limiting toxicities observed including at the Part B dose of 1500 mg
- Biomarker data consistent with target engagement
- Two confirmed partial responses observed in patients with anti-PD-1 resistant clear cell renal cell carcinoma
- Enrollment of DRAGON Part B continues to progress
“Resistance to checkpoint inhibitor therapy remains a significant challenge in the treatment of advanced cancer. The DRAGON trial is investigating our novel TGFβ1 selective monoclonal antibody, SRK-181, which was designed to address this challenge based on the strong, scientific rationale that TGFβ1 is a driving mechanism of resistance to checkpoint inhibitors. Our preclinical work suggests that SRK-181 may overcome this resistance and avoid the cardiotoxicities that have limited other non-selective approaches,” said
Data continue to show SRK-181 is generally well tolerated
Safety data from the dose escalation portion of the trial (Part A) continue to show SRK-181 is generally well tolerated when used alone or in combination with anti-PD-(L)1 checkpoint inhibitor therapy. No dose-limiting toxicities were observed in patients receiving SRK-181 as monotherapy (Part A1) when dosed up to 3000 mg once every three weeks (q3w) or 2000 mg once every two weeks (q2w), or in patients receiving SRK-181 in combination with checkpoint inhibitor therapy (Part A2) when dosed up to 2400 mg q3w. All dose levels were generally well tolerated, including the recommended SRK-181 dose of 1500 mg q3w or 1000 mg q2w in combination with anti‑PD-(L)1 for the dose expansion portion of the trial (Part B).
No Grade 4 or 5 treatment-related AEs occurred. Treatment-related Grade 3 adverse events were increased levels of alanine aminotransferase (one patient in Part A1); pruritus (two patients in Part A2), blister, immune-mediated lung disease, rash and rash maculo-papular (one patient each in Part A2). A treatment-related serious adverse event of elevated troponin I (one patient) was observed in Part A1; blister, pruritus, and rash (all in one patient) and immune-mediated lung disease (one patient) were observed in Part A2.
Early indications of efficacy
The response was assessed by principal investigators based on RECIST 1.1. Partial response (“PR”) is defined as at least a 30% tumor reduction. As of the data cut-off date (
- One confirmed PR in a patient with anti-PD-1 resistant clear cell renal cell carcinoma at 800mg in Part A2 of the trial who remained in the study for 30 weeks.
- One ongoing patient in the 2400 mg dose group of Part A2 with head and neck cancer experienced a 29.4% tumor reduction.
- Nine patients experienced a best response of stable disease. This included six patients whose disease progressed prior to the trial and were stable beyond the 16-week cutoff.
As of the data cut-off date, 14 patients were enrolled in Part
Biomarker data from Part A consistent with target engagement
The biomarker strategy for DRAGON explores early signs of SRK-181 activity, including target engagement and pathway modulation. It includes measuring effects on both circulating and tumor immune contexture, such as CD8+ T cell infiltration and reductions in myeloid-derived suppressor cell (MDSC) populations, as well as analysis of TGFβ-related pathway signaling.
Following treatment with SRK-181 in Part A, circulatory TGFβ1 levels increased in all dose groups. Given the small number of participants in each dosing cohort, dose-dependent increases in circulatory TGFβ1 levels were not apparent. These findings are consistent with preclinical results from a mouse tumor model (MBT-2) that suggest circulatory TGFβ1 may be a potential pharmacodynamic biomarker of SRK-181. Combination treatment with anti-PD-(L)1 therapy also appears to have similar circulatory TGFβ1 levels as monotherapy.
“At this early stage, the biomarker findings are consistent with the circulating TGFβ1 levels observed in our preclinical studies. We also saw target engagement accompanied by robust efficacy measured through MDSC levels as PD biomarker and immune infiltration into tumors and tumor regression in our preclinical studies,” said
The poster will be made available in the Publications & Posters section of Scholar Rock’s website following the conference.
For conference information, visit https://www.sitcancer.org/2022/home
SRK-181 is a selective inhibitor of latent TGFβ1 activation being developed to overcome primary resistance to checkpoint inhibitor therapy, such as anti-PD-(L)1 antibodies, in advanced cancer. TGFβ1 is the predominant TGFβ isoform expressed in many human tumor types. Based on analyses of various human tumors that are resistant to anti-PD-(L)1 therapy, data suggest TGFβ1 is a key contributor to the immunosuppressive tumor microenvironment, excluding and preventing entry of cytotoxic T cells into the tumor, thereby inhibiting anti-tumor immunity. (1)
(1) Martin et al., Sci. Transl. Med. 12:
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