On November 3, 2023 Scholar Rock (NASDAQ: SRRK), a Phase 3, clinical-stage biopharmaceutical company focused on the treatment of serious diseases in which protein growth factors play a fundamental role, reported new data from its Phase 1 DRAGON proof-of-concept trial of SRK-181, a selective inhibitor of latent TGFβ1 activation being developed with the aim of overcoming resistance to checkpoint inhibitor therapy in patients with advanced cancer (Press release, Scholar Rock, NOV 3, 2023, View Source [SID1234636930]). These data will be presented in two poster presentations during the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper)’s (SITC) (Free SITC Whitepaper) 38th Annual Meeting & Pre-Conference being held November 1 – 5th in San Diego.

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The first poster focuses on the safety, efficacy, and preliminary biomarker data in patients with anti-PD-1 resistant clear cell renal cell carcinoma (ccRCC) in Part A2 (dose escalation) and Part B (dose expansion) of the Phase 1 DRAGON trial. The ccRCC cohort was the focus for that poster, as it was the fastest cohort to achieve enrollment goals. The second poster focuses on preliminary biomarker data from part B of the trial in patients with multiple tumor types.

Data presented continues to support proof of concept for SRK-181 in 28 heavily pretreated patients with ccRCC resistant to anti-PD-1. SRK-181 was generally well tolerated and showed promising anti-tumor activity in this patient population. Of 28 evaluable patients in the ccRCC cohort, six patients treated with SRK-181 in combination with pembrolizumab had confirmed partial responses (PRs) and achieved a best tumor reduction of 33% to 93%, with an objective response rate (ORR) of 21.4%. In the biomarker analysis for ccRCC, levels of circulating granulocytic myeloid-derived suppressor cells (gMDSC) correlated with clinical activity in ccRCC patients treated with SRK-181 in combination with pembrolizumab. The data cutoff for all analyses was August 29, 2023.

"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, M.D., M.P.H., President and Chief Executive Officer of Scholar Rock. "We are particularly encouraged by the responses observed in patients with ccRCC who had been treated with multiple lines of therapy before receiving SRK-181."

Safety data from ccRCC cohort continue to show SRK-181 is generally well tolerated

Safety data from the ccRCC cohort (n=30 patients; part A2: 1 patient on 800mg q3w and 1 patient on 1600mg q3w and Part B: 28 patients on 1500 mg q3w) continue to show SRK-181 has been generally well tolerated when used in combination with pembrolizumab. No dose-limiting toxicities were observed at any dose level, including at 1500 mg q3w in combination with pembrolizumab, the recommended dose selected for Part B.

One Grade 4 treatment-related adverse event (AE) was observed, dermatitis exfoliative generalized. No Grade 5 treatment-related AEs occurred. Treatment-related serious adverse events were dermatitis exfoliative generalized (1 patient), pemphigoid and rash (both in 1 patient), immune-related hepatitis (1 patient), and diarrhea, nausea, and vomiting (all three in 1 patient).

Preliminary results of SRK-181 in ccRCC patients show promising anti-tumor activity

The response was assessed by principal investigators based on RECIST 1.1. Out of the 28 ccRCC patients with evaluable responses (defined as all enrolled patients except those who are still on study, but pending post-treatment radiographic evaluation):

Six patients had confirmed PRs (defined as at least a 30% tumor reduction), with best tumor reduction of 33% to 93%, and remained on study for 2.8+ to 16.3+ months (5 of the 6 patients remained on for over 6.5 months).
Ten patients had stable disease (SD) (defined as tumors with neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD). Five of these patients continued in the study.
The objective response rate (ORR), defined as the percentage of patients with a partial or complete response to therapy, was 21.4% and the disease control rate (DCR), defined as the percentage of patients whose disease shrinks or remains stable over a certain time period, was 57%. In this difficult to treat population, anti-PD-1 retreatment is generally associated with single-digit ORR or no response.1
Biomarker data support proof of mechanism in multiple tumor types

The biomarker strategy includes measuring effects of SRK-181 on both circulating and tumor immune cells, such as tumor infiltration by CD8+ T cells and reductions in myeloid-derived suppressor cell (MDSC) populations. The analysis included patients from Part B with ccRCC, melanoma, non-small cell lung cancer (NSCLC), or urothelial carcinoma (UC).

Following treatment with SRK-181 and pembrolizumab, circulating MDSC levels decreased below baseline in all patients with PRs (n=7), which included those in the ccRCC, melanoma, and UC cohorts. CD8+ T cells were measured in tumor types for which paired biopsy samples (i.e., samples before and after treatment for individual patients) of sufficient quality were available: UC, melanoma, and NSCLC. In those patients (n=8), SRK-181 treatment was associated with an increase in CD8+ T cell infiltration into tumors. These findings were consistent with preclinical data showing that treatment with SRK-181 and anti-PD-(L)1 therapy decreased circulating MDSC levels and increased CD8+ T cell infiltration into tumors, which correlated with tumor response and survival benefit.

The results will be presented at the SITC (Free SITC Whitepaper) 38th Annual Meeting in two poster presentations, details of which can be found below. The posters will be made available in the Publications & Posters section of Scholar Rock’s website following the conference.

Title: Establishing Proof of Mechanism in Patients: Preliminary Biomarker Data of SRK-181 (a latent TGFβ1 inhibitor) from DRAGON Study
Presentation Type: Poster 726
Presenter: Susan Henry, PhD, Senior Director, Translational Sciences, Scholar Rock, Inc.
Location: Exhibit Halls A and B1, San Diego Convention Center
Date/Time: November 4, 11:55 AM – 1:25 PM PST and 7 – 8:30 PM PST

Title: Safety, Efficacy, and Biomarker Results of SRK-181, a Latent TGFβ1 Inhibitor, in Anti-PD-1 Resistant Metastatic ccRCC Patients
Presentation Type: Poster 666
Presenter: Timothy Yap, MBBS, PhD, FRCP, Medical Oncologist and Physician-Scientist; and Associate Professor, Department of Investigational Cancer Therapeutics, University of Texas MD Anderson Cancer Center
Location: Exhibit Halls A and B1, San Diego Convention Center
Date/Time: November 4, 11:55 AM – 1:25 PM PST and 7 – 8:30 PM PST

For conference information, visit View Source

(1) Pal, et al. The Lancet. 2023; 15;402(10397):185-195.

About SRK-181

SRK-181 is a selective inhibitor of 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 that 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. (2) SRK-181 specifically targets the latent TGFβ1 isoform in a context-independent manner, designed to enable complete inhibition of TGFβ1 in all compartments within the tumor microenvironment. Scholar Rock believes that SRK-181 has the potential to overcome this immune cell exclusion and induce tumor regression when administered in combination with anti-PD-(L)1 therapy while potentially avoiding toxicities associated with non-selective TGFβ inhibition. The DRAGON Phase 1 proof-of-concept clinical trial (NCT04291079) in patients with locally advanced or metastatic solid tumors is ongoing. The trial is currently enrolling and dosing patients in multiple proof of concept cohorts conducted in parallel, including urothelial carcinoma (UC), cutaneous melanoma (MEL), non-small cell lung cancer (NSCLC), head and neck squamous cell carcinoma (HNSCC), and clear cell renal cell carcinoma (ccRCC). SRK-181 is an investigational product candidate and its efficacy and safety have not been established. SRK-181 has not been approved for any use by the FDA or any other regulatory agency.