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780 SRK-181, a latent TGFβ1 inhibitor: safety, efficacy, and biomarker results from the dose escalation portion of a phase I trial (DRAGON trial) in patients with advanced solid tumors
  1. Timothy Yap1,
  2. Justin Gainor2,
  3. Meredith McKean3,
  4. Melissa Johnson3,
  5. Bruno Bockorny4,
  6. Minal Barve5,
  7. Randy Sweis6,
  8. Ulka Vaishampayan7,
  9. Ahmad Tarhini8,
  10. Deepak Kilari9,
  11. Yawen Ju10,
  12. Si-Tuen Lee-Hoeflich10,
  13. Stephen DeWall10,
  14. Lan Liu10,
  15. Nisha Shah10,
  16. Ann Marie Kennedy10 and
  17. Lu Gan10
  1. 1The University of Texas MD Anderson Cancer Center, Houston, TX, USA
  2. 2Massachusetts General Hospital Harvard Medical School, Boston, MA, USA
  3. 3Sarah Cannon Research Institute, Nashville, TN, USA
  4. 4Beth Israel Deaconess Medical Center, Boston, MA, USA
  5. 5Mary Crowley Cancer Research, Dallas, TX, USA
  6. 6University of Chicago, Chicago, IL, USA
  7. 7University of Michigan, Ann Arbor, MI, USA
  8. 8Moffitt Cancer Center, Tampa, FL, USA
  9. 9Medical College of Wisconsin, Milwaukee, WI, USA
  10. 10Scholar Rock, Inc., Cambridge, MA, USA


Background Transforming growth factor-beta 1 (TGFβ1) plays an important role in mediating the primary resistance to PD-1/PD-L1 [PD-(L)1] blockade. SRK-181 is a fully human, selective anti-latent TGFβ1 IgG4 monoclonal antibody under investigation as a monotherapy or in combination with anti-PD(L)1 therapy in patients with solid tumors. Compared to broad TGFβ inhibitors, SRK-181 was observed to have improved safety profile (no cardiotoxicities) in four-week GLP nonclinical toxicology studies.

Methods The DRAGON trial (NCT04291079) is an ongoing open-label, phase 1 study. Part A followed a 3+3 dose escalation design to evaluate SRK-181 in patients with advanced solid tumors at 80-3000mg every three weeks (q3w) and 2000mg q2w in Part A1, and SRK-181+anti-PD-(L)1 in patients who did not respond to prior anti-PD-(L)1 therapy at 240-2400mg q3w in Part A2. In Part B (expansion phase), SRK-181 (1500mg q3w or 1000mg q2w)+anti-PD-(L)1 are administered in anti-PD-(L)1-resistant patients with non-small cell lung cancer (NSCLC), urothelial carcinoma, melanoma, clear cell renal cell carcinoma (ccRCC) or other advanced solid tumors. The level of circulatory TGFβ1 was assessed as a target engagement biomarker.

Results As of 2 June 2022, Part A1 and Part A2 enrolled 19 and 15 patients, respectively, with median prior lines of therapies of 4 (range 1-10). No dose limiting toxicity (DLT) were observed in Part A. 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). Eight patients had stable disease (SD) as best response (3/colorectal, 3/ovarian, 1/pancreatic, and 1/testicular). The three patients with ovarian cancer were stable for 25 to 42 weeks. In Part A2, the TRAEs (>10%) of any grade were pruritus, rash and rash maculo-papular (each: 20%, n=3), diarrhea (13%, n=2). One confirmed RECIST1.1 partial response (PR) was observed at 800mg in a patient with anti-PD-1 resistant RCC who stayed on study for 30 weeks. Nine patients had best response of SD and five of them were stable for more than 16 weeks (2/head and neck, 1/melanoma, 1/skin squamous cell carcinoma, 1/RCC). SRK-181 treatment resulted in increased levels of circulatory TGFβ1, which suggested target engagement. Part B enrollment is ongoing.

Conclusions As of 2 June 2022, SRK-181 has been tolerated as monotherapy and in combination with anti-PD-(L)1. No DLT was observed up to 3000mg q3w/2000mg q2w as monotherapy and up to 2400mg q3w as combination treatment. Early evidence of efficacy was observed with prolonged stable disease and a confirmed PR.

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