A phase 1b, multicenter, dose-escalation study of subasumstat (TAK-981) in combination with pembrolizumab in patients (pts) with advanced solid tumors.
Authors: Goel Sanjay , Ulahannan Susanna Varkey , Olszanski Anthony J. , LoRusso Patricia , Sanborn Rachel E. , Sharma Sunil , Emens Leisha A. , Reilley Matthew , Priego Victor , Li Shuli , Wang Bingxia , Dong Lixian , Sachsenmeier Kris , Gibbs John , Gharavi Robert , Martinez Alonzo , Proscurshim Igor , Fram Robert J. , Gomez-Pinillos Alejandro , Rasco Drew W. 
Published: June 2022

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Background: SUMOylation is a post-translational modification with a role in limiting type 1 interferon (IFN-1)-dependent immune responses. Subasumstat is a small-molecule inhibitor of SUMOylation with the potential to increase antitumor immunity and overcome tumor resistance to checkpoint inhibitors (CPI) by inducing IFN-1 signaling. Preclinical data suggest that subasumstat enhances antigen cross-presentation, promoting T cell dependent antitumor responses; subasumstat plus an anti-PD-1 CPI has shown synergistic tumor growth inhibition and activation of CD8+ T cells and natural killer cells in syngeneic mouse models. We report data from the dose escalation part of a phase 1b study of subasumstat with pembrolizumab in pts with relapsed/refractory, CPI-exposed, non-squamous non-small-cell lung cancer (NSCLC) or microsatellite-stable colorectal cancer (MSS-CRC). Methods: Pts received escalating doses (40, 60, 90, and 120 mg) of subasumstat IV in 3 dosing schedules: days 1 and 8 (QW), days 1, 4, 8, and 11 (BIW), or days 1, 8, and 15 (90 mg only) of 21-day cycles, plus pembrolizumab 200 mg IV on day 1 of each cycle for 2 years or until disease progression or unacceptable toxicity. Dose escalation was guided by Bayesian optimal interval design. Phase 1b primary objectives were safety, tolerability, and the recommended phase 2 dose of subasumstat with pembrolizumab. Results: As of October 13, 2021, 43 (35 MSS-CRC; 8 NSCLC) pts had received ≥1 dose of subasumstat (22 BIW [40–120 mg]; 15 QW [90 –120 mg]; 6 on days 1, 8, 15 [90 mg)]. Median number of treatment cycles was 3; 28 (65%) pts had discontinued treatment, 21 (49%) due to progressive disease. Median age was 58 years (range 34–77); 56% of pts were male. One pt had a dose-limiting toxicity of grade 3 angioedema at 120 mg BIW. The maximum tolerated dose was not identified. Treatment-emergent adverse events (TEAEs) occurred in 38 (88%) pts; subasumstat-related TEAEs occurred in 34 (79%) pts, and included chills in 20 (47%), pyrexia in 16 (37%), fatigue in 9 (21%), anemia in 6 (14%), and stomatitis in 5 pts (12%; 3 [50%] in the 120 mg BIW cohort). Grade ≥3 TEAEs occurred in 24 (56%) pts; subasumstat-related grade ≥3 TEAEs reported in 10 (23%) pts included anemia, pyrexia, and increased aspartate aminotransferase (2 [5%] pts each). Pharmacokinetic activity of subasumstat was linear and decreased in a tri-phasic manner. Subasumstat exerted pharmacodynamic activity including target engagement, SUMOylation inhibition and increased IFN-1 signaling. Partial responses were observed at ≥40 mg dose levels in pts with NSCLC and MSS-CRC. Conclusions: Subasumstat plus pembrolizumab showed a favorable safety profile and promising anti-tumor activity in pre-treated NSCLC and MSS-CRC pts. Updated data will be presented at the meeting. Subasumstat plus pembrolizumab is currently in phase 2 clinical development (NCT04381650). Clinical trial information: NCT04381650.