Abstract CT266: D3S-001, a next generation GDP-bound KRAS G12C inhibitor, as monotherapy in KRAS G12C inhibitor resistant non-small cell lung cancer
Authors: Herbert H. Loong, Ziming Li, Byoung Chul Cho, Jun Zhao, John Park, Zhengbo Song, Bowyer Samantha, Ki Hyeong Lee, Xiaorong Dong, Jianya Zhou, Cheng Chen, Yangbo Liu, Yandong Shen, Shaonan Wang, Zifei Fan, Qian Chen, Hui Wang, Jing Zhang, Zhi Jian Chen, Tony S. Mok, Shun Lu
Journal: Cancer Research (2025)

Abstract Background: Resistance mechanisms to first-generation (1G) KRAS G12C inhibitors (G12Ci) are diverse, with previous data revealing a heterogeneous pattern characterized by multiple subclonal events emerging after treatment (Tx). Incomplete G12C target engagement (TE) and G12Ci induced G12C amplification contributed to the resistance mechanisms against 1G G12Ci. D3S-001, a next-generation KRAS G12Ci, has demonstrated potent, faster and complete TE to effectively deplete active KRAS mutated protein. In pre-clinical studies, D3S-001 resulted in tumor regression in xenograft models that are resistant to sotorasib (soto) and adagrasib (ada). Phase 1 results demonstrated favorable safety and promising early efficacy across NSCLC, CRC and PDAC; Here, we present findings in G12Ci resistant NSCLC patients (pts) from the ongoing Phase 2 trial (NCT05410145). Methods: Pts of locally advanced or metastatic NSCLC with historically confirmed KRAS G12C mutation were eligible for inclusion if they had radiologically or clinically documented PD following TX of 1 prior KRAS G12Ci achieving CR/PR or SD for &amp;gt;= 6 months. In this cohort, D3S-001 was administered as monotherapy at 600mg once daily. The key objectives included safety, efficacy, and ctDNA kinetics by liquid biopsy. Results: As of 14 Feb 2024, a total of 20 pts were enrolled. Prior G12Ci Tx included FDA approved and experimental G12Cis. 7 pts had soto, 1 pt had ada and 12 pts had other experimental G12Cis. During their prior G12Ci Tx, 8 pts (40%) achieved PR, 7 pts (35%) achieved SD, and 5 pts (25%) were unknown as the BOR. 14 pts (70%) were enrolled into this study immediately after PD from prior G12Ci. Median study follow-up was 4.7 months (range: 1.3-12.8 months), and 9 pts (45%) remain on-study Tx. TRAE of any grade occurred in 18 pts (90%). Of which, 2 (10%) were Grade 3 (no &amp;gt;=G4). PR was achieved in 6 pts (30%). Median DOR was 8.2 months. DCR was 80% and tumor shrinkage was observed in 12 of the 20 (60%) pts. Of the 20 pts, 14 (70%) were KRAS G12C ctDNA positive at baseline [bG12C(+)]. Notable baseline co-mutations included secondary KRAS alterations (A146V, R68S and three G12C amplification), BRAF, EGFR, NTRK1/2/3, TP53, etc. Of the 14 bG12C(+) pts, 11 achieved &amp;gt;90% G12C MAF reduction including 8 with complete clearance. All 6 radiological responders were bG12C(+) and 5 of 6 had complete clearance of G12C MAF. Remarkably, of the 3 pts with KRAS amplification, 2 achieved PR and 1 SD with D3S-001 Tx. Conversely, pts who had immediate PD to D3S-001 carried baseline gene alterations of switch II pocket mutation (KRAS R68S), BRAF V600E, MYC amplification, NTRK2, CDKN2A and PIK3CG. These findings align with preclinical observation that D3S-001 was effective in G12Ci resistant xenograft model including those with KRAS G12C gene amplification. Conclusions: These findings highlight the potential of D3S-001 to overcome the limitations of earlier KRAS G12Ci and address unmet needs in G12Ci resistant NSCLC, offering a promising therapeutic option for pts with KRAS G12C-mutant cancers. Citation Format: Herbert H. Loong, Ziming Li, Byoung Chul Cho, Jun Zhao, John Park, Zhengbo Song, Bowyer Samantha, Ki Hyeong Lee, Xiaorong Dong, Jianya Zhou, Cheng Chen, Yangbo Liu, Yandong Shen, Shaonan Wang, Zifei Fan, Qian Chen, Hui Wang, Jing Zhang, Zhi Jian Chen, Tony S. Mok, Shun Lu. D3S-001, a next generation GDP-bound KRAS G12C inhibitor, as monotherapy in KRAS G12C inhibitor resistant non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT266.