Abstract Non-small cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancers, with activating mutations in the epidermal growth factor receptor (EGFR) strongly associated with tumor progression and poor clinical outcomes. Among these mutations, the L858R mutation in exon 21 serves as a major oncogenic driver that confers initial sensitivity to EGFR tyrosine kinase inhibitors (TKIs). However, patients with L858R-driven tumors exhibit a poorer prognosis and shorter progression-free survival even with third-generation EGFR TKIs, such as osimertinib, compared with those harboring exon 19 deletions, underscoring a substantial unmet clinical need in this molecular subgroup. In addition, the emergence of secondary resistance mutations, including C797S, further limits the long-term efficacy of current TKIs. To address these challenges, targeted protein degradation has emerged as a promising strategy to eliminate both activating and resistance-associated mutant EGFR. We developed SC3613 (IN-207387), a novel heterobifunctional degrader designed to selectively bind an allosteric pocket of mutant EGFR while sparing the wild-type receptor, thereby minimizing off-target toxicities. SC3613 efficiently induced ubiquitin-proteasome-mediated degradation across L858R-containing EGFR variants, including L858R/C797S, and exhibited potent anti-proliferative activity in patient-derived cells harboring resistant EGFR mutations. A potent antitumor effect was also observed in NCI-H1975 (L858R/T790M) cells. Consistent with effective target engagement, SC3613 treatment resulted in marked suppression of downstream EGFR signaling pathways. Importantly, SC3613 demonstrated a superior safety profile. In BALB/c nude mice, SC3613 produced substantially lower levels of skin keratosis on the face, neck, and abdomen compared with osimertinib, indicating a reduced incidence of cutaneous adverse effects and a broader therapeutic window. Furthermore, orally administrated SC3613 induced potent, dose-dependent anti-tumor activity in multiple EGFR TKI-resistant xenograft model. Treatment led to a high incidence of durable complete tumor regressions without associated body-weight loss, highlighting its favorable tolerability. Collectively, these findings identify SC3613 as a potent, highly mutant-selective, and orally active EGFR degrader with robust anti-tumor efficacy and improved safety. SC3613 represents a promising next-generation therapeutic candidate for NSCLC patients harboring activating and resistance mutations such as L858R, T790M, and C797S. Citation Format: Jun Gyu Kim, Jihoon Choi, Ok Young Lee, Young Jun Park, Young Min Jeong, Choongsil Lee, Seo Yoon Jeong, Hye Yeon Lee, Yu Jin Lee, Hyesun Lee, Dae Young Lee, Ah Yeon Park, Hyoeun Jo, Sun Ho Choi, Sun Ho Jeon, Ji-Young An, Jong Hyun Lee, Yang Hun Tae, Mirae An, Keunho Lee, Jong Ryoul Choi, Bong Tae Kim, Mi-Kyung Kim. SC3613 (IN-207387), a mutant-selective EGFR degrader, exhibits potent anti-tumor activity and improved safety profile in EGFR TKI-resistant NSCLC abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 4591.
KIM et al. (Fri,) studied this question.