SC3613 Shows Potent Anti-Tumor Activity and Potential for Tolerable Safety in EGFR-Mutant NSCLC Cells

April 23, 2026 | Ashling Wahner

SC3613 (IN-207387), a novel, mutant-selective EGFR L858R degrader, demonstrated robust antitumor activity and a favorable safety profile in preclinical models of EGFR TKI–resistant non–small cell lung cancer (NSCLC), according to findings from a poster presented at the 2026 AACR Annual Meeting.¹

The EGFR degrader exhibited potent activity against EGFR L858R mutations, including those harboring C797X and T790M resistance alterations. In a Ba/F3 EGFR L858R/C797S–mutated allograft model, SC3613 achieved a tumor growth inhibition (TGI) rate of 100.3% when dosed at 50 mg/kg daily, outperforming lazertinib (Lazcluze), which showed a TGI rate of 8.9% at the same dose.

“SC3613, an orally bioavailable, potent, and selective allosteric EGFR degrader, shows robust antitumor activity in H1975 and patient-derived cell [PDC]/organoid models harboring EGFR L858R/C797S mutations,” lead study author Jun Gyu Kim, MS, and coauthors wrote in the poster.

Kim is an oncology research team leader and a senior research fellow at Dong-A ST in the Republic of Korea.

What was the rationale for developing SC3613?

In 2024, the most recent FDA approval occurred for osimertinib (Tagrisso) occurred for the treatment of adult patients with locally advanced, unresectable, stage III NSCLC with disease that has not progressed during or following concurrent or sequential platinum-based chemoradiation therapy and whose tumors harbor EGFR exon 19 deletions or exon 21 L858R mutations.²  However, primary and acquired resistance to this agent and corresponding treatment decision-making remain key challenges in the field.³

To enhance efficacy against EGFR L858R mutations and overcome osimertinib resistance mutations, such as those in EGFR C797X, investigators sought to develop a selective allosteric EGFR degrader.¹ SC3613 was identified as a lead compound capable of targeting several resistant EGFR genotypes, including L858R, L858R/T790M, L858R/C797S, and L858R/T790M/C797S, with nanomolar-level concentration for 50% degradation (DC₅₀) values. The primary goal was to provide a potent therapeutic option for patients who have progressed on third-generation TKIs that can also maintain high selectivity over wild-type EGFR to improve safety.

How did SC3613 perform in in vitro degradation and selectivity assays?

In vitro analyses showed that SC3613 effectively degraded both total and phosphorylated EGFR across multiple mutant cell lines. The respective maximum drug absorption rates and DC₅₀ values across EGFR mutation subtypes in Ba-F3 cell lines were:

• L858R: 92.0%; 15 nM
• L858R/T790M: 97.7%; 2.0 nM
• L858R/C797S: 94.6%; 2.0 nM
• L858R/T790M/C797S: 94.1%; 5.7 nM

Furthermore, SC3613 demonstrated high selectivity for mutant EGFR over the wild-type form. In EGFR wild-type A549 and A431 cells, the DC₅₀ values for SC3613 were both greater than 10,000 nM. Anti-proliferative testing in patient-derived cells further confirmed the potency of SC3613, with half-maximal effective concentration values of 2.7 nM for EGFR L858R/C797S–mutant NSCLC PDCs and 30.18 nM for EGFR L858R/T790M/C797S–mutant NSCLC PDCs.

What were the key in vivo efficacy findings with SC3613 in NSCLC cells?

Beyond the 100.3% TGI rate observed in the Ba/F3 allograft model, SC3613 induced complete regressions in an H1975 EGFR L858R/T790M–mutant xenograft model. Notably, tumor suppression was sustained after treatment discontinuation. Although osimertinib and lazertinib showed activity in their respective targets, SC3613 provided superior and more durable tumor suppression in the EGFR C797S–mutant setting.

What were the safety and pharmacokinetic profiles of SC3613?

Preclinical safety evaluations indicated that SC3613 has a superior skin safety profile compared with osimertinib. In animal models, osimertinib induced dose-dependent skin lesions characterized by dermal and subcutaneous inflammation, whereas SC3613-treated models generated minimal, non–treatment-related changes in epidermal thickness and inflammatory scores.

Additional safety and pharmacokinetic highlights included:

• No test item–related effects on body weight or mortality were observed at doses up to 450 mg/kg in a 2-week repeat-dose toxicity study in mice
• Stable metabolic profile across mice, rats, dogs, and humans
• Low potential for drug-drug interactions via CYP inhibition or induction
• High rates of tumor distribution and oral exposure in rodent models

“[SC3613 is] currently in lead optimization; we target preclinical candidate nomination by 2026,” the authors concluded.

References

Kim JG, Choi J, Lee OY, et al. SC3613 (IN-207387), a mutant-selective EGFR degrader, exhibits potent anti-tumor activity and improved safety profile in EGFR TKI-resistant NSCLC. Cancer Res. 2026;86(suppl 7):4591-4591. doi:10.1158/1538-7445.AM2026-4591

FDA approves osimertinib for locally advanced, unresectable (stage III) non-small cell lung cancer following chemoradiation therapy. FDA. September 25, 2024. Accessed April 22, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-osimertinib-locally-advanced-unresectable-stage-iii-non-small-cell-lung-cancer

Ferro A, Marinato GM, Mulargiu C, et al. The study of primary and acquired resistance to first-line osimertinib to improve the outcome of EGFR-mutated advanced non-small cell lung cancer patients: the challenge is open for new therapeutic strategies. Crit Rev Oncol Hematol. 2024;196:104295. doi:10.1016/j.critrevonc.2024.104295