EGFR Channel

April 22, 2026 | Kyle Doherty

Key Takeaways

EGFR C797S is a common on-target resistance mechanism to third-generation EGFR TKIs, arising via Cys797-to-Ser substitution and occurring in 7%–20% of EGFR-mutant NSCLC cases.
ABK-EGFR-1 drove marked in vivo regressions in C797S-driven CDX models, including Del19/T790M/C797S and L858R/C797S, supporting activity against complex resistance genotypes.
Cross-species PK/brain distribution were favorable, with ~50% oral bioavailability and strong CNS penetration (unbound brain-to-plasma coefficients 0.77–2.55 at 4 hours).
Mutant selectivity exceeded 1000-fold versus wild-type EGFR, surpassing osimertinib and gefitinib comparators, aligning with a strategy to preserve efficacy while sparing wild-type EGFR toxicity.
Safety pharmacology suggested low QT liability, with hERG inhibition IC50 >10 µM, supporting continued preclinical development toward clinical evaluation.

The novel next-generation EGFR C797S inhibitor ABK-EGFR-1 demonstrated strong in vivo efficacy across multiple EGFR C797S–driven xenograft models and possesses favorable drug-like properties, according to data from a preclinical study presented during the 2026 AACR Annual Meeting.¹

Findings from the preclinical study revealed that ABK-EGFR-1 induced strong tumor regression even at a low dose in both BaF3-EGFR-Del19/T790M/CS797S and BaF3-EGFR-L858R/CS797S CDX models. In terms of pharmacokinetics, the oral bioavailability of ABK-EGFR-1 was 50%, 47%, and 50% across mouse, rat, and dog models, respectively. The agent also displayed strong brain penetration in mouse, rat, and dog models with an unbound brain-to-plasma partition coefficient at 4 hours of 1.04, 0.77, and 2.55, respectively. Regarding safety, ABK-EGFR-1 was found to have a half-maximum inhibitory concentration of the hERG channel of more than 10 uM with a low risk of QT prolongation.

“ABK-EGFR-1 is a leading next-generation EGFR C797S inhibitor with excellent selectivity for C797S mutations over wild-type EGFR and other [receptor tyrosine kinases]; superior in vivo efficacy in various EGFR C797S xenograft models; [and] excellent preclinical brain penetration and other drug-like properties,” Haiyan Ying, PhD, the executive director of Abbisko Therapeutics in Shanghai, China, and her coauthors wrote in a poster presentation of the data.

What is EGFR C797S and what makes it a potential treatment target?

The EGFR C797S mutation is a clinically validated mechanism of resistance to third-generation EGFR TKIs. The mutation occurs in an estimated 51,000-146,000 cases of lung cancer per year globally. Specifically, 7% to 20% of all EGFR-positive cases of non–small cell lung cancer harbor an EGFR C797S mutation.

EGFR C797S mutations typically arise during treatment with third-generation EGFR TKIs with serine SER797 replacing cysteine CYS797.² Although there has been progress in developing fourth-generation EGFR TKIs that are capable of overcoming resistance to third-generation agents, challenges persist, such as reduced efficacy in the presence of high ATP concentrations and the association of ATP-competitive inhibitors with rash and diarrhea. Moreover, inhibitors that occupy the ATP-binding and allosteric pockets tend to be large with low bioavailability.

Ying and her coauthors noted that there are presently no approved small molecule targeted therapies available for the EGFR C797S resistance mutation.¹ “Targeting EGFR C797S mutations and previous resistant mutations, coupled with superior potency, brain penetrating ability, and selective sparing of wild-type EGFR is expected to benefit a wide range of eligible patients,” they wrote in the poster.

ABK-EGFR-1 in EGFR C797S–Driven Xenograft Models

ABK-EGFR-1 is a leading next-generation EGFR C797S inhibitor with excellent selectivity for EGFR C797S mutations over wild-type EGFR and other receptor tyrosine kinases.

ABK-EGFR-1 displayed in vivo efficacy in various preclinical EGFR C797S xenograft models with excellent preclinical brain penetration and other drug like properties.

These findings support the continued preclinical development of ABK-EGFR-1 and its advancement toward clinical evaluation.

How was ABK-EGFR-1 evaluated in the preclinical study?

The study authors evaluated anti-proliferative activity in a panel of cell lines harboring diverse EGFR C797S mutations to assess the potency and mutation coverage of ABK-EGFR-1 in comparison with reference EGFR inhibitors. To assess in vivo antitumor activity, they used multiple xenograft models driven by EGFR C797S mutations. Agent selectivity was evaluated by comparing cellular and in vivo responses in models expression mutant or wild-type EGFR.

What were the additional preclinical data with EGFR C797S that were shared during AACR?

Additional findings from the poster presentation demonstrated that ABK-EGFR-1 showed superior potency across mutations and good selectivity over wild-type EGFR. The agent displayed a selectivity over 1000-fold for mutant EGFR compared with wild-type EGFR. Comparatively, osimertinib (Tagrisso) had an approximate 300- to 500-time selectivity in favor of mutant EGFR vs wild-type. The selectivity of gefitinib (Iressa) for mutant EGFR compared with wild-type of less than 300-fold.

“Collectively, these findings support the continued preclinical development of ABK-EGFR-1 and its advancement toward clinical evaluation,” Ying and her coauthors wrote in their conclusion.

Disclosures: Ying received stock options from Abbisko Therapeutics and is employed by the company.

References

Ning M, Peng J, Guo W, et al. Discovery and characterization of ABK-EGFR-1, a 4th generation EGFR C797S inhibitor with excellent selectivity and brain penetration. Cancer Res. 2026;86(suppl 8):LBA350. doi:10.1158/1538-7445.AM2026-LB350

Zhang D, Zhao J, Yang Y, et al. Fourth-generation EGFR-TKI to overcome C797S mutation: past, present, and future. J Enzyme Inhib Med Chem. 2025;40(1):2481392. doi:10.1080/14756366.2025.2481392