Journal: Zhongguo ying yong sheng li xue za zhi = Zhongguo yingyong shenglixue zazhi = Chinese journal of applied physiology
This publication reviews the emerging role of sunvozertinib (DZD9008), a next-generation EGFR tyrosine kinase inhibitor specifically engineered for EGFR exon 20 insertion–mutated NSCLC, a setting where standard EGFR TKIs have historically been ineffective due to conformational changes in the kinase domain.
Key points:
- Rationale and design: Sunvozertinib is structurally optimized for high potency against a broad range of EGFR Ex20ins variants while sparing wild-type EGFR, aiming to reduce classic EGFR-related toxicities (e.g., severe rash, diarrhea) that limit dosing of less selective agents.
- Clinical context: Patients with EGFR Ex20ins have had limited options, traditionally treated with platinum-doublet chemotherapy. Recently approved agents (amivantamab, mobocertinib) have improved outcomes but are constrained by tolerability, CNS activity, and durability of response.
- Preclinical data: Models show strong inhibition across multiple Ex20ins variants and suggest lower off-target wild-type EGFR inhibition. Animal data also indicate potentially meaningful CNS penetration and activity, important for patients with brain metastases.
- Clinical activity: Early-phase WU-KONG trials demonstrate promising efficacy, with reported objective response rates around 44–60% in previously treated patients and encouraging results in treatment-naïve cohorts.
- Safety/tolerability: The most frequent adverse events are diarrhea, rash, and stomatitis, generally milder than with some other Ex20ins-directed agents, supporting a manageable safety profile at clinically active doses.
Overall, the article positions sunvozertinib as a rationally designed, selective EGFR Ex20ins inhibitor with encouraging early efficacy, potential CNS activity, and a manageable toxicity profile, addressing several limitations of existing therapies for this molecular subset of NSCLC.