Sunvozertinib in EGFR exon 20 insertion-mutated non-small cell lung cancer: expanding targeted therapy beyond standard EGFR inhibitors: a correspondence

Dear Editor,

Non-small cell lung cancer (NSCLC) harboring EGFR exon 20 insertion mutations represents a rare and challenging subgroup, accounting for approximately 2% of all EGFR-mutant NSCLC^[1]. These insertion variants exhibit distinct molecular heterogeneity and are inherently resistant to first- and second-generation EGFR tyrosine kinase inhibitors (TKIs)^[2]. As a result, platinum-based chemotherapy remains the cornerstone of treatment for this population, despite its limited efficacy. Standard regimens typically combine cisplatin or carboplatin with pemetrexed, yielding a median progression-free survival of only 5–6 months^[3]. Also, chemotherapy is associated with severe toxicities, including myelosuppression (neutropenia, anemia, thrombocytopenia), gastrointestinal (nausea, vomiting, diarrhea), nephrotoxicity, as well as peripheral neuropathy, which can lead to reduced quality of life, necessitating dose reductions of treatment or pauses in treatment. These issues underscore the urgency to develop new mutation-specific drugs that can have a positive effect without being systemically toxic. This article is in line with the TITAN Guidelines on the need for transparency in AI use in healthcare^[4].

Treatment of EGFR exon 20 insertion-mutated NSCLC has remained difficult. Unlike the common exon 19 deletions and L858R substitutions, exon 20 insertions create structural conformations in the kinase domain that limit the binding of conventional EGFR inhibitors^[5]. In a retrospective cohort, erlotinib produced an objective response rate (ORR) of 27% among 11 patients with exon 20 insertions, but responses were generally short-lived, with a median time to progression of only 2.5 months^[2]. Even osimertinib, though highly effective in classical EGFR mutations, offers only suboptimal outcomes in exon 20 insertion disease, with median progression-free survival around 3–4 months^[6]. In the majority of patients, platinum-based chemotherapy remains the standard therapy, but responses are short-lived and frequently linked with cumulative toxicities that reduce tolerability^[5]. This therapeutic gap has underscored the need for targeted drugs designed typically for these mutations.

Sunvozertinib (DZD9008) is an oral, next-generation EGFR TKI developed to address the steric hindrance resulting from exon 20 insertions. Unlike earlier TKIs, it achieves strong inhibitory activity against exon 20-mutant EGFR while sparing wild-type receptors, thereby reducing the risk of dose-limiting toxicities such as rash and diarrhea^[6]. Preclinical studies demonstrated potent antitumor effects in xenograft models carrying exon 20 insertion variants, providing the rationale for its clinical development^[7]. This selectivity makes sunvozertinib distinct from other TKIs and positions it as a potential backbone therapy in this rare subset of NSCLC.

Several phase 1 and 2 trials have confirmed the efficacy of sunvozertinib in different clinical settings. The WU-KONG6 trial in China assessed patients with locally advanced or metastatic NSCLC who had progressed on platinum chemotherapy. In this study, sunvozertinib achieved an ORR of 61% and a median duration of response exceeding 12 months, providing clinically significant efficacy^[3]. Toxicities were generally well tolerated, with diarrhea, anemia and increased blood creatine phosphokinase being the most common events. Subsequent studies extended these findings to patients previously treated with other EGFR TKIs. In the multinational WU-KONG1 trial, sunvozertinib showed responses in patients with diverse exon 20 insertion variants and in patients with prior targeted therapy failure, underscoring its broad applicability^[7]. More recently, a single-center phase 2 trial explored sunvozertinib as first-line therapy. ORR reached 73.1%, and most patients sustained disease control at data cutoff, suggesting potential superiority to chemotherapy in the frontline setting^[8]. These results highlight the consistency of benefit across trials and treatment lines.

The clinical activity of sunvozertinib points out the importance of extensive genomic profiling in NSCLC. Detecting exon 20 insertions at diagnosis helps guide patients to targeted therapy instead of empiric chemotherapy^[5]. If confirmed in ongoing global phase 3 trials, sunvozertinib has the potential to establish the new standard of care, moving treatment away from platinum doublets and toward precision oncology^[6]. Broader adoption could reshape management of rare EGFR variants, reinforcing the principle that not all EGFR mutations should be managed uniformly.

Sunvozertinib has emerged as one of the most promising therapies for patients with EGFR exon 20 insertion-mutated NSCLC. It directly addresses a critical unmet need by offering higher response rates, longer disease control, and a tolerable safety profile compared with standard chemotherapy. Early results suggest that sunvozertinib may become a first-line option, pending confirmation from larger randomized trials such as NCT03974022^[9]. For a historically underserved group of patients, this agent represents a significant step forward and expands the reach of precision medicine in lung cancer.

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The authors did not receive any financial support for this work.

Author contributions

E.H.: Conceptualization, Methodology, Project administration, Supervision, Writing – original draft, Writing – review & editing. I.A.: Writing – original draft, Writing – review & editing. J.T.: Writing – original draft, Writing – review & editing. J.E.: Methodology, Supervision, Writing – review & editing.

Conflicts of interest disclosure

All authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Guarantor

Joshua Ekouo.

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Not commissioned, externally peer reviewed.

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