Zegfrovy (sunvozertinib)

P1, N=140, Recruiting, Dizal Pharmaceuticals | N=70 --> 140

Since 1997, EGFR tyrosine kinase inhibitors (EGFR-TKIs) have evolved from first-generation agents, such as gefitinib, erlotinib, and icotinib, to second-generation agents like afatinib and dacomitinib, now to third-generation agents, including osimertinib, aumolertinib, furmonertinib, befotertinib, rezivertinib, rilertinib, limertinib, lazertinib, mifanertinib for EGFR L858R, sunvozertinib for EGFR exon 20 insertion (20ins), and zorifertinib for EGFR-sensitive mutation with brain metastases. Over the past 30 years, substantial advancements have been made in the comprehensive management of EGFR-mutant NSCLC. This systemic review provides the history of the development of EGFR-TKI therapy for NSCLC from 1997 to 2026, highlighting clinical milestones, emerging therapies, and future directions in this rapidly evolving field.

Recently developed agents such as amivantamab and mobocertinib have improved response rates, yet challenges related to tolerability, CNS penetration, and durability of benefit persist. Early-phase clinical trials, including the WU-KONG series, have reported promising clinical efficacy, including objective response rates ranging from 44-60% in previously treated patients and meaningful activity in treatment-naïve cohorts. The tolerability profile of the drug seems manageable, with diarrhea, rash, and stomatitis among the most commonly observed adverse events; these, however, tend to be milder compared with other agents targeting EGFR Ex20ins.

The HO results indicated efficacy of Sunvozertinib and ineffectiveness of ADC, with maximum half-maximal inhibitory concentration (IC50) values of 0.28 and 2.96, respectively. This case demonstrates the potential of Human Organoid Drug Sensitivity Test (HO-DST) to guide effective salvage therapy, bridging the gap between genomic profiling and functional drug response in precision oncology.

P1/2, N=315, Active, not recruiting, Dizal Pharmaceuticals | Trial completion date: Dec 2025 --> Dec 2026

The role and the integration of therapies targeting exon20ins or uncommon mutations into the first- and second-line treatment armamentarium for NSCLC patients is not yet fully established, and the therapeutic impact of monotherapies (e.g., sunvozertinib, firmonertinib) versus combinations with standard platinum-based chemotherapy (e.g., zipalertinib, amivantamab) currently still lacks robust evidence to further change the therapeutic landscape for these patients. Therefore, results from the ongoing trials are eagerly awaited and are expected to shed some light on these open questions.

The following ten drugs received FDA approval in 2025 - avutometinib (inhibiting MEK1/2 in serous ovarian carcinomas), defactinib (blocking FAK in low grade serous ovarian carcinomas), delgocitinib (antagonizing the JAK family in hand eczema), mirdametinib (inhibiting MEK1/2 in type I neurofibromatosis), remibrutinib (blocking BTK in chronic spontaneous urticaria), rilzabrutinib (antagonizing BTK in chronic immune thrombocytopenia), sunvozertinib (blocking mutant exon 21 insertion EGFR NSCLC), taletrectinib (inhibiting mutant ROS1 in NSCLC), vimseltinib (blocking CSF1R in tenosynovial giant cell tumors), and zongertinib (antagonizing mutant HER2 in NSCLC). This article summarizes the physicochemical properties of all 94 FDA-approved small molecule protein kinase inhibitors including the molecular weight, number of hydrogen bond donors/acceptors, ligand efficiency, lipophilic efficiency, polar surface area, and solubility. A total of 45 of the 94 FDA-approved drugs have a least one Lipinski rule of five violation.

Recent developments in targeted therapies, including agents such as amivantamab, mobocertinib, and sunvozertinib, have shown promise in patients with pretreated ex20ins-positive NSCLC. No amendments were made to the registered protocol after commencement of the review. The full review protocol can be accessed on the PROSPERO database (Registration number: CRD420251056825).

P2, N=90, Recruiting, Dizal Pharmaceuticals | Trial completion date: Dec 2025 --> Dec 2026 | Trial primary completion date: Dec 2025 --> Dec 2026

P1/2, N=200, Recruiting, Dizal (Jiangsu) Pharmaceutical Co., Ltd. | Not yet recruiting --> Recruiting

P2, N=34, Recruiting, Fudan University | N=14 --> 34

P3, N=360, Recruiting, Dizal (Jiangsu) Pharmaceutical Co., Ltd. | Not yet recruiting --> Recruiting