Sunvozertinib — Drug Monograph

Sunvozertinib (Zegfrovy) — EGFR Exon 20 Insertion NSCLC Oral TKI

Sunvozertinib (Zegfrovy) is an oral, irreversible, mutation-selective EGFR tyrosine kinase inhibitor for advanced non-small cell lung cancer (NSCLC) with EGFR exon 20 insertion mutations. It covalently binds the ATP pocket of EGFR exon 20 insertions (and HER2 exon 20 mutations) while relatively sparing wild-type EGFR, and is active across 30+ exon 20 insertion subtypes including in patients with brain metastases. It is the first oral targeted therapy for previously treated EGFR exon 20 insertion NSCLC — a subtype historically resistant to conventional EGFR TKIs. This monograph covers sunvozertinib oral daily dosing, EGFR exon 20 insertion biomarker selection, selective tyrosine kinase inhibition, and baseline/ongoing toxicity monitoring.

Indications (FDA / NCCN)

• Locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations after platinum-based chemotherapy (WU-KONG1B)
• Accelerated approval (July 2025) based on ORR and duration of response
• EGFR exon 20 insertion confirmed by an FDA-approved test before starting

Dosing

• Standard dose: 200 mg orally once daily
• Take with food
• Continue until progression or unacceptable toxicity
• Interrupt, reduce, or discontinue based on toxicity

Monitoring

• EGFR exon 20 insertion status before initiation
• ILD / pneumonitis — withhold and permanently discontinue if confirmed
• Diarrhea and GI toxicity (antidiarrheals, dose modification)
• Dermatologic reactions and ocular toxicity (ophthalmology referral as needed)

Brand names: Zegfrovy

Drug class: Tyrosine Kinase Inhibitor

Mechanism of Action

Oral, irreversible, mutation-selective EGFR tyrosine kinase inhibitor. Sunvozertinib covalently binds the ATP pocket of EGFR harboring exon 20 insertion mutations (and HER2 exon 20 mutations), blocking downstream oncogenic signaling while relatively sparing wild-type EGFR activity. Its structure accommodates the distinct spatial conformation of exon 20 insertions, which are refractory to conventional EGFR TKIs, and it is active across a broad range of exon 20 insertion subtypes including in patients with brain metastases.

FDA Indications

• Locally advanced or metastatic non-small cell lung cancer (NSCLC) with EGFR exon 20 insertion mutations (detected by an FDA-approved test) in adults whose disease has progressed on or after platinum-based chemotherapy (accelerated approval July 2, 2025; WU-KONG1B: confirmed ORR 46%, median DOR 11.1 months)

Common Side Effects

• Diarrhea
• Rash
• Decreased appetite
• Stomatitis
• Fatigue
• Nausea
• Paronychia
• Vomiting

Clinical Pearl

Sunvozertinib is the first oral targeted therapy approved for previously treated EGFR exon 20 insertion NSCLC - a subtype historically resistant to conventional EGFR TKIs that previously relied on the intravenous bispecific amivantamab. It is active across 30+ exon 20 insertion subtypes and shows intracranial activity. Take with food; watch for ILD/pneumonitis and the EGFR-class diarrhea and rash.

Related Therapies & Mechanisms

• Afatinib (Gilotrif) — Tyrosine Kinase Inhibitor · NSCLC
• Alectinib (Alecensa) — Tyrosine Kinase Inhibitor · NSCLC
• Capmatinib (Tabrecta) — Tyrosine Kinase Inhibitor · NSCLC
• Dabrafenib (Tafinlar) — Tyrosine Kinase Inhibitor · NSCLC