Sutetinib for Patients with NSCLC Harboring Uncommon EGFR Mutations: A Multicenter, Open-Label, Phase IIb Trial

Introduction: Uncommon EGFR mutations account for approximately 10% of EGFR-altered NSCLC and show heterogeneous sensitivity to EGFR-tyrosine kinase inhibitors (TKIs), with limited prospective evidence to inform first-line therapy. Sutetinib is an irreversible EGFR-TKI. We assessed the safety and antitumor efficacy of sutetinib in patients with locally advanced or metastatic NSCLC harboring uncommon EGFR mutations. Methods: In this multicenter, open-label, single-arm phase IIb trial, adults with locally advanced or metastatic NSCLC harboring EGFR G719X, S768I, L861Q, or predefined compound mutations and no prior EGFR-TKI therapy were enrolled. Patients received sutetinib 80 mg orally once daily in 28-day cycles until radiographic progression or unacceptable toxicity. Patients who received at least one dose of treatment and were evaluable for efficacy analysis were included in the primary analysis, and all patients who received at least one dose of treatment were included in the safety analysis. The primary endpoint was the objective response rate (ORR), as assessed by the independent review committee. Secondary endpoints included the duration of response, disease control rate, time to response, progression-free survival, overall survival, and safety. Results: From December 9, 2021 to May 5, 2024, 99 patients were enrolled (efficacy-evaluable, N = 96; safety, N = 99). As of the data cutoff in October 2024, the median follow-up was 16.6 months. The independent review committee-confirmed ORR was 70.8% (95% confidence interval [CI]: 60.7–79.7), and the disease control rate was 90.6% (95% CI: 82.9–95.6). The median duration of response was 12.0 months (95% CI: 9.3–15.7), and the median progression-free survival was 13.7 months (95% CI: 10.9–16.4). The median overall survival was not reached (95% CI: 22.2–not reached). The ORR was numerically higher in patients with compound versus solitary uncommon EGFR mutations (84.4% versus 64.1%), with a median progression-free survival of 13.8 versus 11.0 months, respectively.Treatment-related adverse events (TRAEs) of any grade occurred in 97.0% (96/99) of patients, and grade ≥ 3 TRAEs occurred in 42.4% (42/99). The most common grade ≥ 3 TRAEs were diarrhea (28.3% [28/99]), hypokalemia (8.1% [8/99]), and increased gamma-glutamyl transferase (5.1% [5/99]). TRAEs led to dose reduction in 34.3% (34/99) and treatment discontinuation in 4.0% (4/99). No treatment-related deaths occurred. Conclusions: Sutetinib met the prespecified primary endpoint and demonstrated clinically meaningful antitumor activity with a manageable safety profile in advanced NSCLC harboring uncommon EGFR mutations (G719X, S768I, and L861Q). These findings support the use of sutetinib as a potential treatment option for this molecularly heterogeneous population. Clinical Trial Information: NCT05168566.