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First-in-human phase I study of BEBT-109 in previously treated EGFR exon 20 insertion-mutated advanced non-small cell
Liang Zeng1, Lianxi Song1, Li Liu2
1Department of Medical Oncology, Lung Cancer and Gastrointestinal Unit, Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410013, China; Graduate Collaborative Training Base of Hunan Cancer Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China.
Background:
BEBT-109 is an oral pan-mutant-selective inhibitor of epidermal growth factor receptor (EGFR) that demonstrated promising antitumor potency in preclinical models.
Methods:
This first-in-human study was a single-arm, open-label, two-stage study. Phase Ia dose-escalation study evaluated the safety and pharmacokinetics of BEBT-109 in 11 patients with EGFR T790M-mutated advanced non-small cell lung cancer (aNSCLC). Phase Ib dose-expansion study evaluated the safety and efficacy of BEBT-109 in 18 patients with EGFR exon 20 insertion (ex20ins)-mutated treatment-refractory aNSCLC. The primary outcomes were adverse events and antitumor activity. Clinical trial registration number CTR20192575.
Findings:
The phase Ia study demonstrated no dose-limiting toxicity, no observation of the maximum tolerated dose, and no new safety signals with BEBT-109 in the dose range of 20-180 mg/d, suggesting that BEBT-109 had an acceptable safety profile among patients with EGFR T790M-mutated aNSCLC. Plasma pharmacokinetics of BEBT-109 showed a dose-proportional increase in the area under the curve and maximal concentration, with no significant drug accumulation. The dose-expansion study demonstrated that BEBT-109 treatment was tolerable across the three dose levels. The three most common treatment-related adverse events were diarrhea (100%; 22.2% ≥Grade 3), rash (66.7%; 5.6% ≥Grade 3), and anemia (61.1%; 0% ≥Grade 3). The objective response rate was 44.4% (8 of 18). Median progression-free survival was 8.0 months (95% confidence intervals, 1.33-14.67).
Conclusion:
Preliminary findings showed that BEBT-109 had an acceptable safety profile and favorable antitumor activity in patients with refractory EGFR ex20ins-mutated aNSCLC.
Funding:
National Natural Science Foundation of China.
Insights
BEBT-109, an oral EGFR inhibitor, shows a good safety profile and promising antitumor effects in patients with advanced non-small cell lung cancer (aNSCLC) harboring EGFR exon 20 insertion mutations. Further research is warranted for this refractory patient population.
Area of Science:
- Oncology
- Pharmacology
- Clinical Trials
Background:
- BEBT-109 is an oral pan-mutant-selective epidermal growth factor receptor (EGFR) inhibitor with preclinical antitumor activity.
- EGFR mutations, including T790M and exon 20 insertions (ex20ins), are key drivers in advanced non-small cell lung cancer (aNSCLC).
Purpose of the Study:
- To evaluate the safety, pharmacokinetics, and preliminary efficacy of BEBT-109 in patients with advanced non-small cell lung cancer (aNSCLC).
- To assess BEBT-109 in patients with EGFR T790M mutations (Phase Ia) and EGFR ex20ins mutations (Phase Ib).
Main Methods:
- A first-in-human, single-arm, open-label, two-stage study (Phase Ia dose-escalation, Phase Ib dose-expansion).
- Phase Ia: 11 patients with EGFR T790M-mutated aNSCLC.
- Phase Ib: 18 patients with EGFR ex20ins-mutated, treatment-refractory aNSCLC. Primary outcomes: adverse events and antitumor activity.
Main Results:
- Phase Ia: BEBT-109 was safe and well-tolerated up to 180 mg/d, with dose-proportional pharmacokinetics and no significant accumulation.
- Phase Ib: BEBT-109 was tolerable in EGFR ex20ins-mutated aNSCLC. Most common adverse events: diarrhea (100%), rash (66.7%), and anemia (61.1%).
- Objective response rate was 44.4% (8/18), with a median progression-free survival of 8.0 months in the Phase Ib expansion cohort.
Conclusions:
- BEBT-109 demonstrated an acceptable safety profile and favorable antitumor activity in patients with refractory EGFR ex20ins-mutated aNSCLC.
- These preliminary findings support further investigation of BEBT-109 for this patient population.
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