Authors: Qing Zhou, Bin Gan, Liwei Yuan, Ye Hua, Yi-Long Wu
Background: Epitinib is a selective EGFR-TKI designed for optimal brain penetration. In preclinical species, epitinib demonstrated favorable drug exposures in the brain and is warranted clinical investigation for CNS tumors with EGFRm+ such as NSCLC brain metastases.
Methods: This is a first-in-human study. Patients with advanced solid tumors were enrolled in dose escalation phase. In expansion phase, only EGFRm+ NSCLC patients with brain metastases were eligible. Epitinib was administered orally q.d. Dose escalation started at 20 mg and followed a classic 3+3 design. All patients were assessed for AEs/ DLTs, PK, and tumor response.
Results: A total of 36 patients were enrolled in dose escalation phase at 7 dose levels up to 240 mg. No DLT was observed. Although MTD was not reached, 160 mg q.d. was selected as the RP2D. The most common AEs were skin rash (60.0%), diarrhea (34.3%), elevated AST (34.3%)/ALT (31.4%) and hyperbilirubinemia (28.6%). AEs of Elevated AST (2.9%)/ALT (2.9%) and hyperbilirubinemia (5.7%) were grade 3. Among 34 evaluable patients, one (2.9%) patient (80 mg cohort, EGFRm+ and TKI naïve) reached PR with a duration of response over 36 months. Epitinib drug exposure increased proportionally up to 160 mg and appeared to plateau above 160 mg. The average T 1/2 ranged between 38 and 54h. A dose expansion study in EGFRm+ NSCLC patients with brain metastases is ongoing. As of 30 Oct, 2015, 12 patients were treated with epitinib at 160 mg q.d. Among 12 evaluable patients, 5 reached PR (all treatment naïve) and showed dramatic shrinkage of brain lesions. The rest 5 prior -TKI treated patients had SD in the brain. 2 progression events observed with one in liver and the other in brain, respectively.
Conclusions: Epitinib was well tolerated in patients with advanced solid tumors. Its safety profile is consistent to EGFR-TKIs. The RP2D of 160 mg q.d. was selected based on safety, PK and preliminary efficacy data. Clear clinical efficacy was observed in untreated EGFRm+ NSCLC patients with brain metastases. Taken together, these data support further development of epitinib for the treatment of EGFRm+ NSCLC patients with brain metastasis. Clinical trial information: NCT02590952