A phase I study of FCN-411, a pan-HER inhibitor, in EGFR-mutated advanced NSCLC after progression on EGFR tyrosine kinase inhibitors

Abstract

BackgroundThere are no approved epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) for EGFR-mutated non-small cell lung cancer (NSCLC) without EGFR T790M mutation after progression on first- or second-generation EGFR-TKIs. MethodsWe conducted this phase I, open-label, multicenter, dose-escalation/dose-expansion study to evaluate the safety, tolerability, antitumor activity, and pharmacokinetics of FCN-411, a TKI targeting EGFR, HER2, and HER4, in patients with EGFR-mutated advanced NSCLC whose disease had progressed during treatment of EGFR-TKIs. Adult patients with stage IIIB–IV NSCLC harboring EGFR mutations (exon 18/19/20/21) who had progressed on prior EGFR-TKIs were enrolled. In the dose-escalation phase, patients received 4 mg, 8 mg, 12 mg, and 16 mg FCN-411 once daily until the maximum tolerated dose (MTD). In the dose-expansion phase, patients received FCN-411 at the recommended phase II dose (RP2D) continuously in 21-day cycles. The primary endpoints were safety, tolerability, MTD, and RP2D. ResultsFrom July 23, 2018 to September 29, 2020, 77 patients were enrolled, including 30 with EGFR T790M mutation in tumor tissues. The cut-off date was February 1, 2021. No dose-limiting toxicities were observed. The most common grade ≥ 3 treatment-emergent adverse events among all patients were diarrhea (8; 10.4%) and dermatitis acneiform (7; 9.1%). Ten of 67 evaluable patients achieved confirmed partial response, with an objective response rate (ORR) of 14.9% (95% confidence interval [CI], 8.3–24.0); the ORR was 33.3%, 14.0%, 0, and 25.0% at 4 mg, 8 mg, 12 mg, and 16 mg, respectively. Besides, the ORR in patients without and with EGFR T790M mutation was 20.5% and 7.4%, respectively. Moreover, 39 patients achieved stable disease across all doses, and the disease control rate was 73.1% (95% CI, 60.9–83.2). Median progression-free survival was 4.1 (95% CI, 2.9–5.3) months. Median duration of response and overall survival have not been reached. ConclusionsFCN-411 was well tolerated and demonstrated preliminary antitumor activity in patients with EGFR-mutated NSCLC after progression on EGFR-TKIs, especially in those without EGFR T790M mutation. The RP2D was defined as 8 mg once daily. Future studies are warranted.Trial registration: ClinicalTrials.gov, NCT03420079.