A phase I study of FCN-411, a pan-HER inhibitor, in EGFR-mutated advanced NSCLC after progression on EGFR tyrosine kinase inhibitors
Mené sur 77 patients atteints d'un cancer du poumon non à petites cellules avec mutation du gène EGFR, de stade avancé et ayant progressé après un traitement par inhibiteurs de tyrosine kinase de l'EGFR, cet essai de phase I évalue la dose maximale tolérée de FCN-411, un inhibiteur de EGFR, HER2 et HER4, et analyse ses caractéristiques pharmacocinétiques
Introduction : There are no targeted therapies for EGFR-mutated non-small cell lung cancer (NSCLC) without EGFR T790M mutation after progression on EGFR tyrosine kinase inhibitors (TKIs). We evaluatedthe safety, tolerability, antitumor activity, and pharmacokinetics of FCN-411, aninhibitor of EGFR, HER2, and HER4, in EGFR TKI-treated, EGFR-mutated advanced NSCLC. Methods : This was a phase I, open-label, multicenter, dose-escalation/dose-expansion studyin China. Adult patients with stage IIIB/V 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 4–16 mg FCN-411 once daily until themaximum tolerated dose (MTD). In the dose-expansion phase, patients received FCN-411at the recommended phase II dose (RP2D) continuously in 21-day cycles. The primaryend points were safety, tolerability, MTD, and RP2D. Results : As of February 1, 2021, 77 patients were enrolled, including 30 with detectable EGFR T790M mutation in tumors. No dose-limiting toxicities were observed. The RP2D wasdefined as 8 mg based on safety, pharmacokinetics, and antitumor activity. The mostcommon 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 achievedconfirmed partial response, with an objective response rate (ORR) of 14.9% (95% confidenceinterval [CI], 8.3–24.0); at 8 mg, ORR was 14.0% (7.2–23.9). Moreover, 39 patientsachieved stable disease across all doses (disease control rate, 73.1%; 95% CI, 60.9–83.2).Median progression-free survival was 4.1 months (95% CI, 2.9–5.3). Median durationof response and overall survival were not reached. ORR was 20.5% and 7.4% in patientswithout and with EGFR T790M, respectively. Conclusions : FCN-411 was well tolerated up to 16 mg once daily and demonstrated antitumor activityin patients with EGFR-mutated NSCLC after progression on EGFR TKIs, especially in those without EGFR T790M mutation.