PFL-721 (mutant-selective EGFR/HER2 exon 20 TKI) posts 54% ORR in heavily pretreated ex20 NSCLC

PFL-721 is an oral, mutant-selective tyrosine kinase inhibitor designed to inhibit activating EGFR and ERBB2 (HER2) exon 20 alterations while sparing wild-type EGFR, aiming to reduce classic EGFR skin toxicity. In this ongoing first-in-human Phase 1 dose-escalation study in locally advanced/metastatic NSCLC with EGFR/ERBB2 exon 20 alterations (NCT06043817), 45 patients (median 3 prior lines) received 30–600mg QD; MTD was 480mg and exposure was dose-proportional with “predicted effective” levels reached at ≥240mg. In the efficacy population (n=42), at doses ≥360mg QD, ORR was 54% (15/28 PRs; 95%CI 33.9–72.5) and DCR 79% (95%CI 59.0–97.7); ctDNA molecular responses (>50% VAF decrease) occurred in 12/25 (48%) evaluable patients—numerically above historical post-platinum EGFR ex20 benchmarks with amivantamab (ORR 40%, mPFS 8.3mo) and mobocertinib (IRC ORR 28%, mPFS ~7.3mo), acknowledging cross-trial differences and that PFS/DoR aren’t yet reported here. Safety was dominated by GI toxicity (any AE 96%; GI AEs 87%), with grade ≥3 diarrhea 22%, hypokalemia 9%, creatinine increased 7%, and only one grade 3 rash; DLTs (6/39) were mainly grade 3 diarrhea (360–600mg) plus one grade 4 hypokalemia (600mg), and the randomized dose-optimization is ongoing (360mg QD, 480mg QD, 240mg BID).