Safety and efficacy of APS03118, a next-generation RET inhibitor, in patients with non-small cell lung cancer (NSCLC): Results from a phase I clinical trial.

8617 Background: Acquired resistance to first-generation selective RET inhibitors (SRIs) remains a significant clinical challenge in the treatment of RET fusion-positive NSCLC. APS03118 is a next-generation, highly selective RET inhibitor also with additional potent inhibitory activity against YES1, a SRC family kinases. This Phase I study evaluated the safety, tolerability, pharmacokinetics, and preliminary efficacy of APS03118 treatment in patients with advanced RET fusion-positive NSCLC. Methods: This multicenter Phase I trial enrolled 108 patients, including 85 patients with NSCLC harboring RET aberrations. In the dose escalation stage (Ia), APS03118 was administered orally at doses ranging from 40 mg once daily to 120 mg twice daily (BID) 28 days a cycle in 29 patients with solid tumors. In the expansion stage (Ib), 79 patients received 80 mg BID and 100 mg BID, including 66 patients of NSCLC with RET fusions. Efficacy was assessed per RECIST v1.1 every 2 cycles (4 weeks/cycle). Safety was evaluated according to CTCAE v5. Molecular profiling was performed using next-generation sequencing on blood and, when available, tumor tissue. This report focuses mainly on the NSCLC cohorts, including treatment-naïve and previously treated patients with 1-4 lines of therapy, including six different SRIs, (e.g., pralsetinib and selpercatinib). Results: Out of 85 NSCLC patients (Ia+Ib), the Objective Response Rate (ORR) was 80% (confirmed) in 20 (20/22) evaluable treatment-naïve patients. The median Progression-Free Survival (mPFS) is not reached, with 10 patients up to or over the 16 cycles at the data cutoff date. In 22 (22/25) evaluable patients with prior systemic therapy not including the SRIs, the ORR was 55%. There were 38 patients in the cohort of prior SRIs treatment failure. Among 22 (22/26) evaluable patients without known bypass pathway mutations, ORR was 23% with 14 patients’ PFS up to or over 6 cycles and 10 patients up to or over 8 cycles (data cutoff date). Promising anti-tumor action was observed in the two patients with G810S and G810C mutations, who experienced tumor shrinkage of up to 50%. Grade ≥3 TRAEs occurred in 50.9% of patients. The most common AEs were creatine phosphokinase, AST and ALT elevation, which were reversible and mostly observed within cycle 1-3 and rarely after cycle 5. Dose reductions in 22.2%, and permanent discontinuation in 4.6%. Overall, APS03118 demonstrated a manageable and predictable safety profile. Conclusions: APS03118 shows highly promising clinical activity in both treatment-naïve and SRI failed NSCLC patients harboring RET fusions. Its survival benefit may result from potent inhibition of RET and YES1. The safety profile is manageable, characterized primarily by reversible enzyme elevations. Further development in NSCLC patients harboring RET fusion is warranted. Clinical trial information: NCT05653869 .