Efficacy and safety of lunbotinib (A400/EP0031), a next-generation selective RET inhibitor (SRI), from a pivotal phase II study in patients with advanced RET fusion–positive non–small cell lung cancer (NSCLC).

8505 Background: RET-fusion positive NSCLC accounts for 1-2% of all lung cancers. Lunbotinib is a next gen brain-penetrant SRI with high potency against RET fusion and mutant proteins ( Zhou et al., 2023; Alonso et al., 2025 ). We report findings from a pivotal phase Ⅱ study in advanced RET-fusion positive NSCLC in China (NCT05265091). An ongoing study is assessing lunbotinib alone or in combination with chemotherapy in Western patients (pts) (NCT05443126). Methods: The phase Ⅱ part enrolled two single-arm cohorts: cohort 1 included pts with prior platinum-based chemotherapy and immunotherapy (pre-treated), and cohort 2 included treatment-naïve pts. All pts received oral lunbotinib 90 mg once daily in 28-day cycles until disease progression or unacceptable toxicity. The primary endpoint was ORR assessed by an independent review committee (IRC) per RECIST v1.1. Results: As of Oct 29, 2025, 71 pre-treated pts and 92 treatment-naïve pts were enrolled, with median follow-up of 22.6 and 20.7 mos, respectively. Among pre-treated and treatment-naïve pts in full analysis set (FAS), ECOG PS 1 rates were 90% and 80.2%, and metastases involving ≥3 organ sites were observed in 75.7% and 57.1%. IRC-assessed confirmed ORR was 87.1% (95% CI: 77.0-93.9) in pre-treated pts and 81.3% (95% CI: 71.8-88.7) in treatment-naïve pts. mPFS was 27.5 mos and NR, respectively. Among pts with baseline CNS metastases (23 pre-treated, 16 treatment-naïve), ORR was 82.6% and 75.0%, respectively, and 6 pts in each cohort had complete intracranial response. Full efficacy data are in Table. Treatment-related AEs (TRAEs) occurred in 98.8% of pts, the most common were AST (72.4%), ALT (68.1%), anemia (63.2%), urinary retention (45.4%), dry eye (43.6%), and increased blood creatinine (42.9%). Grade ≥ 3 TRAEs observed in 40.5%. Two pts (1.2%) discontinued due to TRAEs. No fatal TRAEs occurred. Conclusions: Lunbotinib demonstrated robust efficacy in pts with advanced RET-fusion positive NSCLC, with high ORR and prolonged PFS in both pre-treated and treatment-naïve populations, and notable intracranial activity. Safety profile was manageable, with no new signals identified. These data support the potential of lunbotinib as a valuable therapeutic option for this population. Clinical trial information: NCT05265091 . Pre-treated pts (Cohort 1) N=71 Treatment-naïve pts (Cohort 2) N=92 Confirmed ORR a /DCR a , % (95% CI) 87.1 (77.0, 93.9)/ 91.4 (82.3, 96.8) 81.3 (71.8, 88.7)/ 92.3 (84.8, 96.9) mDoR a (95% CI), mo 25.7 (14.8, NE) NR (NE, NE) 24-mo DoR rate, % (95% CI) 55.4 (41.1, 67.5) NE mPFS (95% CI), mo 27.5 (16.1, NE) NR (19.4, NE) 24-mo PFS rate, % (95% CI) 52.1 (39.3, 63.5) 59.9 (47.8, 70.0) mOS (95% CI), mo NR (26.1, NE) NR (NE, NE) 24-mo OS rate, % (95% CI) 65.7 (51.5, 76.6) 74.1 (62.1, 82.8) Baseline CNS metastases, n 23 16 ORR, % (95% CI) 82.6 (61.2, 95.0) 75.0 (47.6, 92.7) a In FAS; N was 70 and 91.