Ficonalkib (SY-3505) in Advanced ALK-Positive NSCLC: A Multicenter, Open-Label, Single-Arm, Phase 1/2 Study
Yuankai Shi1, Xingsheng Hu1, Xingya Li2
1Department of Medical Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, Beijing, the People's Republic of China.
Introduction:
Treatment options for second-generation (2nd-gen) ALK tyrosine kinase inhibitor (TKI)-resistant patients are limited. We evaluated the safety, pharmacokinetics, and efficacy of ficonalkib (SY-3505), a third-generation (3rd-gen) ALK TKI, in patients with advanced ALK-positive non-small cell lung cancer.
Methods:
This first-in-human, phase 1/2 study (Chinese Clinical Trial Registry identifier: ChiCTR1900025619; ClinicalTrials.gov identifier: NCT05257512) had two parts. Phase 1 included a dose-escalation phase (25-800 mg quaque die [QD]) and a dose-expansion phase (500 mg QD or 600 mg QD). Phase 2 enrolled patients treated at recommended phase 2 dose. Primary end points were safety in phase 1 and objective response rate (ORR) in phase 2.
Results:
Between April 21, 2020, and August 31, 2023, a total of 127 patients with advanced ALK-positive non-small cell lung cancer were enrolled, with 62 in phase 1. Ficonalkib was well absorbed and tolerated, with one dose-limited toxicity event occurring at 800 mg QD. Treatment-related adverse events occurred in 85.5% of patients, with 19.4% experienced greater than or equal to grade 3 events. The ORR was 38.3% (23 of 60, 95% confidence interval [CI]: 26.1%-51.8%) in phase 1, and 600 mg QD was established as recommended phase 2 dose. In phase 2, a total of 65 patients received ficonalkib at 600 mg QD. In total, 88 patients received ficonalkib at 600 mg QD in phase 1/2, and all had received prior 2nd-gen ALK TKI treatment. Furthermore, 90.9% of the patients experienced treatment-related adverse events and 14.8% experienced greater than or equal to grade 3 events. The ORR in efficacy-assessable patients who received ficonalkib at 600 mg QD was 47.5% (38 of 80, 95% CI: 36.2%-59.0%), with an intracranial ORR of 37.5% (12 of 32, 95% CI: 21.1%-56.3%) in these patients with measurable brain lesions at baseline.
Conclusions:
Ficonalkib (SY-3505) was well tolerated, with favorable safety profiles and promising efficacy in patients resistant to prior 2nd-gen ALK TKI.
Insights
Ficonalkib (SY-3505), a third-generation ALK TKI, shows promising efficacy and a favorable safety profile in patients with advanced ALK-positive non-small cell lung cancer resistant to second-generation ALK TKIs.
Area of Science:
- Oncology
- Pharmacology
Background:
- Limited treatment options exist for patients with advanced ALK-positive non-small cell lung cancer (NSCLC) who are resistant to second-generation ALK tyrosine kinase inhibitors (TKIs).
- Third-generation ALK TKIs represent a potential therapeutic advancement for this patient population.
Purpose of the Study:
- To evaluate the safety, pharmacokinetics, and efficacy of ficonalkib (SY-3505), a novel third-generation ALK TKI.
- To determine the recommended phase 2 dose (RP2D) of ficonalkib in patients with advanced ALK-positive NSCLC.
Main Methods:
- A first-in-human, phase 1/2 clinical trial was conducted, including dose-escalation and dose-expansion phases.
- Patients received ficonalkib orally once daily (QD).
- Primary endpoints included safety in phase 1 and objective response rate (ORR) in phase 2.
Main Results:
- Ficonalkib was well absorbed and tolerated, with 600 mg QD established as the RP2D.
- The overall ORR in patients treated with ficonalkib at 600 mg QD was 47.5%, including an intracranial ORR of 37.5% in patients with brain metastases.
- Treatment-related adverse events were observed in 90.9% of patients, with 14.8% experiencing grade 3 or higher events.
Conclusions:
- Ficonalkib demonstrates a favorable safety profile and promising efficacy in patients with ALK-positive NSCLC resistant to prior second-generation ALK TKIs.
- Ficonalkib represents a potential new treatment option for this challenging patient group.
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