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Foritinib in advanced ROS1-rearranged non-small-cell lung cancer in China: a multicentre, open-label, single-arm,
Jin-Ji Yang1, Jianying Zhou2, Si-Yang Maggie Liu3
1Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China.
Background:
Currently approved targeted treatment for ROS1-rearranged non-small-cell lung cancer (NSCLC) has either inadequate intracranial activity or CNS-related toxicities. We evaluated the efficacy and safety of foritinib, a novel ALK and ROS1 inhibitor, in patients with advanced ROS1-rearranged NSCLC.
Methods:
This two-part (phase 2a and 2b), multicentre, single-arm, open-label, phase 2 study was done in 29 centres in China. Eligible participants were adults (aged ≥18 years) with histologically or cytologically confirmed ROS1-rearranged, locally advanced or metastatic stage IIIB-IV NSCLC, with an Eastern Cooperative Oncology Group performance status of 2 or less. Patients who had previously received no or one ROS1 inhibitor were enrolled into phase 2a, and patients who were naive to ROS1 inhibitor therapy were enrolled into phase 2b cohort 1. Participants in phase 2a received 80, 120, 160, or 210 mg foritinib succinate (foritinib) orally once daily over 21-day cycles; patients in phase 2b received the recommended phase 2 dose of 160 mg. The primary endpoint was objective response rate, assessed by the independent review committee in the full analysis set (ie, all participants who received at least one dose of study treatment). The safety analysis set included all participants who received at least one dose of study treatment and had available safety assessments. This study is ongoing and is registered with ClinicalTrials.gov, NCT04237805.
Findings:
Between March 26, 2020, and Dec 29, 2022, 104 patients were enrolled and treated. Six patients who had previously received more than one ROS1 inhibitor were enrolled in phase 2a before a protocol amendment stating that patients in this phase should have received no more than one ROS1 inhibitor; these patients were included in the safety analysis but excluded from the efficacy analysis of the ROS1-inhibitor-pretreated cohort. Therefore, the efficacy analysis set (n=98) included 42 patients from phase 2a (17 who were ROS1 inhibitor naive and 25 who had previously received ROS1 inhibitor) and 56 patients from phase 2b cohort 1. In phase 2a, the objective response rate was 94% (95% CI 71-100; 16 of 17 patients) in patients who were ROS1 inhibitor naive and 40% (21-61; ten of 25) in patients who had previously received ROS1 inhibitor. In phase 2b cohort 1, the objective response rate was 88% (95% CI 76-95; 49 of 56 patients). In a prespecified exploratory analysis in 41 patients with CNS metastases at baseline, the objective response rate was 100% (95% CI 48-100; five of five patients) in patients in phase 2a who were ROS1 inhibitor naive, 40% (16-68; six of 15) in patients in phase 2a who had previously received ROS1 inhibitor, and 90% (70-99; 19 of 21) in patients in phase 2b cohort 1. Grade 3-4 treatment-related adverse events occurred in 33 (32%) of 104 patients; the most common were hyperglycaemia (12 [12%] patients) and electrocardiogram prolonged QT interval (six [6%]). Serious treatment-related adverse events occurred in 11 (11%) patients, with hyperglycaemia (six [6%]) being most common. No treatment-related adverse events led to death.
Interpretation:
Foritinib showed systemic and intracranial antitumour activity and good tolerability in ROS1-inhibitor-naive patients with ROS1-rearranged NSCLC. Foritinib represents a promising treatment for these patients, especially in those with CNS metastases.
Funding:
Fosun Pharma, Wanbang Biopharmaceuticals, and Guangdong Provincial Key Lab of Translational Medicine in Lung Cancer.
Insights
Foritinib demonstrated significant efficacy and intracranial activity in patients with ROS1-rearranged non-small-cell lung cancer (NSCLC). This novel inhibitor shows promise as a treatment option, particularly for those with central nervous system metastases.
Area of Science:
- Oncology
- Pharmacology
- Clinical Trials
Background:
- Targeted therapies for ROS1-rearranged non-small-cell lung cancer (NSCLC) often have limited intracranial activity or cause central nervous system (CNS) toxicities.
- Foritinib, a novel inhibitor targeting ALK and ROS1, was evaluated for its efficacy and safety in advanced ROS1-rearranged NSCLC.
Purpose of the Study:
- To assess the efficacy and safety of foritinib in patients with advanced ROS1-rearranged NSCLC.
- To evaluate the drug's activity, including intracranial response, in a challenging patient population.
Main Methods:
- A two-part, multicentre, single-arm, open-label, phase 2 study (NCT04237805) conducted in China.
- Patients with advanced ROS1-rearranged NSCLC and ECOG performance status ≤2 were enrolled.
- Phase 2a included patients previously treated with 0-1 ROS1 inhibitor, while phase 2b (cohort 1) included ROS1 inhibitor-naive patients. Dosing varied in phase 2a, with 160 mg daily in phase 2b.
Main Results:
- The objective response rate (ORR) was 94% in ROS1 inhibitor-naive patients in phase 2a and 88% in phase 2b cohort 1.
- In patients with CNS metastases, ORR was 100% (phase 2a, naive), 40% (phase 2a, pretreated), and 90% (phase 2b).
- Grade 3-4 treatment-related adverse events occurred in 32% of patients, most commonly hyperglycemia (12%) and QT interval prolongation (6%). No treatment-related deaths were reported.
Conclusions:
- Foritinib exhibits significant systemic and intracranial antitumor activity in ROS1-rearranged NSCLC patients, particularly those naive to ROS1 inhibitors.
- The drug demonstrates good tolerability, suggesting it is a promising treatment option, especially for patients with CNS metastases.
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