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Conteltinib (CT-707) in patients with advanced ALK-positive non-small cell lung cancer: a multicenter, open-label,
Puyuan Xing1, Qian Zhao2, Li Zhang3
1Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, No. 17 Panjiayuan Nanli, Chaoyang District, Beijing, 100021, China.
Background:
Conteltinib (CT-707) is a potent second-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI) showing promising anti-tumor activities in preclinical studies. This study aimed to assess the safety, pharmacokinetic (PK), and efficacy of conteltinib in patients with ALK-positive non-small cell lung cancer (NSCLC).
Methods:
In this multicenter, single-arm, open-label, first-in-human phase 1 study, conteltinib was taken orally at doses of 50 to 800 mg quaque die (QD) in a dose-escalation phase. If the response was observed in a dose cohort of the dose-escalation phase, dose expansion was started. The primary endpoints were maximum tolerated dose (MTD), dose-limiting toxicity (DLT), and adverse events assessed by investigators.
Results:
Between April 13, 2016, and February 8, 2020, 64 ALK-positive NSCLC patients were enrolled, including 41 (64.1%) patients with ALK TKI-naïve and 23 (35.9%) patients who received crizotinib previously. In the dose-escalation phase, 26 patients were treated with conteltinib at doses of 50 mg, 100 mg, 200 mg, 300 mg, 450 mg, 600 mg, and 800 mg QD. One DLT event was reported at the dose of 600 mg. MTD was not reached. Overall, 58 (90.6%) patients experienced treatment-related adverse events (TRAEs) and 9 (14.1%) patients had grade ≥ 3 TRAEs. The most common TRAEs were diarrhea (46 [71.9%]), serum creatinine elevated (29 [45.3%]), aspartate aminotransferase elevated (25 [39.1%]), and nausea (24 [37.5%]). Among 39 ALK TKI-naïve patients, the overall response rate (ORR) was 64.1% (25 of 39; 95% confidence interval [CI], 47.2-78.8), median progression-free survival (PFS) was 15.9 months (95% CI, 9.26-23.3), and median duration of response (DoR) was 15.0 months (95% CI, 9.06-25.8). Among 21 patients who received crizotinib previously, the ORR was 33.3% (7 of 21; 95% CI, 14.6-57.0), median PFS was 6.73 months (95% CI, 4.73-8.54), and median DoR was 6.60 months (95% CI, 3.77-13.3).
Conclusions:
In this study, conteltinib showed manageable safety profile, favorable PK properties, and anti-tumor activity in advanced ALK-positive NSCLC patients. The recommended phase 2 dose was determined to be 600 mg QD for ALK TKI-naïve patients and 300 mg bis in die (BID) for patients who received crizotinib previously.
Trial Registration:
ClinicalTrials.gov, NCT02695550.
Insights
Conteltinib (CT-707), a potent ALK inhibitor, demonstrated promising anti-tumor activity and a manageable safety profile in patients with ALK-positive non-small cell lung cancer (NSCLC). Recommended Phase 2 doses were established for both treatment-naïve and previously treated patient groups.
Area of Science:
- Oncology
- Pharmacology
- Clinical Trials
Background:
- Conteltinib (CT-707) is a potent second-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI).
- Preclinical studies indicated promising anti-tumor activities for conteltinib.
- This study assessed the safety, pharmacokinetics (PK), and efficacy of conteltinib in ALK-positive non-small cell lung cancer (NSCLC).
Purpose of the Study:
- To evaluate the safety and tolerability of conteltinib in patients with ALK-positive NSCLC.
- To determine the pharmacokinetic profile of conteltinib.
- To assess the anti-tumor efficacy of conteltinib in this patient population.
Main Methods:
- A multicenter, single-arm, open-label, first-in-human Phase 1 study was conducted.
- Conteltinib was administered orally at doses ranging from 50 to 800 mg once daily (QD).
- Dose escalation and expansion phases were employed, with primary endpoints including maximum tolerated dose (MTD), dose-limiting toxicity (DLT), and adverse events.
Main Results:
- 64 ALK-positive NSCLC patients were enrolled; 41 were ALK TKI-naïve and 23 had prior crizotinib treatment.
- Overall, 90.6% of patients experienced treatment-related adverse events (TRAEs), with diarrhea being the most common (71.9%).
- In ALK TKI-naïve patients, the overall response rate (ORR) was 64.1% and median progression-free survival (PFS) was 15.9 months. In patients previously treated with crizotinib, ORR was 33.3% and median PFS was 6.73 months.
Conclusions:
- Conteltinib exhibits a manageable safety profile and favorable PK properties in advanced ALK-positive NSCLC.
- The drug demonstrated significant anti-tumor activity in both treatment-naïve and previously treated patients.
- Recommended Phase 2 doses were determined as 600 mg QD for ALK TKI-naïve patients and 300 mg twice daily (BID) for patients previously treated with crizotinib.
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