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OA02 - A New Vision of Targets and Strategies (ID 120)
- Event: WCLC 2019
- Type: Oral Session
- Track: Targeted Therapy
- Presentations: 1
- Now Available
OA02.01 - Alectinib in Previously Treated RET-Rearranged Advanced Non-Small-Cell Lung Cancer: A Phase 1/2 Trial (ALL-RET) (Now Available) (ID 1651)
10:30 - 12:00 | Author(s): Yasuhito Imai
RET rearrangements occur in 1–2% of non-small cell lung cancers (NSCLCs). Alectinib (300 mg twice daily) has been approved for the treatment of ALK-rearranged NSCLC in Japan; it also has a high activity against RET in vitro. A global trial (ALEX study) showed the efficacy and safety of alectinib (600 mg twice daily) in ALK-rearranged NSCLC patients. We conducted a phase 1/2 study of alectinib to establish the recommended dose (RD) and examined its activity in RET-rearranged Japanese NSCLC patients.Method
This study was a single-arm, open-label, multi-institutional phase 1/2 trial. RET-rearranged NSCLC patients treated with at least one regimen of chemotherapy were recruited. RET rearrangements were screened using LC-SCRUM-Japan, a nationwide genomic screening network. In phase 1, alectinib (600 or 450 mg twice daily) was administered, following a 3 + 3 design. The primary endpoint was safety. During phase 2, alectinib at the RD defined in phase 1 was administered. The primary endpoint was the objective response rate in RET inhibitor-naïve patients.Result
Between March 8, 2016 and January 29, 2018, 35 patients were enrolled, and 34 patients were administered alectinib. KIF5B-RET was the most common fusion gene (22 cases [63%]), and the CCDC6-RET fusion was identified in 8 cases. The remaining 5 cases were not distinguishable. In cohort 1 (600 mg twice daily), we observed 5 DLTs (grade 3 rash, increased aspartate aminotransferase, erythema multiforme, thromboembolic event, and increased CPK) in 3 of 6 patients. In accordance with the protocol, we moved to cohort 2 (450 mg twice daily) and observed no DLTs in 3 patients. Additionally, pharmacokinetic analysis indicated that the mean exposure (AUC0–10) of 600 mg twice daily was higher than that previously reported in AF-002JG trial (global phase 1 study). Therefore, we determined 450 mg twice daily as the RD for phase 2. Twenty-five RET inhibitor-naïve patients were treated with the RD, of whom 1 achieved an objective response (4%) and 13 achieved disease control at 8 weeks (52%) as determined by central review. The median progression-free survival was 3.4 months (95% CI 2.0-5.4), and the median overall survival was 19.0 months (5.4-NE). We observed grade 3 neutropenia, pneumonitis, diarrhea, hyponatremia, increased CPK and blood bilirubin (4%) in patients treated with 450 mg alectinib twice daily; no grade 4 adverse events were observed.Conclusion
Alectinib had limited activity in patients with RET-rearranged NSCLC. Further investigation of new targeted therapeutics is required to improve outcomes for these patients.
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