Entrectinib Meets Objective Response Rate End Point in ROS1+ NSCLC

The safety profile of entrectinib with liquid biopsy in the BFAST study was consistent with prior reports for patients with ROS1-positive NSCLC.

ROS1, TRK, and ALK tyrosine kinase inhibitor (TKI) entrectinib (Rozlytrek) met the primary end point of objective response rate (ORR) for patients with ROS1-positive non–small cell lung cancer (NSCLC), according to results from the phase 2/3 BFAST study (NCT03178552) published in Nature Medicine.

Data from Cohort D from the trial, which assessed patients with ROS1-positive disease, showed that the confirmed investigator-assessed ORR was 81.5% (95% CI, 68.6%-90.8%), which matched independent review facility (IRF) assessment. Additionally, the safety profile of entrectinib with liquid biopsy in the BFAST study was consistent with prior reports of the agent. The results with liquid biopsy in comparison with tissue-based testing may support their clinical value as a less invasive diagnostic alternative with faster turnaround times.

Patients with ROS1-positive NSCLC (n = 92) were identified for the open-label study between January 11, 2018, and December 9, 2020. Fifty-five treatment-naïve patients were enrolled. In Cohort D, all but 1 had measurable disease. Patients received 600 mg of entrectinib orally once daily until disease progression, unacceptable toxicity, withdrawal of consent, or study termination.

Tumor assessments occurred every 8 weeks and started at baseline. Additionally, 200 mg dose reductions were allowed for adverse effects (AEs), with treatment interruption allowed for up to 28 days.

The primary end point of the study was investigator-confirmed ORR. Secondary end points included investigator-assessed clinical benefit rate (CBR), duration of response (DOR), and progression-free survival (PFS), as well as overall survival (OS), time to central nervous system (CNS) progression, and safety.

Median follow-up was 18.3 months, and the data cutoff was November 26, 2021. There were 2 (3.7%) complete responses, 42 (77.8%) partial responses, 7 (13.0%) instances of stable disease, and 3 (5.6%) instances of disease progression according to investigator assessment. According to IRF assessment, there were 3 (5.6%) complete responses, 41 (75.9%) partial responses, 7 (13.0%) instances of stable disease, and 1 (1.9%) instance of disease progression, with 2 (3.7%) responses being non-evaluable.

CBR between investigator and IRF assessment was 87.0% (95% CI, 75.1%-94.6%) vs 81.5% (95% CI, 68.6%-90.8%). Median DOR was 13.0 months (95% CI, 6.3-18.4) and 16.7 months (95% CI, 5.6-24.0), respectively, with 12-month event-free rates of 53.2% and 57.3%.

Median PFS was 12.9 months (95% CI, 8.7-18.5) vs 14.8 months (95% CI, 7.2-24.0) according to investigator and IRF assessment, respectively, with 12-month PFS rates of 50.7% and 52.4%. Furthermore, median time to CNS progression was not evaluable, and 12-month event-free rates were 83.5% and 86.4% for each assessment. OS data were immature; 20 events (36.4%) were recorded, and 12-month OS probability was 79.0%.

All Cohort D patients (n= 55) received at least 1 dose of entrectinib, and the median duration of treatment was 12.8 months (range, 1-33). Treatment-related AEs (TRAEs) occurred in 51 patients (92.7%), including 7 (12.7%) patients with at least 1 serious TRAE. TRAEs led to 20 (36.4%) dose reductions, 11 (20.0%) dose interruptions, and 3 (5.5%) dose discontinuations. Additionally, 31 (56.4%) patients had AEs at or greater than grade 3, with 2 (3.6%) deaths resulting from an AE.

“Overall, the safety profile of entrectinib in BFAST was generally consistent with that reported previously. Entrectinib was well tolerated and no new safety signals were identified. The high median dose intensity [>97%] indicates that almost all patients received the full, planned dose and that dose reductions and/or interruptions did not impact overall dose exposure….In conclusion, these data provide further evidence that entrectinib is effective and well tolerated in patients with ROS1-positive, advanced/metastatic NSCLC,” concluded Solange Peters, MD, PhD, professor and chair of medical oncology in the Department of Oncology at the University Hospital of Lausanne in Switzerland, and study coinvestigators.

Reference

Peters S, Gadgeel SM, Mok T, et al. Entrectinib in ROS1-positive advanced non-small cell lung cancer: the phase 2/3 BFAST trial. Nat Med. 2024;30:1923-1932. doi:10.1038/s41591-024-03008-4