In an updated integrated analysis of three phase I or II clinical studies ALKA-372-001, STARTRK-1, and STARTRK-2, comprising more patients and a longer follow-up than the primary analysis, entrectinib continued to demonstrate a high level of clinical benefit for patients with ROS1 fusion–positive locally advanced or metastatic non-small cell lung cancer (NSCLC), including those with central nervous system (CNS) metastases at baseline. A high proportion of enrolled patients were pretreated and had CNS metastases at baseline, highlighting the relatively poor prognostic population included in the study. The findings from this largest prospective study in that population are published by Prof. Fabrice Barlesi of the Gustave Roussy Cancer Campus in Villejuif, France and colleagues on 1 March 2021 in the Journal of Clinical Oncology.

ROS1 fusions are found in 1-2% of NSCLC where it is considered a distinct disease subtype. Up to 40% of patients with ROS1 fusion–positive metastatic NSCLC have CNS metastases at diagnosis. To maximise efficacy, novel targeted agents must demonstrate activity in the CNS.

The authors wrote in the background that a tyrosine kinase inhibitor (TKI) crizotinib is approved as first-line treatment for metastatic ROS1 fusion–positive NSCLC. However, crizotinib has poor CNS penetration and is actively exported from the CNS by P-glycoprotein. Furthermore, almost half of patients with ROS1 fusion–positive NSCLC who receive crizotinib experience first progression solely in the CNS. 

The small-molecule TKI entrectinib is a potent inhibitor of ROS1, specifically designed to cross the blood-brain barrier and remain active within the CNS. Contrary to crizotinib, preclinical models confirmed that entrectinib is a weak P-glycoprotein substrate and achieves high CNS concentrations, associated with strong efficacy in brain tumour models.

Based on positive findings from an integrated analysis of ALKA-372-001, STARTRK-1, STARTRK-2 with data cut-off on 31 May 2018, entrectinib was approved by the US Food and Drug Administration and the European Medicines Agency for patients with ROS1 fusion–positive NSCLC. The investigators now report in the Journal of Clinical Oncology updated efficacy and safety data for entrectinib in patients with ROS1 fusion–positive NSCLC, based on an integrated analysis of these three studies with more patients and longer follow-up. These updated data were also presented at the ESMO 2020 Virtual Congress.

The efficacy-evaluable population included adults with locally advanced or metastatic ROS1 fusion–positive NSCLC with or without CNS metastases who received entrectinib ≥600 mg orally once per day. Co-primary endpoints were objective response rate (ORR) assessed by blinded independent central review (BICR) and duration of response (DoR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), intracranial ORR, intracranial DoR, intracranial PFS, and safety.

In total, 161 patients with a follow-up of ≥ 6 months were evaluable. The median treatment duration was 10.7 months (IQR, 6.4-17.7).

The ORR was 67.1% (n = 108, 95% confidence interval [CI] 59.3 to 74.3), and responses were durable (12-month DoR rate, 63%, median DoR 15.7 months).

The 12-month PFS rate was 55% (median PFS 15.7 months), and the 12-month OS rate was 81% (median OS not estimable).

In 24 patients with measurable baseline CNS metastases by BICR, the intracranial ORR was 79.2% (n = 19; 95% CI 57.9 to 92.9), the median intracranial PFS was 12.0 months (95% CI 6.2 to 19.3), and the median intracranial DoR was 12.9 months (12-month rate, 55%).

The safety profile in this updated analysis was similar to that reported in the primary analysis, and no new safety signals were found.

The authors underlined that before entrectinib approval, there was an unmet need for a CNS-active treatment for patients with locally advanced or metastatic ROS1 fusion–positive NSCLC. They concluded that entrectinib continued to have strong overall and intracranial efficacy in these patients. The safety profile was consistent with previous reports.

The work was supported by F. Hoffmann-La Roche Ltd.


Dziadziuszko R, Krebs MG, de Barud F, et al. Updated Integrated Analysis of the Efficacy and Safety of Entrectinib in Locally Advanced or Metastatic ROS1 Fusion–Positive Non–Small-Cell Lung Cancer. Jounrla of Clinical Oncology; Published online 1 March 2021. DOI: 10.1200/JCO.20.03025.