Longer-Term Clinical Benefit of Entrectinib Shown in ROS1-Positive NSCLC

Treatment with the tyrosine kinase inhibitor entrectinib may lead to continued clinical benefit as treatment of patients with ROS1-positive non–small cell lung cancer, including those with central nervous system metastases, according to an updated from an integrated analysis of 3 clinical trials.

Treatment with the tyrosine kinase inhibitor entrectinib (Rozlytrek) may lead to continued clinical benefit as treatment of patients with ROS1-positive non–small cell lung cancer (NSCLC), including those with central nervous system metastases (CNS), according to an updated from an integrated analysis of 3 clinical trials.

In multiple studies, entrectinib was shown to be safe and effective for the treatment of patients with locally advanced or metastatic ROS1 fusion–positive NSCLC, leading to the FDA approval of entrectinib in this setting. The updated integrated analysis assessed data from the phase 1 ALKA-372-001 trial (NCT02097810), the phase 1 STARTRK-1 study (NCT02097810), and the phase 2 STARTRK-2 (NCT02568267) to determine whether entrectinib would remain beneficial when used in a larger cohort of patients and with longer follow-up.

The pooled analysis included 161 patients who were 18 years or older with metastatic or locally advanced solid tumors harboring a ROS1fusion. Those enrolled had an ECOG performance status of 0, 1, or 2. Patients who received prior therapy were allowed with the exception of those who were previously treated with tyrosine kinase inhibitors. Individuals were also required to have measurable disease at baseline and at least 6 months of follow-up after the start of treatment. Entrectinib was administered at once daily doses of at least 600 mg.

At baseline, patients were screened for characteristics, disease status, and metastatic disease in the central nervous system (CNS). Patients had a median age of 54.0 years (range, 20-86), and 64.6% were female. The majority of patients in the study were Asian (45.3%) followed by White (44.1%). Most patients also had an ECOG performance status of 1 (49.0%). In terms of patient history, 62.7% of the patients screened were never smokers. The top histology found at baseline was adenocarcinoma in 97.5%, but there was 1 patient with adenosquamous carcinoma and no information for 3 of the patients.

Most patients included in the analysis had received at least 1 prior line of therapy (39.8%), but there was also a large population of newly diagnosed patients (37.3%), and 23.0% of patients had at least 2 prior lines of therapy. Chemotherapy was the most commonly seen prior treatment, which was received by 68.3% of the study population.

More than a third of the patients (34.8%) presented with CNS metastases at baseline. Most of the lesions were not measurable, but 7.5% of patients with CNS metastases had measurable disease. There was also a significant number of patients (46.4%) who had prior radiotherapy of the brain, and for most, the integrated analysis began less than 2 months after their last radiotherapy treatment to the brain.

The analysis investigated the objective response rate (ORR) and duration of response (DOR) by Blinded Independent Committee Review (BICR). In addition, progression-free survival (PFS) per BICR, overall survival (OS), and safety were assessed as key secondary end points. Per the study protocol, results were in favor of the primary end points if 50% of the population achieved an objective response.

Patients with ROS1-positive NSCLC in the study received entrectinib for a median duration of 10.7 months (interquartile range, 6.4-17.7). The treatment led to reductions in tumor size for the majority of patients treated showing an ORR of 67.1% (95% CI, 59.3%-74.3%), meeting the primary end point of the study. Response to entrectinib in the study included complete responses in 8.7% of patients and partial responses in 58.4% of patients. In addition, 8.7% of the study population had stable disease.

Responses to entrectinib were seen in multiple fusion partners including CD74 and SLC34A2 with ORRs of 72.9% (95% CI, 60.9%-82.8%) and 57.1% (95% CI, 34.0%-78.2%), respectively.

Investigators noted that response occurred early on in the course of treatment with a median time to response of 0.95 months (range, 0.7-26.6). The median DOR was 15.7 months (95% CI, 13.9-28.6) in the overall population with a 12-month DOR rate of 63%.

Notably, patients with CNS metastases at baseline had a similar response to entrectinib as the overall population with an ORR of 62.5%. Patients with cranial metastases also had durable responses with a 12-month DOR rate of 55.0%. The intracranial ORR in patients with baseline CNS metastases was 79.2% (95% CI, 57.9%-92.9%).

As of the data cutoff date, there were 36 cases of disease progression and 12 deaths in the study. However, progression-free survival was maintained in a large proportion of the population and the median PFS was 15.7 months (95% CI, 11.0-21.1). In the CNS population, the median PFS was 8.3 months (95% CI, 6.4-15.7). OS data were still immature, but at 12 months, the OS rate was 81%.

More than 93% of the ROS1 fusion–positive study population (n = 210) experienced treatment-related adverse events (TRAEs) of any grade. Most of the events were grade 1 or 2 in severity, including most commonly dysgeusia (42.9%), dizziness (34.3%), and constipation (31.4%). Grade 3 or higher TRAEs were also observed in patients, with the most common being weight increase (8.1%), alanine aminotransferase increase (3.3%), and diarrhea (2.9%). Notably, 3.3% of patients experienced grade 4 TRAEs.

Cases of serious AEs were uncommon in the study, but of those observed, the most common were pyrexia (1.4%), cognitive disorder (1.0%), and vomiting (1.0%).

There were treatment discontinuations in 7.6% of patients, which were mainly related to respiratory events. In addition, 29.0% of patients required dose reduction, and 30.5% required dose interruption.


Dziadziuszko R. Krebs MG, Braud FD, 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. J Clin Oncol. 2021;39(11):1253-1263. doi: 10.1200/JCO.20.03025