In a phase II/III Blood First Assay Screening Trial (BFAST) study, the investigators evaluated entrectinib in treatment-naïve patients with ROS1-positive, advanced/metastatic non-small cell lung cancer (NSCLC) identified solely by liquid biopsies. BFAST Cohort D met its primary endpoint; the confirmed objective response rate (ORR) per investigator in this analysis was 81.5% and was above the protocol-defined threshold, suggesting that these data are consistent with those from the historical analysis of entrectinib in patients with ROS1-positive NSCLC identified by tissue-based testing.

Furthermore, entrectinib demonstrated durable responses and progression-free survival (PFS); overall survival (OS) data were immature, but the 12-month OS rate was high. The safety profile of entrectinib was consistent with previous reports. The prevalence of ROS1 fusions identified in this study was 1.8%. The study findings are published by Dr. Solange Peters of the Lausanne University Hospital, Centre Hospitalier Universitaire Vaudois (CHUV) in Lausanne, Switzerland, and colleagues on 19 June 2024 in the Nature Medicine

Comprehensive biomarker testing to identify the presence of oncogenic driver alterations (including various EGFR mutations, ALK, RET, NTRK1/2/3, ROS1, BRAF V600E, METex14 skipping and ERBB2) is recommended for patients with advanced/metastatic NSCLC before initiation of first-line treatment, and for patients with KRAS G12C mutation, ERBB2 mutation or EGFR exon 20 insertion mutation, targeted therapy is recommended as a second-line treatment. However, the percentage of patients with metastatic NSCLC who receive molecular testing for multiple targetable biomarkers via next-generation sequencing (NGS) remains low. Furthermore, many patients do not receive targeted therapies due to factors associated with obtaining biomarker test results.

Tissue biopsies in patients with advanced NSCLC may not always be feasible, due to either the patient’s comorbidities or the location of their tumour. The yield of viable tumour cells collected during biopsy may also be too low for molecular testing. Furthermore, repeat biopsies are associated with risk of complications and are undesirable from the patient’s perspective. Genomic testing in liquid biopsies can be utilised to overcome the inherent limitations of tissue sampling.

Studies have demonstrated high concordance between tissue and liquid biopsies, albeit that the latter are less sensitive than the former. Despite this, due to their faster turnaround time compared with tissue-based testing and equivalent time-to-treatment, liquid biopsies are commonly used as a first-line diagnostic and have demonstrated clinical benefit. Liquid biopsies can also be used to explore mechanisms of resistance to kinase inhibitors. Liquid biopsies can also be used in parallel with tissue-based assays, immunohistochemistry or fluorescence in situ hybridisation to facilitate more extensive testing.

ROS1 fusions occur in a variety of different tumour types, including in 1–2% of NSCLC cases. Brain metastases are detected in approximately 40% of patients with ROS1-positive, advanced NSCLC, which highlights the need for central nervous system (CNS)-penetrating treatments with proven intracranial efficacy. Entrectinib is a potent ROS1, TRK and ALK tyrosine kinase inhibitor (TKI) that was specifically developed for its ability to cross the blood–brain barrier and remain within the CNS.

Results from an integrated analysis of three phase I/II studies, ALKA-372-001, STARTRK-1 and STARTRK-2, have demonstrated deep and durable responses with entrectinib in patients with ROS1-positive NSCLC. Entrectinib also yielded durable intracranial responses in patients with baseline CNS metastases. These studies enrolled patients with ROS1-positive tumours identified by tissue-based testing.

BFAST is a global, open-label, multicohort study evaluating the efficacy and safety of targeted therapies or immunotherapy in patients with advanced/metastatic NSCLC harbouring actionable genetic alterations detected solely by genomic testing in liquid biopsies. Data from the ALK-positive cohort (Cohort A) and the tumour mutational burden (TMB)-high cohort (Cohort C) of BFAST have been published previously. Data from Cohort A demonstrated the clinical application of liquid biopsies in identification of patients with ALK-positive NSCLC to be treated with alectinib. Cohort C did not meet its primary endpoint of investigator-assessed PFS in patients with blood TMB of ≥16.

In the latest article published in the Nature Medicine, the study team presents efficacy and safety data from Cohort D of BFAST, an evaluation of entrectinib in treatment-naïve patients with ROS1-positive NSCLC identified by NGS testing in liquid biopsies alone. The objective of this study is to demonstrate consistency in data when patients with ROS1-positive NSCLC are identified via liquid biopsies and when they are identified via tissue-based testing.

Patients ≥18 years of age with stage IIIB/IV, ROS1-positive NSCLC detected by liquid biopsies received entrectinib 600 mg daily. At data cut-off in November 2021, 55 patients were enrolled and 54 had measurable disease. Cohort D met its primary endpoint with confirmed ORR by investigator of 81.5%, which was consistent with the ORR from the integrated analysis of entrectinib, where investigator-assessed ORR was 73.4% at data cut-off in May 2019 and with at least 12 months of follow-up.

Furthermore, entrectinib demonstrated durable responses and survival, median duration of response was 13.0 months by investigator assessment and 16.7 months by independent review facility (IRF) assessment; median PFS was 12.9 months by investigator assessment and 14.8 months by IRF; and OS data were immature, but the 12-month OS rate was 79%.

In BFAST Cohort D only four patients had baseline CNS metastases by investigator, and two of these achieved a partial response. Due to the low incidence of CNS disease in this cohort, intracranial efficacy could not be assessed. Time to CNS progression was assessed in all patients and the 12-month CNS progression-free rate was 86.4% by IRF and the median was not reached. These results suggest a role for entrectinib in delaying or preventing the development of CNS metastases, even in patients without baseline CNS disease. However, further data are required to make any definitive conclusions.

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.

BFAST Cohort D was designed to demonstrate consistency with the integrated analysis of entrectinib in terms of investigator-assessed ORR; the primary endpoint was met. The integrated analysis of entrectinib is the most relevant dataset for comparison of the results of BFAST Cohort D, and the only other analysis of patients with ROS1-positive, advanced/metastatic NSCLC who have been treated with entrectinib.

Post hoc exploratory analyses were conducted to further characterise the patient population and identify any potential prognostic biomarkers; however, because the number of patients in all biomarker analyses was low, the results should be interpreted with caution. Clearance of ctDNA from baseline to C3D1 may be prognostic of clinical outcomes, because patients who had cleared ROS1 by C3D1 had prolonged survival outcomes compared with those who had not. The presence of TP53 mutation, the most common co-mutation found in these patients, was associated with worse prognosis, which is consistent with previous reports. CD74 and EZR have previously been reported as the most common fusion partners for ROS1, consistent with the findings in BFAST Cohort D.

Post hoc exploratory analyses were conducted to determine whether the level of ctDNA in the blood had any prognostic value in these patients, but did not find an association between cTF levels (an estimate of tumour fraction) and clinical outcomes. In BFAST Cohort D, cTF levels did correlate with tumour burden as measured by sum of the longest diameters. Due to the small number of patients in BFAST, further research is required. Preliminary analyses were conducted to determine whether there is a relationship between levels of ctDNA and clinical response with no clear relationship identified.

Potential molecular mechanisms of resistance to entrectinib were explored in patients who had disease progression and available plasma samples from the time of treatment discontinuation. Potential acquired-resistance mutations were identified, including ROS1 G2032R, which has previously been associated with resistance to lorlatinib and entrectinib. Additional analyses are required to fully elucidate the mechanisms of resistance in this study.

The authors concluded that these results demonstrate consistency with those from the integrated analysis of entrectinib in patients with ROS1-positive NSCLC identified by tissue-based testing, and support the clinical value of liquid biopsies to inform clinical decision-making. The integration of liquid biopsies into clinical practice provides patients with a less invasive diagnostic method than tissue-based testing and has faster turnaround times that may expedite the reaching of clinical decisions in the advanced/metastatic NSCLC setting.

Other ROS1 inhibitors are also approved and/or in development for the treatment of ROS1-positive, advanced/metastatic NSCLC. Crizotinib is approved for the treatment of ROS1-positive, advanced NSCLC; lorlatinib, taletrectinib and repotrectinib are next-generation ROS1 inhibitors that are currently under investigation for the treatment of patients with ROS1-positive NSCLC who are treatment-naïve and who have received previous treatment, including ROS1 TKIs. The authors commented that in the clinical studies of ROS1 inhibitors, patients are identified by tissue-based biomarker testing and there are inherent differences between study populations that make cross-trial comparisons with BFAST inappropriate.

All clinical and ctDNA data for BFAST Cohort D are deposited to the European Genome-Phenome Archive.

The study was sponsored by Roche.

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. Nature Medicine; Published online 19 June 2024. DOI: https://doi.org/10.1038/s41591-024-03008-4

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