Serial cell-free DNA sequencing in ROS1 fusion-positive lung cancers during treatment with entrectinib Journal Article
| Authors: | Choudhury, N. J.; Woo, H. J.; Chen, M.; Shah, R.; Donoghue, M.; Berger, M.; Drilon, A. |
| Article Title: | Serial cell-free DNA sequencing in ROS1 fusion-positive lung cancers during treatment with entrectinib |
| Abstract: | PURPOSEPatients with metastatic ROS1 fusion-positive non-small cell lung cancer (NSCLC) are effectively treated with entrectinib, a multikinase inhibitor. Whether serial targeted gene panel sequencing of cell-free DNA (cfDNA) can identify response and progression along with mechanisms of acquired resistance to entrectinib is underexplored.METHODSIn patients with ROS1 fusion-positive NSCLC, coclinical trial plasma samples were collected before treatment, after two cycles, and after progression on entrectinib (global phase II clinical trial, ClinicalTrials.gov identifier: NCT02568267). Samples underwent cfDNA analysis using MSK-ACCESS. Variant allele frequencies of detectable alterations were correlated with objective response per RECIST v1.1 criteria.RESULTSTwelve patients were included, with best response as partial response (n = 9, 75%), stable disease (n = 2, 17%), and progressive disease (PD; n = 1, 8%). A ROS1 fusion was variably detected in cfDNA; however, patients without a ROS1 fusion in cfDNA had no other somatic alterations detected, indicative of possible low cfDNA shedding. Clearance of the enrolling ROS1 fusion or concurrent non-ROS1 alterations (TP53, CDH1, NF1, or ARID1A mutations) was observed in response to entrectinib therapy. Radiologic PD was accompanied by redemonstration of a ROS1 fusion or non-ROS1 alterations. On-target resistance was rare; only one patient acquired ROS1 G2032R at the time of progression. Several patients acquired new off-target likely oncogenic alterations, including a truncating alteration in NF1.CONCLUSIONSerial cfDNA monitoring may complement radiographic assessments as determinants of response and resistance to entrectinib in ROS1 fusion-positive lung cancers in addition to detecting putative resistance mechanisms on progression. © 2024 by American Society of Clinical Oncology. |
| Keywords: | adult; controlled study; aged; unclassified drug; human cell; major clinical study; sequence analysis; systemic therapy; progression free survival; phase 2 clinical trial; gene frequency; lung cancer; health care quality; lung adenocarcinoma; gene rearrangement; bioinformatics; dynamics; disease exacerbation; complement; non small cell lung cancer; fusion protein; institutional review; very elderly; human; male; female; article; ros1 fusion protein; circulating tumor dna; entrectinib; chloroplast dna; circulating free dna |
| Journal Title: | JCO Precision Oncology |
| Volume: | 8 |
| ISSN: | 2473-4284 |
| Publisher: | American Society of Clinical Oncology |
| Date Published: | 2024-09-01 |
| Start Page: | e2300721 |
| Language: | English |
| DOI: | 10.1200/po.23.00721 |
| PUBMED: | 38848521 |
| PROVIDER: | scopus |
| PMCID: | PMC11545664 |
| DOI/URL: | |
| Notes: | The MSK Cancer Center Support Grant (P30 CA008748) is acknowledge in the PDF -- Corresponding authors is MSK author: Alexander Drilon -- Source: Scopus |
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