Serial Cell-Free DNA Sequencing in Fusion-Positive Lung Cancers During Treatment With Entrectinib

Overview

Journal JCO Precis Oncol

Specialty Oncology

Date 2024 Jun 7

PMID 38848521

Authors

Noura J Choudhury

Hyung Jun Woo

Monica Chen

Ronak Shah

Mark Donoghue

Michael Berger

Alexander Drilon

Affiliations

Soon will be listed here.

Abstract

Purpose: Patients with metastatic 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.

Methods: In patients with 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.

Results: Twelve 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 fusion was variably detected in cfDNA; however, patients without a fusion in cfDNA had no other somatic alterations detected, indicative of possible low cfDNA shedding. Clearance of the enrolling fusion or concurrent non- alterations (, , , or mutations) was observed in response to entrectinib therapy. Radiologic PD was accompanied by redemonstration of a fusion or non- alterations. On-target resistance was rare; only one patient acquired G2032R at the time of progression. Several patients acquired new off-target likely oncogenic alterations, including a truncating alteration in .

Conclusion: Serial cfDNA monitoring may complement radiographic assessments as determinants of response and resistance to entrectinib in fusion-positive lung cancers in addition to detecting putative resistance mechanisms on progression.

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