RESUMO
INTRODUCTION: Remote consent and enrollment offer a unique opportunity to provide rare cancer populations with access to clinical research. The genomic analysis of plasma cell-free DNA (cfDNA) permits remote characterization of the cancer genome. We hypothesized we could leverage these approaches to remotely study drug resistance in patients with metastatic ALK-positive NSCLC. METHODS: The SPACEWALK study (Study of Plasma Next-Generation Sequencing for Remote Assessment, Characterization, Evaluation of Patients With ALK Drug Resistance) enrolled patients with ALK-positive NSCLC and progression on a next-generation ALK inhibitor who could participate remotely. Plasma was collected for next-generation sequencing (NGS) of cfDNA before initiating subsequent therapy, with results returned and subsequent therapy studied. RESULTS: Of the 62 patients enrolled, an ALK fusion was detected in 27 (44%) with a median allelic fraction of 2.6%. Among these 27 patients, a potential resistance mechanism was identified in 17 patients (63%): eight cases (30%) had secondary ALK kinase domain resistance mutations, three cases (11%) had bypass track resistance, and six cases (22%) had both ALK resistance mutations and bypass resistance. The most frequently detected mechanism of bypass resistance was MET amplification. Repeat plasma NGS was performed in 14 patients after subsequent treatment was initiated, with seven (50%) patients exhibiting greater than 50% reductions in ALK fusion allelic fraction. CONCLUSIONS: Through the leveraging of remote participation, plasma NGS offers an optimal mechanism for characterizing resistance to emerging targeted therapies in rare cancer populations, though sensitivity depends on adequate tumor DNA samples. Repeat cfDNA analysis on therapy may offer an objective monitoring approach to remotely study treatment response.
RESUMO
PURPOSE: Next-generation sequencing (NGS) is an important component of first-line treatment selection for metastatic non-small-cell lung cancer (NSCLC) and is typically ordered by medical oncologists in the outpatient setting after the pathologic diagnosis has been established. Time to treatment initiation is an important clinical challenge, especially for patients with rapidly progressive disease. METHODS: Plasma cell-free DNA (cfDNA) NGS was performed on 20 patients with suspected metastatic NSCLC hospitalized at an academic cancer center, before pathologic diagnosis. Clinicopathologic and treatment data were analyzed. Time from pathologic diagnosis to genotyping result was compared with standard care groups who underwent plasma or tumor NGS in routine clinical care. RESULTS: The median time from pathologic diagnosis to the plasma cfDNA NGS result was 3 days in the study cohort, versus 18 days and 35.5 days in the standard care plasma and tumor NGS groups, respectively. 68.4% of evaluable patients had metastatic NSCLC, and 21.1% had another advanced solid tumor. Forty-five percent of plasma cfDNA results demonstrated actionable or informative genomic variants, and 20% of patients received standard or investigational first-line targeted therapy as a direct result of the plasma cfDNA NGS. CONCLUSION: Plasma cfDNA NGS before pathologic diagnosis in hospitalized patients with suspected metastatic NSCLC results in substantially shorter time to genotyping result compared with standard outpatient workflows. This provides important initial evidence for the use of plasma-based genotyping earlier in the diagnostic journey, especially for patients with clinically aggressive disease. Additional studies and innovative approaches toward regulatory and reimbursement considerations are needed.
