SPACEWALK: A Remote Participation Study of ALK Resistance Leveraging Plasma Cell-Free DNA Genotyping

Marissa N. Lawrence, Rubii M. Tamen, Pablo Martinez, Alicia Sable-Hunt, Tony Addario, Pete Barbour, Tristan Shaffer, Seyed Ali Hosseini, Caterina Bertucci, Lee P. Lim, Fangxin Hong, Kesi Michael, George R. Simon, Jonathan W. Riess, Mark M. Awad, Geoffrey R. Oxnard

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Article number100151
JournalJTO Clinical and Research Reports
Volume2
Issue number4
DOIs
StatePublished - Apr 2021

Keywords

  • ALK
  • Drug resistance
  • Plasma NGS
  • Remote participation

ASJC Scopus subject areas

  • Oncology
  • Pulmonary and Respiratory Medicine

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