Clinical Outcomes in Non-Small-Cell Lung Cancer Patients Treated With EGFR-Tyrosine Kinase Inhibitors and Other Targeted Therapies Based on Tumor Versus Plasma Genomic Profiling

Abstract

Purpose: To compare clinical outcomes in a cohort of patients with advanced non-small-cell lung cancer (NSCLC) with targetable genomic alterations detected using plasma-based circulating tumor DNA (ctDNA) or tumor-based next-generation sequencing (NGS) assays treated with US Food and Drug Administration-approved therapies at a large academic research cancer center.

Methods: A retrospective review from our MD Anderson GEMINI database identified 2,224 blood samples sent for ctDNA NGS testing from 1971 consecutive patients with a diagnosis of advanced NSCLC. Clinical, treatment, and outcome information were collected, reviewed, and analyzed.

Results: Overall, 27% of the ctDNA tests identified at least one targetable mutation and 73% of targetable mutations were EGFR-sensitizing mutations. Among patients treated with first-line epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) therapies, there were no significant differences in progression-free survival of 379 days and 352 days (P value = .41) with treatment based on tissue (n = 40) or ctDNA (n = 40), respectively. Additionally, there were no differences in progression-free survival or objective response rate among those with low (n = 8, 0.01%-0.99%) versus high (n = 16, ≥ 1%) levels of ctDNA of the targetable mutation as measured by variant allele frequency (VAF). Overall, there was excellent testing concordance (n = 217 tests) of > 97%, sensitivity of 91.7%, and specificity of 99.7% between blood-based ctDNA NGS and tissue-based NGS assays.

Conclusion: There were no significant differences in clinical outcomes among patients treated with approved EGFR-TKIs whose mutations were identified using either tumor- or plasma-based comprehensive profiling and those with very low VAF as compared with high VAF, supporting the use of plasma-based profiling to guide initial TKI use in patients with metastatic EGFR-mutant NSCLC.

FIG 1.

PFS in patients with advanced non–small-cell lung cancer treated with US Food and Drug Administration–approved frontline epidermal growth factor receptor-tyrosine kinase inhibitor directed by genomic profiling from tissue-based (blue) versus ctDNA-based (red) testing, log-rank test. ctDNA, circulating tumor DNA; HR, hazard ratio; PFS, progression-free survival.

FIG 2.

Comparison of clinical responses from patients with advanced NSCLC treated with FDA-approved EGFR-TKI in first line on the basis of ctDNA-identified molecular alterations. (A) Tumor responses (RECIST V1.1) on the basis of low (0.01%-0.99%, blue circle) versus high (≥ 1.00%, red box) VAF, unpaired t test. (B) PFS of low VAF (blue) and high VAF (red), log-rank test. ctDNA, circulating tumor DNA; EGFR, epidermal growth factor receptor; FDA, US Food and Drug Administration; NSCLC, non–small-cell lung cancer; PFS, progression-free survival; TKI, tyrosine kinase inhibitor; VAF, variant allele frequency.