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.

Genomic Alteration Spectrum of Non-Small Cell Lung Cancer Patients in East-China Characterized by Tumor Tissue DNA and Cell-Free DNA

“…In addition, the level of VAF may affect the prognosis of cancer. 18 Therefore, VAFs in tissue and blood specimens were analyzed. As we speculated, VAFs in tissue specimens (mean = 14.4%) were significantly (P < 0.001) higher than that in blood specimens (3.9%).…”

Circulating Tumor DNA-Based Genomic Profiling Assays in Adult Solid Tumors for Precision Oncology: Recent Advancements and Future Challenges

“…It is unclear whether targeting alterations detected at low VAF from plasma could result in clinical benefits. Two recent exploratory studies have observed no significant differences in treatment response between NSCLC patients detected with EGFR mutations below or above ctDNA VAF of 1% [66,67]. The authors from both studies also reported that a trend of greater clinical benefit was observed in those with a low VAF (<1%), suggesting better disease control in those patients with lower tumor burden as reflected by ctDNA [66,67].…”

“…The clinical benefits of ctDNA CGP were validated in recent large retrospective studies with cohort sizes of over 1000 patients. No significant differences were observed in the PFS and overall survival (OS) of patients selected based on ctDNA or tissues across several studies [59,66,68]. The clinical outcomes of liquid biopsy CGP compared to tissue CGP in advanced NSCLC patients were assessed in a multi-institutional, retrospective analysis of the real-world data [68].…”

Advantages and Challenges of Using ctDNA NGS to Assess the Presence of Minimal Residual Disease (MRD) in Solid Tumors

“…Nevertheless, they proposed to prioritize tissue-based testing in these situations where the detection of fusion variants is the primary goal. In the same line, a team from MD Anderson institute [69] analyzed 1971 patients with metastatic NSCLC out of which 217 were paired samples. Their results showed high concordance between ctDNA testing (Guardant360, Guardant Health) and tissue testing (50-gene customized panel or OncoMine Comprehensive Assay V1).…”