Results of an exploratory, retrospective analysis that evaluated comprehensive genomic profiling (CGP) assay results performed on cell-free, circulating tumor DNA (ctDNA) and tumor tissue obtained from “real-world” patients with advanced non-small cell lung cancer (NSCLC) supported the routine clinical use of ctDNA-based CPG to facilitate selection of targeted therapy in this setting, according to findings published in Lung Cancer.

Although previous studies have evaluated the use of ctDNA CGP assays in the genomic characterization of tumors in real-world settings, most of those studies were conducted in academic settings as opposed to routine clinical practice. Furthermore, there is a paucity of data comparing tumor genomic profiling results obtained using ctDNA assays and tissue-based assays.

In this study, a multi-institutional, real-world, clinicogenomic database created through a collaboration between Flatiron Health and Foundation Medicine, Inc., was interrogated for the purpose of comparing CGP assay results using ctDNA and tumor tissue from real-world patients with advanced NSCLC within the context of their clinical outcomes following receipt of a targeted therapy matched to a targetable genomic alteration. The data represented patients primarily treated in a community oncology setting.

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Patients diagnosed with advanced NSCLC 90 days or more prior to their inclusion in the database were excluded from this study in an attempt to minimize those cases where administration of a targeted therapy matched to a genomic alteration included in National Comprehensive Cancer Network (NCCN) guidelines was not captured.

Of the 6491 patients eligible for this analysis, 934 patients and 5570 patients were included in the ctDNA- and tissue-based cohorts, respectively. More than 1 CGP assay was performed for only 379 patients. For these patients, only results of the first CGP assay were considered with the following exceptions: 1) those patients with an EGFR-activating mutation who were found to have tumor characterized by the EGFR T790M resistance mutation on a second test; 2) those patients who underwent 2 tests in which a targetable genomic alteration, also defined by its inclusion in the NCCN guidelines, was detected only on the second test; and 3) those patients for whom both ctDNA- and tissue-based CPG were performed before initiation of matched targeted therapy.

The median patient age was 70 years in the ctDNA cohort and 67 years in the tissue-based cohort, and approximately three-quarters of patients in both cohorts had disease characterized by nonsquamous histology.

While 53% of patients who underwent ctDNA-based CPG had received at least 1 prior line of therapy in the setting of advanced NSCLC, this was the case for only 13% of patients who underwent tissue-based testing. Cell-free DNA was detected in more than 90% of patients who underwent ctDNA testing, and at least 1 targetable genomic alteration was found in 20% and 21.8% of those in the ctDNA and tissue cohorts, respectively.

Although the frequencies of a number of the targeted genomic alterations were similar when results from the 2 types of assays were compared, exceptions were observed.

For example, a comparison of particular targeted genomic alterations detected using ctDNA- vs tissue-based test results revealed similar frequencies for alterations represented by EGFR exon19del/L858R (7.9% vs 8.2%, respectively), ALK rearrangement (2.3% vs 2.6%, respectively), ROS1 rearrangement (0.7% vs 0.7%, respectively), and RET rearrangement (0.9% vs 0.8%, respectively). However, there were notable differences in the frequencies of EGFR T790M (3.7% vs 1.4%, respectively) and MET exon 14 and/or high-level amplification (1.9% vs 3.6%, respectively) detected using these 2 types of assays.

“In contrast to tissue-based testing, where histological confirmation of tumor cell content can be performed, clinical sensitivity for liquid biopsy testing is limited by minimal tumor DNA shedding into the blood in some cases. Therefore, liquid biopsy results that are negative for targetable [genomic alterations] require further confirmatory tissue-based testing,” the study authors noted.

Regarding the clinical outcomes of the patients with disease characterized by a targetable genomic alteration using either a ctDNA- or tissue-based assay, those who received a matched targeted therapy in the first-line setting (287 individuals) had longer median real-world progression-free survival (rwPFS; 9.4 months) compared with those treated with other types of first-line therapy (130 individuals; 6.9 months; adjusted hazard ratio [aHR], 0.72; 95% CI, 0.54-0.95).

Furthermore, when only standard-of-care targetable genomic alterations were considered, such as specific mutations in EGFR or BRAF V600E, or rearrangements in ALK and ROS1, median rwPFS was similar for those receiving first-line matched targeted therapy after identification of a standard-of-care targeted genomic alteration through ctDNA- (33 individuals; 13.8 months) or tissue-based CGP (229 individuals; 10.6 months; aHR, 0.68; 95% CI, 0.36-1.26).

In addition, no significant difference was observed in the real-world overall response rate of patients receiving matched targeted therapy as directed by either ctDNA-based (52 individuals; 75%) or tissue-based CPG (385 individuals; 66%; P =.51).

In their concluding remarks, the study authors noted that “retrospective analysis of real-world clinico-genomic data demonstrated that clinical outcomes on matched targeted therapy were similar following liquid biopsy and tissue CGP in NSCLC, which suggests routine clinical use of liquid biopsy CGP can reliably guide therapy selection.”

Disclosure: Some of the authors of this study disclosed financial relationships with Foundation Medicine, a wholly owned member of the Roche Group; Revolution Medicines; and Flatiron Health, which is an independent subsidiary of the Roche Group. For a full list of disclosures, please refer to the original study.

Madison R, Schrock AB, Castellanos E, et al. Retrospective analysis of real-world data to determine clinical outcomes of patients with advanced non-small cell lung cancer following cell-free circulating tumor DNA genomic profiling. Lung Cancer. 2020;148:69-78. doi:10.1016/j.lungcan.2020.07.033