Appeal type: Experimental/Investigational
Decision: Upheld

This is a patient with metastatic, epidermal growth factor receptor positive (EGFR+) non-small cell lung cancer. The patient has received Tagrisso. The Guardant360 assay was obtained and is under review.
At issue is whether the proposed health service or treatment Guardant360 genetic testing likely to be more beneficial than any standard treatment or treatments for the insured's life threatening or disabling condition or disease.

The health plan's determination is upheld. The requested laboratory test is not likely to be more beneficial than standard treatment(s). The use of next generation sequencing gene panels to guide the treatment of patients with lung cancer has not been demonstrated to be of benefit. The assay in question is not Food and Drug Administration (FDA) approved. This approach remains the subject of multiple clinical trials including, but not limited to, National Clinical Trial (NCT) 03477474, NCT03615443 and NCT03576937.
To date, the SHIVA (clinical) trial is the only large randomized trial to evaluate the off-label use of molecularly targeted agents based on identified molecular alterations for which results have been published in the peer-reviewed literature. 741 patients were enrolled in this multi-institutional trial that included adult patients with any kind of metastatic solid tumor refractory to standard of care, provided they had an Eastern Cooperative Oncology Group performance status of 0 or 1, disease that was accessible for a biopsy or resection of a metastatic site, and at least one measurable lesion. The molecular profile of each patient's tumor was established with a mandatory biopsy of a metastatic tumor and large-scale genomic testing. Patients with an actionable mutation were randomized these (1:1) to receive a matched molecularly targeted agent (experimental group) or treatment at physician's choice (control group) by central block randomization (blocks of size six). Treatments in both groups were given in accordance with the approved product information and standard practice protocols at each institution and were continued until evidence of disease progression. The primary endpoint was progression-free survival in the intention-to-treat population. Median follow-up was 11.3 months (Interquartile Range (IQR) 5.8-11.6) in the experimental group and 11.3 months (8.1-11.6) in the control group at the time of the primary analysis of progression-free survival. Median progression-free survival was 2.3 months (95% confidence interval (CI) 1.7-3.8) in the experimental group versus 2.0 months (1.8-2.1). The conclusion of the authors was "The use of molecularly targeted agents outside their indications does not improve progression-free survival compared with treatment at physician's choice in heavily pretreated patients with cancer. Off-label use of molecularly targeted agents should be discouraged, but enrollment in clinical trials should be encouraged to assess predictive biomarkers of efficacy"
Further complicating the role of liquid biopsies is that their results are limited in sensitivity to between 60 and 80 percent. The limited sensitivity of liquid biopsies is thought to reflect the biology that some cancers do not shed deoxyribonucleic acid (DNA) into the bloodstream rather than a feature of any given assay. However, mutation detection in blood has been associated with more advanced disease characteristics, including worsened performance status and prognosis and the presence of more metastatic sites. A second limitation of liquid biopsies is that the types of studies have a higher chance of being falsely negative compared with traditional biopsies, given the minuscule and variable amounts of DNA that tumors may shed into circulation. Finally, tests for programmed death-ligand 1 (PD-L1) expression cannot be conducted on liquid biopsies.
Based on the paucity of supporting data, neither the National Comprehensive Cancer Network (NCCN) nor the authors of UpToDate recommend the use of the Guardant360 assay in this clinical scenario. Treatment based on published literature and guideline recommendations has been encouraged.