Appeal type: Experimental/Investigational
Decision: Upheld

Diagnosis: Urothelial Cancer. 
Treatment: FoundationOne CDx and PD-L1 testing. 

The insurer denied FoundationOne CDx and PD-L1 testing. 
The determination is upheld. 

The patient has resected, locally advanced muscle invasive urothelial cancer. Adjuvant checkpoint inhibitor therapy is planned. The FoundationOne CDx and PD-L1 testing has been requested; these are under review. 

The requested services are not likely to be more beneficial than any standard treatment or treatments for the insured's life threatening or disabling condition or disease. 

Regarding Foundation One CDx, the use of next generation sequencing gene panels to guide the treatment of patients with locally advanced urothelial cancer has not been demonstrated to be of benefit. The assay in question is Food and Drug Administration (FDA) approved. Several ongoing trials (eg, the National Cancer Institute [NCI] Molecular Analysis for Therapy Choice [MATCH] and the American Society of Clinical Oncology (ASCO) Targeted Agent and Profiling Utilization Registry [TAPUR] trails) are using next-generation sequencing of multiple genes (gene panel tests) to identify molecular abnormalities in the tumors of patients with refractory cancers that may potentially match molecularly targeted therapies that are either in clinical trials or approved for treatment of other cancer types (National Clinical Trial (NCT) 02465060 and NCT02693535). 

To date, the SHIVA trial is the only large randomized trial to evaluate off-label use of molecularly targeted agents on the basis of 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.... Another important point is that simply having a potentially targetable mutation does not guarantee that the patient will benefit from a therapy that presumably targets that mutation. Another potential pitfall is if targeted testing identifies a potentially actionable genetic abnormality for which a molecularly targeted treatment is available but not yet approved. 

Based on the paucity of supporting data, neither the National Comprehensive Cancer Network (NCCN) nor the authors of UpToDate recommend the use of the Foundation Medicine NGS assay in this clinical scenario. Treatment based on published literature and guideline recommendations has been encouraged. 

Regarding PD-L1 (Programmed death-ligand 1), in the phase III trial (CheckMate 274) of 709 patients with muscle-invasive urothelial carcinoma of the urinary bladder or upper urinary tract who underwent radical cystectomy and had high-risk disease on postoperative pathology, patients either received neoadjuvant cisplatin-based chemotherapy and had persistent muscle-invasive or nodal disease or did not receive neoadjuvant chemotherapy, had extravesical extension or nodal involvement at surgery, and were ineligible for (or declined) adjuvant cisplatin-based chemotherapy. Patients were randomly assigned to either nivolumab at 240 milligrams (mg) intravenously every two weeks or placebo for up to one year. At median follow-up of approximately 20 months, compared with placebo, adjuvant nivolumab resulted in improved disease free survival (67 versus 46 percent at one year in patients with PD-L1 expressing cancers. FDA approval was given for adjuvant treatment regardless of PD-L1 expression, however, Therefore, testing of PD-L1 expression is irrelevant and does not alter management in this clinical scenario.