FDA Approves xT CDx, a NGS-Based in Vitro Diagnostic Device

FDA

The FDA has approved xT CDx, a 648-gene next-generation sequencing (NGS) assay for solid tumor profiling, and companion diagnostic for patients with colorectal cancer (CRC).¹

The qualitative NGS-based in vitro diagnostic device is intended to be leveraged to identify substitutions like single nucleotide variants and multinucleotide variants and insertion and deletion alterations in 648 genes. The test can also detect microsatellite instability status by using DNA isolated from formalin-fixed paraffin embedded tumor tissue specimens, as well as DNA isolated from matched normal blood or saliva speciments from patients with solid malignant neoplasms who had received a prior diagnosis.

xT CDx can serve as a companion diagnostic to determine identify those with KRAS wild-type CRC (absence of mutations in codons 12 or 13) who could benefit from receiving cetuximab (Erbitux).² It can also be used to identify those who could receive panitumumab (Vectibix) by detecting biomarkers like KRAS wild-type (absence of mutations in exons 2, 3, and 4) and NRAS wild-type (absence of mutations in exons 2, 3, or 4).

“This is a significant milestone for Tempus as we continue to establish a regulatory pathway for our platform, which offers solutions to advance both clinical care and support cutting-edge research,” Eric Lefkofsky, founder and chief executive officer of Tempus, stated in a press release. “We designed xT CDx to be a smart test that can empower physicians to provide personalized care for their patients and support researchers in developing better therapeutics.”

The detection of alterations by xT CDx had been compared with data from an externally validated orthogonal method (OM). Between the 2 assays, there were 114 overlapping genes. Investigators utilized 416 samples representing 31 tumor types to compare mutations, insertions, and deletions detected with xT CDx and the OM.

Tumor types included CRC (n = 69), breast cancer (n = 44), ovarian cancer (n = 38), glioblastoma (n = 34), non–small cell lung cancer (n = 29), endometrial cancer (n = 26), clear cell renal cell carcinoma (n = 22), bladder cancer (n = 18), melanoma (n = 17), pancreatic cancer (n = 14), thyroid cancer (n = 12), low-grade glioma (n = 12), sarcoma (n = 10), tumor of unknown origin (n = 8), meningioma (n = 7), prostate cancer (n = 7), gastrointestinal stromal tumor (n = 7), endocrine tumor (n = 6), gastric cancer (n = 5), head and neck squamous cell carcinoma (n = 4), kidney cancer (n = 3), brain cancer (n = 3), small cell lung cancer (n = 3), biliary cancer (n = 3), cervical cancer (n = 3), esophageal cancer (n = 3), oropharyngeal cancer (n = 2), liver cancer (n = 2), head and neck cancer (n = 2), mesothelioma (n = 2), and adrenal cancer (n = 1).

Investigators examined concordance in hotspot and non-hotspot regions. To understand the accuracy of xT CDx, they identified positive and negative percent agreements (PPA, NPA) for each type of variant. However, differences in the number of reportable variants between the 2 tests were expected.

Across the 416 samples examined, 148 variants that were reported as somatic by the OM were detected as germline by xT CDx. "However, because the OM is unable to distinguish germline from somatic variants these were included as an output of xT CDx for the purposes of this analytical concordance study," according to Tempus.

To conduct the hotspot concordance analysis with the OM, investigators examined variants reported in hotspot regions that overlapped with OM targeted regions. Of the 416 samples, 164 had at least 1 reported variant in an overlapping hotspot region. A total of 214 base pairs were at the intersection of the defined hotspot regions of both the xT CDx and OM targeted regions.

In hotspots, 192 reported variants from both assays were assessed; this comprised 187 substitutions spanning 10 genes, and 5 INDELs spanning 4 genes. The PPA and NPA for substitutions and INDELS within hotspot regions were calculated by examining the total variant counts of each classification across the samples. These metrics were leveraged to determine the accuracy of the assay.

Moreover, in the 69 CRC samples tested with the OM, the detection of specific KRAS and NRAS CDx variants was also examined. Of the 31 CDx variants identified via OM, 31 were also detected by xT CDx, yielding a PPA of 100% (95% CI: 88.8%-100.0%). Of the total 649 CDx variants identified as negative by the OM, 648 were determined to be negative by xT CDx, thus yielding a NPA of 99.8% (95% CI: 99.1%-100.0%).

References

1. Tempus receives US FDA approval of xT CDx, a NGS-based in vitro diagnostic device. News release. Tempus. May 1, 2023. Accessed May 1. 2023.https://www.tempus.com/news/tempus-receives-u-s-fda-approval-for-xt-cdx-a-ngs-based-in-vitro-diagnostic-device/
2. xT CDx: Technical information. Tempus Labs, Inc. February 2023. Accessed May 1, 2023. https://www.tempus.com/wp-content/uploads/2023/05/Tempus-xT-CDx_Technical-Information.pdf