Resolution ctDx FIRST plasma assay as a companion diagnostic for adagrasib and its application to longitudinal monitoring.

Abstract

3057 Background: KRAS is one of the most commonly mutated oncogenes in cancer. There is a significant need for new treatment options for patients with non–small cell lung cancer (NSCLC) harboring the KRAS G12C mutation. Adagrasib is an investigational, highly selective, oral small molecule inhibitor of KRAS G12C that has demonstrated clinical benefit in patients with KRAS G12C–mutant NSCLC and CRC. Detection of KRAS G12C in cfDNA is minimally invasive and is of benefit to NSCLC patients, many without lesions accessible by tissue biopsy testing. Methods: Resolution ctDx FIRST is a 113 gene comprehensive genomic profiling assay that identifies oncogenic alterations including substitutions, insertions, deletions, gene fusions, and homozygous deletions using targeted NGS sequencing of cfDNA. The Resolution ctDx FIRST assay is being developed as a companion diagnostic for adagrasib in NSCLC patients of the Mirati Study 849-001. Results: The LOD95 for SNVs and indels in KRAS and EGFR at a cfDNA input level of 15ng ranged from 0.34% to 0.82%. No false positives were detected in any samples from healthy donors (N = 60). A total of 230 NSCLC plasma samples were orthogonally tested using a ddPCR assay for KRAS G12C, using 76 plasma samples from Study 849-001 where KRAS G12C positive results had previously been obtained by a tissue assay, and 154 commercially procured NSCLC samples representative of the trial population. The PPA and NPA for Resolution ctDx FIRST plasma testing relative to ddPCR assay (95% CI) were 87.0% (75.1–94.6%) and 97.6% (94.1–99.4%) respectively. Of 112 Study 849-001 patients, 71 (63.4%) were tested for KRAS G12C mutations with Resolution ctDx FIRST in pretreatment plasma samples. Seventy-four commercially procured matched tissue and plasma samples were tested by Resolution ctDx FIRST and tissue assay. The PPA and NPA for Resolution ctDx FIRST plasma testing relative to tissue assay (95% CI) were 66.2% (54.0-77.0%) and 100% (94.7-100%) respectively. The detection of EGFR variants in the Resolution ctDx FIRST assay was compared to results from a ddPCR assay for each variant. A total of 165 NSCLC plasma samples generated a total of 317 comparative valid results. PPA was 100% for EGFR L858R, 88.9% for EGFR T790M, and 91.3% for EGFR Exon 19 Deletions. NPA was 97.8% for EGFR L858R, 100% for EGFR T790M, and 100% for EGFR Exon 19 Deletions. Application of the assay in longitudinally collected NSCLC and CRC patient samples will be presented highlighting changes of VAF over time including identification of oncogenes involved in emerging resistance. Conclusions: The Resolution ctDx FIRST assay offers highly sensitive, specific, and robust test results, and meets analytical requirements for clinical applications. [Table: see text]