B-099 Optimizing Comprehensive Genomic Profiling in NSCLC: A Multimodal Workflow for Accelerated Timelines and Efficient Resource Utilization

Abstract

Comprehensive genomic profiling (CGP) is the gold-standard analytical technology for identifying the complete landscape of complex signatures and rare alterations across diverse malignancies. As a definitive characterization tool, the unmatched depth of CGP is essential for comprehensive resolution, although its analytical complexity can extend turnaround times. The DelPHI 2.0 collaboration between Protean BioDiagnostics and Roche Diagnostics evaluated a multimodal workflow where rapid digital PCR (dPCR) and immunohistochemistry (IHC) provided an immediate primary screen, ensuring early insights while progressing toward the definitive resolution provided by CGP. A retrospective analysis was conducted on 103 late-stage NSCLC specimens comprising an enriched cohort of known positives previously characterized by next-generation sequencing. Performance was evaluated in a 70-case cohort where all three modalities were performed: a rapid primary screen (Step 1) using dPCR (LightMix Assays* on the Digital LightCycler System*; Roche) and IHC (VENTANA PD-L1 [SP263], ALK [D5F3], ROS1 [SP384], and pan-TRK [EPR17341]; Roche) with analysis via Roche Digital Pathology Dx**. This was followed by comprehensive genomic profiling (Step 2) via the AVENIO Tumor Tissue CGP Kit V2* (Roche) with analysis via navify Mutation Profiler* (Roche). Calculated costs included assay kits and reagents, software licenses, and technician labor. Economic impact was evaluated by benchmarking the multimodal workflow against a CGP-only baseline of $813/sample. Across the 70-case cohort, the primary screen (Step 1) identified key drivers in 50.0% of cases via dPCR and IHC. However, focused testing alone resulted in incomplete molecular characterization for the majority of specimens. CGP (Step 2) identified at least one additional key biomarker in 64.4% of cases, averaging 1.63 new targets per case. CGP successfully identified complex genomic signatures, including TMB-High and HRD-sig positive results, in over one-third of the 70 cases. Furthermore, CGP expanded the scope by detecting critical low-allele frequency variants residing below standard assay detection limits (e.g., EGFR L858Q at 0.62% AF), rare FGFR2 fusions, and EGFR and PIK3CA amplifications not covered by Step 1 testing. Notably, in 11/103 specimens (10.7%), the rapid screen provided critical data where tissue was insufficient for CGP. While the desire is to run CGP on every case, the prioritization of rapid results optimized total resources by $13,455 and reduced the time to first result by 6.9 days compared to a CGP-only baseline. A multimodal primary screen offers a pragmatic solution to the challenges of tissue exhaustion and analytical lead time. By resolving common alterations immediately, the laboratory can prioritize high-value CGP resources for the definitive resolution of complex molecular profiles, ensuring critical results are delivered even when tissue constraints preclude comprehensive sequencing. *Research Use Only. Not for diagnostic procedures; **Roche Digital Pathology Dx, including navify Digital Pathology, is cleared for specific clinical applications and is intended for research and educational use for other applications. Please review product labeling prior to utilization.