Adapting a prescreening program from VHIO to match molecular alterations in over 10,000 patients' tumors with targeted agents and immunotherapies in early clinical trials.

Abstract

e23071 Background: VHIO's Molecular Prescreening Program (MPP) began in 2010 to catalyze precision medicine at the institution. Over the last decade, this program has provided access to advanced molecular diagnostics to more than 10,000 cancer patients (pts) and is critical in matching targeted therapeutic approaches to clinical trials (CTs). Here we report the clinical utility of our program given the evolving molecular testing landscape and trends in drug development. Methods: We assess the adoption and impact of the VHIO’s MPP in CTs recruitment. All tests were developed in-house: a. from 2010 to 2014 we used formalin fixed paraffin embedded tumor samples to test for hotspot mutations (Sequenom, 20 oncogenes) plus FISH/IHC of selected markers; b. from 2015 to 2017 we moved to a amplicon-based NGS panel (MiSeq, 61 genes), a copy number alteration (CNA) panel (Nanostring, 44 genes) and a fusion + gene expression assay (Nanostring, 26 genes) with additional FISH/IHC in selected cases, including PDL1 and MSI status; c. since 2019, we use a custom capture-based NGS assay for mutations (mut), CNA and Tumor Mutation Burden (TMB) estimation (NextSeq, 435 genes); d. since 2022, we run a liquid biopsy panel in-house (Guardant360, technology transfer). Results: We found a stepwise increase in the MPP adoption, from 207 pts in 2010 to 1,965 pts in 2023, representing almost a tenfold increase. Most common tumours analysed were colorectal, lung, breast, gynaecologic, pancreato-biliary, and gastric. The number of CTs requiring biomarker match has increased from 13 in 2010 to more than 201 in 2023, the most frequent in the last year being HER2 (33), PDL1 (20), EGFR (17), RAS (15) and FGFR (9), MSI (9) and ALK (7). In 2023, 1,230 patients had broad tissue NGS panel, 1,235 were tested with IHC, 373 with fusions + expression assay and 991 with liquid biopsy. Inclusion rate in CTs with biomarker match has fluctuated between 13% and 19% in the past 5 years. Overall, close to 50% of these trial recruitments are with genomically-informed enrichment strategies and not mandatory inclusion criteria. On average, 20% of the patients were still enrolled in unmatched trials after molecular testing. Conclusions: The success of VHIO's MPP is related to agile innovation and clinical deployment of new technologies in a timely manner, critical for the development of new drugs in CTs. Biomarker matched trials evolved from a “few targets/ large populations” scenario to a complex situation with “many targets/ small populations”. Many pts benefit from enrichment strategies in Phase 1 CTs. The impact of the recent implementation of liquid biopsy and ongoing development of genomic + transcriptomic signatures will be closely monitored.