Actionability landscape and biomarker utility in a colorectal cancer alliance cohort: Initial results from the Know Your Biomarker program.

e15605 Background: Actionable biomarkers have a prominent role in frontline decision-making for pts with metastatic colorectal cancer (CRC). Strategies targeting the EGFR/HER2, KRAS/BRAF, and PD-1/PD-L1 pathways are now being combined with chemotherapy with new approvals and active trials. Here, we explore relationships between actionable biomarkers and molecularly-matched therapies versus other therapies given in 1st line and how actionability evolves in later lines. Methods: We analyzed outcomes and NGS results across 533 pts from the Know Your Biomarker initiative and Perthera’s real-world evidence database. Actionability in a 1st line context was analyzed retrospectively and prospectively in multiple settings via the Perthera Report. Progression-free survival (PFS) was evaluated from initiation of 1st line for advanced disease until discontinuation due to disease progression. Hazard ratios and p-values were computed via Cox regression when comparing PFS on subsets (n=161) who received either a 1st line regimen including any biomarker-based molecularly-targeted agent versus a standard triplet (FOLFOXIRI) or doublet (FOLFOX or FOLFIRI). Frequencies of other genomic alterations with actionability for later lines of therapy were analyzed in the context of prospectively ranked therapy options. Results: Overall actionability for upfront biomarkers in CRC was 54% (287 / 533) including MSI-high (4%), HER2-positive (4%), KRAS G12C (4%), BRAF V600 (4%), and RAS/RAFwt (38%). Median PFS on a biomarker matched therapy was significantly longer than either FOLFOX or FOLFIRI (p<0.05) but not FOLFOXIRI (Table). Ranked therapy options were prospectively provided at any line of therapy and 33 pts who initiated a new therapy post-report often received the #1 (58%), #2 (18%), #3 (6%) or lower (18%) ranked options based on actionability guidance. Conclusions: Upfront biomarker testing is increasingly important in CRC and the initial results from this real-world initiative further support the clinical utility of molecularly-matched therapies; however, the rapidly evolving treatment landscape for chemotherapy combinations (+/- other agents) is a challenge for trial design. Median PFS (months) on 1st line therapies in CRC for actionable biomarker-matched therapies versus typical chemotherapy (+/- VEGFi) triplets or doublets. Therapy Subgroup mPFS [95% CI] on 1st line (# pts) Biomarker Matched 28.4m [18.7-N/R] (n=32) FOLFOXIRI 30.6 [15.2-N/R] (n=22) FOLOX or FOLFIRI 11.0 [8.0-20.9] (n=107)