397P Early decreases in KRAS mutant allele frequency (MAF) predicts clinical benefit to the PLK1 inhibitor onvansertib in combination with FOLFIRI/bev in 2L treatment of metastatic colorectal carcinoma (mCRC)

Patients (pts) with mCRC have few treatment options and poor outcome, particularly those with KRAS mutation (mKRAS). After failure of 1L treatment, the ORR for FOLFIRI/bev is 5-13%, with PFS 4-6 mos, and OS 10-12 mos. Onvansertib (Onv), is a highly specific PLK1 inhibitor, currently being investigated in combination with FOLFIRI/bev in 2L treatment of mKRAS mCRC (NCT03829410). Preliminary results indicate that Onv+ FOLFIRI/bev is well tolerated and efficacious (Lenz et al, JCO 2022). We investigated the utility of measuring early changes of KRAS MAF, using liquid biopsies, to predict clinical benefit to Onv+FOLFIRI/bev. In the phase Ib/II, pts were treated with Onv (Days 1-5 and 15-19) in combination with FOLFIRI/bev (Days 1 and 15) of each 28-day cycle. Efficacy endpoints included ORR (RECIST v1.1) and PFS. Blood samples were collected at baseline and after 1st cycle to measure KRAS MAF in circulating tumor DNA (ctDNA) by digital droplet PCR and analyze the association between KRAS MAF changes and clinical efficacy (ORR and PFS). As of 05-Apr-2022, 48 pts were evaluable for efficacy: 17 (35%) pts had a response (1CR, 16PR), including 14 (29%) confirmed responses (1 CR, 13 PR). Median PFS was 9.4 mos (CI: 7.6- NR), with 7 pts still on treatment at data cutoff. Using clinical data from 29 pts (data cutoff 02-Jul-2021), a ROC analysis identified a decrease in KRAS MAF of ≥90% after the 1st cycle of treatment as the optimal threshold for predicting radiographic response (PR/CR). As of 05-Apr-2022, pts with a decrease in KRAS MAF of ≥90% (n=22) versus pts with <90% reduction (n=23) had a significantly greater ORR of 64% versus 9% (OR=16.2 [CI 3.5-131.4], p=0.00014) and longer PFS of 15.1 mos (CI: 9-NR) versus 7.1 mos (CI: 5.3-11.1; p=0.005). Onv+FOLFIRI/bev shows promising efficacy compared to historical control of FOLFIRI/bev for 2L mKRAS mCRC. Stratification of pts based on KRAS MAF changes in ctDNA after 1 treatment cycle identified a subset of pts (∼50%) with increased clinical benefit (ORR and PFS). This data supports the use of KRAS MAF changes in liquid biopsies as a response biomarker to Onv+FOLFIRI/bev in future clinical studies.