Efficacy and circulating protein biomarkers of second-line aflibercept plus FOLFIRI according to prior bevacizumab or cetuximab treatment in advanced colorectal cancer (KCSG CO21-21).

초록

Background: Prospective data evaluating second-line aflibercept plus FOLFIRI according to prior bevacizumab (BEV) or cetuximab (CET) exposure and incorporating circulating protein biomarkers remain limited. Methods: This open-label, single-arm, nationwide phase II study (NCT04810585) evaluated aflibercept plus FOLFIRI as second-line with stratification by prior BEV or CET exposure. Seventeen circulating biomarkers were measured by ELISA at baseline and before cycle 4 and analyzed for associations with PFS and OS using Cox models. Plasma proteins were processed using a single-pot solid-phase enhanced SP3 protocol followed by tryptic digestion and analyzed by data-independent acquisition liquid chromatography tandem mass spectrometry, with protein identification and quantification performed using DIA-NN. Results: A total of 159 patients were enrolled (prior BEV, n=83; prior CET, n=76). mPFS was 7.5 months (95% CI, 6.8–8.4), and mOS was 14.4 months (95% CI, 12.9–16.0), with no significant differences by prior biologic therapy (mOS: 13.8 vs 14.7 months for prior BEV vs CET; mPFS: 7.4 vs 7.5 months). Among 146 evaluable patients, the ORR was 28.1% (1 CR [0.7%], 40 PR [27.4%]), and the DCR was 88.4%. The most common TRAEs were proteinuria (47.1%; grade ≥3, 14.0%), neutropenia (43.4%; grade ≥3, 37.5%), nausea (27.2%), and fatigue (24.3%). Baseline PlGF (PFS HR 2.04, q=0.008; OS HR 2.86, q<0.001), IL-8 (PFS HR 1.87, q=0.008; OS HR 2.13, q=0.002), TIMP-1 (PFS HR 1.74, q=0.021; OS HR 3.49, q<0.001), and VEGF-A (PFS HR 1.74, q=0.021; OS HR 1.91, q=0.009) were independently associated with inferior PFS and OS, whereas on-treatment and C1-to-C4 biomarker ratios showed no associations. Enrichment of inflammation/immune related proteins S100A8 (log2 FC -0.41; p=0.037) and MPO (log2 FC -1.51; p=0.006), as well as lipid metabolism related proteins APOC3 (log2 FC -0.58; p <0.001) and APOC2 (log2 FC -0.47; p=0.003), was observed in patients with prior BEV at baseline. Enrichment of PIGR (log2 FC -1.21; p<0.001) and OLFM1 (log2 FC -0.66; p-value <0.001) was observed in PD patients at C4, while SERPINF1 (log2 FC 0.33; p= 0.003) and FETUB (log2 FC 0.41; p=0.013) were enriched in PR+CR patients at C4. Further, PIGR expression increased 1.30-fold in PD patients (mean log2Δ (C4-C1) = 0.38), compared to a relatively stable expression in PR patients (mean log2Δ(C4-C1) = -0.076, p=0.033). Increased PIGR expression at C4 showed an association with inferior OS in Cox models (HR 1.92, p=0.004). Conclusions: Clinical outcomes and safety profiles of aflibercept plus FOLFIRI were comparable regardless of prior BEV or CET exposure. Elevated baseline PlGF, IL-8, TIMP-1 and VEGF-A levels were associated with shorter PFS and OS. Exploratory plasma proteomics identified dynamic PIGR expression as a response-associated biomarker linked to inferior OS. Clinical trial information: NCT04810585.