Dynamics of circulating monomeric C-reactive protein (mCRP) to predict outcomes with first-line alternating oxaliplatin-based chemotherapy and nivolumab in metastatic microsatellite-stable (MSS) colorectal cancer (CRC).

Abstract

3606 Background: Elevated CRP levels at CRC diagnosis are consistently associated with poor outcomes, suggesting a tumor-promoting and potentially immuno-suppressive inflammatory state. The clinically assessed CRP is a pentameric protein that can dissociate to mCRP, an isoform with pro-inflammatory effects on innate immune responses. The randomized METIMMOX trial (NCT03388190) evaluated potentially immunogenic short-course oxaliplatin-based chemotherapy (FLOX) alternating with nivolumab in previously untreated, unresectable metastatic MSS CRC. We investigated whether oxaliplatin-induced immunogenicity is measurable as an early change in circulating mCRP and may identify patients more likely to derive clinical benefit from sequential nivolumab. Methods: Patients were randomly assigned to the control group of FLOX (oxaliplatin, 5-fluorouracil, folinic acid) Q2W or the experimental group of alternating 2 cycles each of FLOX Q2W and nivolumab Q2W with prespecified break periods. The primary endpoint was progression-free survival (PFS). This post hoc analysis included 29 patients from the experimental group, of whom 28 had paired mCRP and clinical CRP measurements from baseline (Pre) and post second FLOX cycle (Post) timepoints. CRP was measured by standard immunoturbidimetry. Plasma mCRP was separated from CRP by 100-kDa filtration and quantified by targeted nano LC-timsTOF Pro mass spectrometry with AQUA standards. CRP at the reference limit 5.0 mg/L and mCRP at the median value 45 ng/mL were used as cutoff values. Changes from Pre to Post were denoted ΔmCRP and ΔCRP and categorized as ³0 (stable/increase) and < 0 (decrease). Results: Low Pre and low Post CRP were associated with prolonged PFS (log-rank p = 0.080 and p = 0. 002, respectively), while ΔCRP showed no association (log-rank p = 0.57). By contrast, a significant association was observed for ΔmCRP (log-rank p = 0.015), where median PFS was longer among the ΔmCRP ≥0 population (16.4 months [95% CI 8.8-23.9]; n = 15) versus the ΔmCRP < 0 population (9.2 months [95% CI 3.6-14.8]; n = 13). Notably, patients with the combination ΔCRP < 0 and ΔmCRP ≥0 ( n = 8) had an undefined median PFS (≥41.6 months) at data cutoff, compared to median PFS 9.2 months (95% CI 1.4-16.9; n = 20) for all other patients (log-rank p = 0.022). Conclusions: Patients with metastatic MSS CRC who exhibited an increase in mCRP and decrease in clinical CRP following the initial 2 chemotherapy cycles of first-line oxaliplatin-based chemotherapy alternating with nivolumab had markedly prolonged PFS. Moreover, increased PFS was observed alongside increased circulating mCRP regardless of change in CRP. These data suggest an early increase in mCRP may be an indicator of immunotherapy-associated efficacy. Clinical trial information: NCT03388190 .