LAUSR

Purpose: Most mCRC patients harbor MSS disease without inherent immunogenicity. The METIMMOX study (NCT03388190) explored an unconventional concept, that patients with previously untreated, unresectable abdominal metastases from MSS-CRC may achieve therapeutic efficacy from short-course oxaliplatin-based chemotherapy (FLOX) and sequential ICB (nivolumab). Among study patients who were assigned this highly experimental treatment, 15% obtained long-lasting complete response and more than a half met an early occurring radiologic signal of ICB responsiveness predicting significantly extended progression-free survival (PFS) compared to study control arm patients given standard FLOX chemotherapy [PMID: 36229579]. The aim of the present study was to verify if systemic tumor-defeating immunity had been invoked by the short-course FLOX treatment in the responding patients. The fms-related tyrosine kinase-3 ligand (Flt3L) is a circulating factor that reflects the direct cytotoxic effects of chemotherapy and also activates dendritic cells that present the shed tumor antigens to tumor-targeting T-cells. Procedures: Study patients were randomly assigned to the control arm of FLOX (oxaliplatin 85 mg/m2 on day 1 and bolus 5-fluorouracil 500 mg/m2 and folinic acid 100 mg on days 1 and 2) Q2W or the experimental arm of repeat sequential cycles of 2 FLOX Q2W and 2 nivolumab (240 mg) Q2W. Radiologic response assessment was done every 8 weeks with PFS as the primary endpoint. Patients were categorized into those with target lesion (TL) reduction of ≥10% or <10% at the first post-baseline assessment (8 weeks) [PMID: 36229579]. Serum Flt3L was measured at baseline and following the initial 2 FLOX cycles (at 4 weeks) using a Luminex assay. Results: For all subjects, median Flt3L was 103.8 pg/ml (range 24.6-306.1) at baseline and 162.4 pg/ml (range 53.3-503.8) at 4 weeks. For the experimental arm patients (n = 34), the higher 4-week Flt3L level, the deeper overall radiologic response (rho = -0.39, p = 0.022, Spearman correlation). The 4-week Flt3L level was higher in patients who obtained ≥10% TL reduction (n = 18; median 233.5 pg/ml, range 94.9-466.7) than in those who did not meet this 8-week predictive signal of extended PFS (n = 16; median 161.9 pg/ml, range 53.3-374.8; p = 0.022, Mann-Whitney U test). Selecting a 160 pg/ml cut-off, patients with 4-week Flt3L values above (n = 21) obtained longer PFS (median of 13.6 months, 95% CI 7.6-19.7) than those with serum values below (n = 13; median PFS of 5.9 months, 95% CI 2.4-9.3; p = 0.046, log-rank test). Conclusions: High circulating Flt3L after initial short-course FLOX chemotherapy, as a proxy of invoked tumor-defeating immunity, was associated with an early radiologic signal of ICB responsiveness and improved PFS in patients with MSS-mCRC. Citation Format: Sebastian Meltzer, Kjersti Flatmark, Anniken J. Fuglestad, Hanne M. Hamre, Christian Kersten, Eva Hofsli, Marianne G. Guren, Halfdan Sorbye, Anne Negård, Anne Hansen Ree. Systemic immune response invoked by short-course oxaliplatin-based chemotherapy (FLOX) for efficacy of sequential immune checkpoint blockade (ICB; nivolumab) in microsatellite-stable (MSS) metastatic colorectal cancer (mCRC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3279.