Comparative effectiveness of oxaliplatin or irinotecan rechallenge vs standard third-line therapies in patients with metastatic colorectal cancer.

Abstract

79 Background: Following first- (1L) and second-line (2L) treatment including a fluoropyrimidine, oxaliplatin, irinotecan, anti-VEGF, and anti-EGFR treatment (for KRAS/NRAS/BRAF wild-type patients), standard third-line (3L) treatments for metastatic colorectal cancer include trifluridine-tipiracil +/- bevacizumab, regorafenib, or fruquintinib. We aimed to compare the effectiveness of 3L chemotherapy rechallenge with an oxaliplatin or irinotecan-based regimen compared to standard 3L systemic treatment. Methods: We performed a retrospective cohort study using the US-based, electronic health record-derived Flatiron Health Research Database, comprising de-identified patient-level structured and unstructured data from ~280 cancer clinics curated via technology-enabled abstraction. Patients ≥18 years old who received 1L chemotherapy including oxaliplatin or irinotecan, 2L chemotherapy including oxaliplatin or irinotecan (whichever the patient had not received in the 1L), and who initiated a 3L treatment consisting of either chemotherapy rechallenge with the same backbone used in the 1L or standard 3L therapy including trifluridine-tipiracil +/- bevacizumab, regorafenib, or fruquintinib were eligible. Patients with documented mismatch repair deficiency or microsatellite instability-high status, BRAF V600E alterations, bilirubin > 3x the upper limit of normal, and those who received triplet chemotherapy (FOLFIRINOX) in the 1L setting were excluded. Multiple imputation with chained equations imputed missing values for prespecified covariates (age, sex, tumor sidedness, KRAS/NRAS status, CEA, performance status, duration of 1L therapy, time from end of 1L irinotecan or oxaliplatin to start of 2L therapy and 3L therapy, largest gap in systemic therapy and 1L chemo backbone). Cox proportional hazards modeling with multivariable adjustment examined the association of chemo rechallenge vs standard 3L therapy with overall survival. Results: 2,199 patients met inclusion criteria: 714 underwent chemotherapy rechallenge and 1,485 underwent standard 3L treatment (291 received trifluridine-tipiracil + bevacizumab). Patients who received chemotherapy rechallenge had a 20% reduced hazard of death that was statistically significant (HR 0.80; 95% CI 0.71 – 0.89; p < 0.001) following multivariable adjustment. When compared to patients who received trifluridine-tipiracil + bevacizumab, there was no benefit to chemotherapy rechallenge (HR 1.00; 95% CI 0.83 – 1.19; p =0.96). Conclusions: While we observed a benefit to chemotherapy rechallenge compared to any standard 3L therapies, no benefit was observed when the comparison was limited to trifluridine-tipiracil + bevacizumab. Ongoing work will examine predictive biomarkers for chemotherapy rechallenge in the 3L+ setting.