Tumor load change as a functional biomarker for prognosis and treatment modulation in metastatic colorectal cancer (mCRC): Individual patient data (IPD) analysis of 12 randomized trials.

3561 Background: The use of overall response rate (ORR) and progression-free survival (PFS) as surrogacy of overall survival (OS) has limitations in mCRC. Change in tumor load (ΔTL; tumor burden at progressive disease [PD] vs baseline) at treatment failure may reflect tumor aggressiveness and resistance biology. We evaluated the prognostic value of ΔTL in mCRC using IPD from twelve randomized first-line trials. Methods: IPD from ATEZOTRIBE, FIRE3, FIRE4, FIRE4.5, MACBETH, ML22011, MOMA, PANAMA, TRIBE, TRIBE2, TRIPLETE, and VALENTINO were pooled. ΔTL was defined as the ratio of the sum of longest target lesion diameters at PD vs baseline, per RECIST. Primary endpoint was OS; secondary endpoints included post-progression survival (PPS). Estimated marginal means were controlled for treatment type. Associations between ΔTL and outcomes were assessed using Cox models adjusted for prespecified baseline tumor burden and clinical covariates (ECOG, age, sex, sidedness, RAS/BRAF status, metastatic patterns, previous therapies). Incremental prognostic value beyond early tumor shrinkage (ETS) and depth of response (DpR) was assessed using likelihood ratio testing. Effect modification by treatment regimen was evaluated using ΔTL × treatment interaction terms for EGFR- vs VEGF-based therapy and for triplet vs doublet-chemotherapy across trials. Results: A total of 4852 patients evaluable for ΔTL were included. Mean ΔTL was 0.63 (SD 0.45) and significantly lower in patients receiving EGFR- vs VEGF-based therapy (0.58 vs 0.66, p<0.001) and triplet vs doublet chemotherapy (0.57 vs 0.67, p<0.001). Lower ΔTL (lower tumor load at PD vs baseline) was associated with better OS (HR 0.58 [95% CI 0.55–0.61], p<0.001) and PPS (HR 0.65 [0.61–0.69], p<0.001) after adjustment for baseline tumor burden and clinical covariates. For OS, ΔTL added prognostic information beyond ETS (likelihood ratio χ² = 282.13, p<0.001) and DpR (likelihood ratio χ² = 121.91, p<0.001). Lower ΔTL was associated with improved OS in patients receiving EGFR- (n = 1609; HR 0.62 [0.58–0.67], p<0.001) and VEGF-based therapy (n = 1916; HR 0.39 [0.35–0.43], p<0.001); doublet (n = 2177; HR 0.61 [0.57–0.65], p<0.001) and triplet (n = 1348; HR 0.34 [0.30–0.38], p<0.001) chemotherapy, with significant ΔTL × treatment interaction (VEGF vs EGFR: HR 0.50 [0.46–0.54], p<0.001; triplet vs doublet: HR 0.60 [0.54–0.66], p<0.001) after adjustment for treatment regimen, RAS/BRAF status and other clinical covariates. Conclusions: TL appears to be a strong, independent prognostic marker for OS and PPS in mCRC. ΔTL seems to vary by biologic and chemotherapy intensity, indicating it captures differential treatment effect/resistance not captured by ORR or PFS. Prospective validation as an early, treatment-sensitive prognostic endpoint is warranted.