Purpose: FOLFOX, FOLFIRI, or FOLFOXIRI chemotherapy with bevacizumab (BV) are considered standard 1^st line treatment options for patients with metastatic colorectal cancer (mCRC). We developed and validated a molecular signature predictive of efficacy of oxaliplatin-based chemotherapy combined with BV in patients with mCRC. Experimental Design: A machine-learning approach was applied and tested on clinical and NGS data from a real-world evidence (RWE) data set and samples from the prospective TRIBE2 study resulting in identification of a molecular signature – FOLFOXai. Algorithm training considered time-to-next-treatment (TTNT). Validation studies used TTNT, PFS and overall survival (OS) as the primary endpoints. Results: A 67 gene signature was cross-validated in a training cohort (N=105) which demonstrated the ability of FOLFOXai to distinguish FOLFOX-treated mCRC patients with increased benefit (IB) from those with decreased benefit (DB). The signature was predictive of TTNT and OS in an independent RWE dataset of 412 patients who had received FOLFOX/BV in 1^st line and inversely predictive of survival in RWE data from 55 patients who had received 1^st line FOLFIRI. Blinded analysis of TRIBE2 samples confirmed that FOLFOXai was predictive of OS in both oxaliplatin-containing arms (FOLFOX HR=0.629, p=0.04 and FOLFOXIRI HR=0.483, p=0.02). FOLFOXai was also predictive of treatment benefit from oxaliplatin-containing regimens in advanced esophageal/gastro-esophageal junction cancers (EC/GEJC) as well as pancreatic ductal adenocarcinoma (PDAC).

Conclusions: Application of FOLFOXai could lead to improvements of treatment outcomes for patients with mCRC and other cancers since patients predicted to have less benefit from oxaliplatin-containing regimens might benefit from alternative regimens.