<div>AbstractPurpose:<p>FOLFOX, FOLFIRI, or FOLFOXIRI chemotherapy with bevacizumab is considered standard first-line treatment option for patients with metastatic colorectal cancer (mCRC). We developed and validated a molecular signature predictive of efficacy of oxaliplatin-based chemotherapy combined with bevacizumab in patients with mCRC.</p>Experimental Design:<p>A machine-learning approach was applied and tested on clinical and next-generation sequencing data from a real-world evidence (RWE) dataset and samples from the prospective TRIBE2 study resulting in identification of a molecular signature, FOLFOX<i>ai</i>. Algorithm training considered time-to-next treatment (TTNT). Validation studies used TTNT, progression-free survival, and overall survival (OS) as the primary endpoints.</p>Results:<p>A 67-gene signature was cross-validated in a training cohort (<i>N</i> = 105) which demonstrated the ability of FOLFOX<i>ai</i> to distinguish FOLFOX-treated patients with mCRC with increased benefit from those with decreased benefit. The signature was predictive of TTNT and OS in an independent RWE dataset of 412 patients who had received FOLFOX/bevacizumab in first line and inversely predictive of survival in RWE data from 55 patients who had received first-line FOLFIRI. Blinded analysis of TRIBE2 samples confirmed that FOLFOX<i>ai</i> was predictive of OS in both oxaliplatin-containing arms (FOLFOX HR, 0.629; <i>P</i> = 0.04 and FOLFOXIRI HR, 0.483; <i>P</i> = 0.02). FOLFOX<i>ai</i> was also predictive of treatment benefit from oxaliplatin-containing regimens in advanced esophageal/gastro-esophageal junction cancers, as well as pancreatic ductal adenocarcinoma.</p>Conclusions:<p>Application of FOLFOX<i>ai</i> could lead to improvements of treatment outcomes for patients with mCRC and other cancers because patients predicted to have less benefit from oxaliplatin-containing regimens might benefit from alternative regimens.</p></div>
<p>Kaplan Meier estimates of progression-free survival in the pMMR population (optimized cut-point), according to IO status (a) and to both IO status and treatment arm (b).Legend: HR: hazard ratio, NR: not reached. Control arm indicates FOLFOXIRI plus bevacizumab. Atezo arm indicates FOLFOXIRI plus bevacizumab and atezolizumab.</p>
<p>Kaplan Meier estimates of progression-free survival in the overall population (optimized cut-point), according to IO status (a) and to both IO status and treatment arm (b). Legend: HR: hazard ratio, NR: not reached. Control arm indicates FOLFOXIRI plus bevacizumab. Atezo arm indicates FOLFOXIRI plus bevacizumab and atezolizumab.</p>
<p>Kaplan Meier estimates of progression-free survival in the pMMR population (optimized cut-point), according to IO status (a) and to both IO status and treatment arm (b). Legend: HR: hazard ratio, NR: not reached. Control arm indicates FOLFOXIRI plus bevacizumab. Atezo arm indicates FOLFOXIRI plus bevacizumab and atezolizumab.</p>
