PD-12 Characterization of best responder patients to oxaliplatin rechallenge in patients with refractory metastatic colorectal cancer (mCRC)

Oxaliplatin in combination with fluoropyrimidines constitute one of the most effective treatments in front-line mCRC patients. Rechallenge with oxaliplatin-based regimens in the refractory setting is practiced although based on scarce and heterogeneous evidence. Further clinical and molecular data to determine which patients do benefit from this treatment strategy are needed. We analyzed all patients treated with oxaliplatin in a third- or fourth-line setting in our institution between 2015 and 2021. Outcomes were analyzed with overall response rate (ORR), disease control rate (DCR) and median progression free survival (mPFS). The best-responders group was defined-as those patients who achieved mPFS > 6 months. As part of the descriptive analysis, we divided patients into three clinical groups according to the prognostic characteristics previously reported: Good Prognostic Characteristics (GPC) defined as having passed ≥18 months since metastatic disease debut, < 3 metastatic sites and presence of liver metastasis, Best Prognostic Characteristics (BPC) defined as ≥18 months since metastatic disease debut, < 3 metastatic sites and absence of liver metastases and Poor Prognostic Characteristics (PPC) defined as < 18 months since metastatic disease debut and/or with ≥3 metastatic sites. An Amplicon-seq panel was used to analyze regions of interest in 61 genes using an Illumina sequencing platform. A total of 102 out of 735 mCRC patients (13,9%) were analyzed. Median age was 57.3 year and 55% were male. The outcomes were as follows: ORR 12%, DCR 39%, and mPFS 4.0 months (CI95% 3.29-5.03). Of note, 28 patients (27%) had a mPFS > 6 months with rechallenge (range from 6.57 to 14.2 months) and constituted the best-responders group. Data of prognostic characteristics and molecular alterations are available for 19 of these patients. The prognostic subgroup classification was as follows: 9 patients (47.4%) PPC, 5 patients (26.3%) GPC, and 5 (26.3%) BPC. Most frequent molecular alterations were: APC (68.4%), TP53 (63%), RAS (47.4%), and PIK3CA (21%). Concomitant APC and TP53 mutations were detected in 47.4% of patients. No associations between prognostic characteristics and molecular alterations were observed. This study suggests that rechallenge with oxaliplatin can achieve a clinically meaningful mPFS > 6 months in 27% of patients. No enrichment in GPC and BPC was observed. APC, TP53 and RAS detected in this best-responders group are the major tumour genes which are frequently mutated in mCRC. A more extensive molecular analysis should be carried out to better characterise the patients who benefit the most from this treatment strategy.