**2.2 Predictive markers**

According to Komori et al., colorectal cancer patients who showed early decrease in carbohydrate antigen 19-9 (Ca19-9) levels had significantly longer PFS after regorafenib than individuals in whom this marker remained elevated (3.7 vs. 2.0 months). Multivariate analysis confirmed that early decrease in Ca19-9 level was a significant independent predictor of better response to regorafenib [6].

The authors of the CORRECT study analyzed an association between mutational status of the tumor and survival. The study demonstrated that the presence of KRAS-wild type and PIK3CA-wild type in primary tumor was a biomarker of PFS benefit [7]. In another study, conducted by Ma et al., the lack of EGFR expression turned out to be associated with longer PFS and OS (14 vs. 2.5 months and 19.7 vs. 9.6 months, respectively). While the presence of KRAS-wild type correlated with

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*Further Therapeutic Options in Heavily Pretreated Colorectal Cancer Patients*

observed in the case of the left-sided malignancies [8].

of patients treated with this anticancer agent [14].

presented with a high-grade AST elevation [12].

relatively rarely observed in regorafenib-treated patients [16].

**2.4 Regorafenib combined with other anticancer agents**

transcription (JAK-STAT) signaling pathway [19].

longer OS, no significant association was found between this biomarker and PFS [8]. Furthermore, multivariate analysis documented prognostic value of tumor's location in the right or left side of the abdominal cavity, with better prognosis

regorafenib therapy seems to be a novel radiological predictor of PFS [9].

Adverse event (AE) profile of regorafenib is similar as in the case of other tyrosine multikinase inhibitors, and the AEs of this agent are generally manageable. The most common non-hematological toxicity, which may worsen patient's quality of life, is hand-foot skin reaction (HFSR) (54%) [10–12]. Hence, many patients who experienced this AE may require treatment modification [10]. Interestingly, the incidence of HFSR seems to vary by primary tumor type. According to literature, HFSR symptoms can be found in up to 50% of regorafenib-treated patients with hepatocellular carcinoma, 60.2% of individuals with GIST, and 46.6% of persons with metastatic colorectal cancer [11]. The second most common AE in regorafenib-treated patients is arterial hypertension. Based on the data from five clinical trials, the overall incidence of arterial hypertension in regorafenib-treated patients can be estimated at 44.4% and the incidence of high-grade (G3 and higher) hypertension at 12.5%. Similar to HFSR, the risk of this AE seems to vary according

Treatment with regorafenib may also contribute to all-grade hepatotoxicity (bilirubin, AST, ALT, and ALP elevation), an AE observed in approximately one-third

Other AEs frequently associated with regorafenib treatment are oral mucositis, fatigue, nausea, weight loss, and diarrhea [12, 15]. All-grade anorexia was shown to occur more often in patients who had been previously treated with tyrosine multikinase inhibitors. On the other hand, patients from this group less commonly

The incidence of hematologic toxicities, such as thrombocytopenia, anemia, neutropenia, and leukopenia, varies between 22% (thrombocytopenia) and 13% (leukopenia). However, high-grade (G3 or higher) hematologic toxicities are

In a phase I study, regorafenib combined with an anti-VEGF inhibitor, cetuximab, provided a clinical benefit, defined as the presence of stable disease or partial response. However, these promising preliminary findings need to be verified in

Combination therapy with regorafenib and FOLFIRI produced highly promising results, with overall disease control rate (DCR), median PFS, and median OS equal to 58.5%, 6.0 and 12.0 months, respectively [8]. An objective response rate to regorafenib combined with modified FOLFOX (mFOLFOX6) as the first-line treatment was no better than that observed in historical controls, with 85.4% DCR and median PFS of 8.5 months [18]. Negative results, specifically the lack of either OS or PFS benefit, were obtained in a study investigating the efficacy and toxicity of regorafenib plus ruxolitinib, a Janus kinase/signal transducer and activator of

RECIST 1.1 is an established instrument to assess a response to anticancer treatment based on radiologically determined cumulative diameter of target lesions. Cavitation of lung metastases assessed on CT scans at the baseline and at 8 weeks of

*DOI: http://dx.doi.org/10.5772/intechopen.85027*

**2.3 Toxicity**

to tumor type [13].

future studies [17].
