Proactive strategies for regorafenib in metastatic colorectal cancer: implications for optimal patient management

Abstract

Regorafenib is a broad-spectrum oral multikinase inhibitor that targets several angiogenic, oncogenic, and stromal receptor tyrosine kinases that support the tumor microenvironment. Results from the pivotal Phase III Patients with Metastatic Colorectal Cancer Treated with Regorafenib or Placebo After Failure of Standard Therapy (CORRECT) trial showed that the addition of regorafenib to best supportive care resulted in a significant improvement in median overall survival and progression-free survival compared with placebo plus best supportive care in patients with metastatic colorectal cancer (mCRC) following all available approved therapies. Thus, regorafenib is the first oral multikinase inhibitor indicated for mCRC; it currently has approval in the USA, EU, Japan, Canada, and Singapore for the treatment of mCRC patients who have been previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti-vascular endothelial growth factor therapy, and, if the tumor is KRAS wild-type, an anti-epidermal growth factor receptor therapy. In this review, we highlight regorafenib’s mechanism of action, present key efficacy data from the CORRECT trial, and discuss how to proactively manage common adverse events (eg, hand-foot skin reaction, hypertension, oral mucositis, diarrhea, and fatigue) experienced by patients receiving regorafenib. Increased awareness of potential adverse events associated with regorafenib and the implementation of proactive strategies to prevent, monitor, and manage these events early in the course of treatment will be instrumental in ensuring optimal patient management and continuation of regorafenib therapy.

Mutational analysis of genes coding for cell surface proteins in colorectal cancer cell lines reveal novel altered pathways, druggable mutations and mutated epitopes for targeted therapy

“…Different FGFR specific inhibitors are currently under development [ 40 ], and further evaluation of their activity in the subset of colorectal cancer with FGFR/FGFRL1 alterations should be pursued. Moreover, Regorafenib, a multi-kinase inhibitor that targets FGFR1 among other RTKs, was recently approved by the FDA for the treatment of advanced colorectal cancer [ 41 ], but predictive biomarkers for this indication are not yet currently available.…”

Third- or Later-line Therapy for Metastatic Colorectal Cancer: Reviewing Best Practice

“…These expert opinions are based on the prescribing information, clinical study data, and clinical practice guidelines, which state that regorafenib monitoring should be carried out weekly during the first 2 cycles of treatment and monthly thereafter, 75 with special attention to toxicities detected during prior cycles to prevent their worsening. 63,75,76 Similarly, trifluridine/tipiracil monitoring should be weekly or biweekly following treatment initiation. 8,27 Expert opinions from Korea and France describe a slightly different approach to patient monitoring in their clinics, with weekly followup only during the first cycle of treatment.…”

An update on the safety and efficacy of regorafenib in the treatment of solid cancers

“…A recently published safety analysis from the CORRECT study found that the occurrence of these commonly encountered toxicities tend to peak in terms of severity during the earlier treatment cycles, and then became stable in later cycles [27]. Therefore, these common toxicities do not appear to be cumulative and should be manageable with the increasing availability of consensus guidelines on supportive treatment and prevention [28,29]. For instance, in the CORRECT study, 32% of regorafenib-treated patients experienced HFSR during cycle 1, but the incidence dropped to only 5% in cycle 8, suggesting that discontinuation due to this toxicity can be avoided with preemptive dermatological treatment and dose modifications [29].…”

“…Therefore, these common toxicities do not appear to be cumulative and should be manageable with the increasing availability of consensus guidelines on supportive treatment and prevention [28,29]. For instance, in the CORRECT study, 32% of regorafenib-treated patients experienced HFSR during cycle 1, but the incidence dropped to only 5% in cycle 8, suggesting that discontinuation due to this toxicity can be avoided with preemptive dermatological treatment and dose modifications [29]. In the USA FDA review of regorafenib, the mean exposure of M2 and M5 were higher in patients older than 65 years of age in Phase I studies [16].…”

“…Rarely, regorafenib can be associated with serious liver toxicity, as one case of fatal liver failure that was attributed to regorafenib was reported in the GRID study. This highlights the importance of monitoring liver function during the first few months of therapy [28,29]. In the product label for regorafenib, the liver function test should be monitored every 2 weeks during the first 2 months of therapy, and the frequency of monitoring should be increased to weekly if elevation in liver function tests is encountered until the level returns to less than three times the upper limit of normal or the baseline.…”