Regorafenib is an oral tyrosine kinase inhibitor (TKI) approved for patients with treatment-refractory metastatic colorectal cancer (mCRC), advanced gastrointestinal stromal tumors (GISTs) after imatinib and sunitinib, and unresectable hepatocellular carcinoma (HCC) following sorafenib. This article will introduce the effect of regorafenib among the above three diseases^[1].

Figure 1 Mechanism of Regorafenib^[2]

mCRC

The mainstay of mCRC treatment is combination chemotherapy with an antiepithelial growth factor receptor (EGFR)-targeted monoclonal antibody or an antiangiogenic agent (i.e. bevacizumab), taking RAS/BRAF status and primary tumor location into consideration.

Phase 3 trials and observational cohort studies demonstrated that most patient mCRC subgroups had improved survival with regorafenib and about 20% achieved an extended progression-free survival (PFS) benefit >4 months. Although there are currently no genetic or protein biomarkers to predict response to regorafenib in mCRC, evidence suggests that previous exposure to targeted therapy is associated with poorer outcome. Notably, in CORRECT, all patients received prior bevacizumab and 52% received prior anti-EGFR therapy versus 41% and 35%, respectively, in CONCUR, which may contribute to the greater OS benefit in CONCUR. More recently, a single-arm, phase 2b study evaluating regorafenib in antiangiogenic-na?ve patients with chemotherapy-refractory, advanced CRC reported a median PFS and OS of 3.5 and 7.4 months, respectively, consistent with CONCUR, but comparing favorably with CORRECT. In the randomized, phase 2 REVERCE study, previously treated patients with mCRC receiving regorafenib followed by cetuximab (plus irinotecan) had better survival outcomes versus cetuximab followed by regorafenib, supporting the rationale for introducing regorafenib earlier in the treatment sequence. 

GISTs

Imatinib followed by sunitinib are standard systemic therapies for unresectable or metastatic GIST; however, most patients develop resistance within a few years. In GRID, regorafenib showed a statistically significant improvement in PFS versus placebo (4.8 vs 0.9 months; HR = 0.27; P < 0.0001) in advanced GIST following imatinib and sunitinib. These benefits were observed across all subgroups, including treatment line, duration of previous imatinib/sunitinib therapy, age, and Eastern Cooperative Oncology Group performance status (ECOG PS). PFS benefit was observed in patients with the two most common primary KIT mutations, exon 11 (HR = 0.21; 95% CI 0.10–0.46) and exon 9 (HR = 0.24; 95% CI 0.07–0.88). Another smaller phase 2 study (NCT01068769) suggested a benefit in patients with exon 17 mutations (a subtype of GIST resistant to imatinib and sunitinib) based on a matched historical control comparison. These results are clinically important in GIST because primary/secondary KIT mutations are commonly associated with resistance to standard TKIs. Long-term follow-up over a median of 41 months also revealed durable benefit of regorafenib in KIT/PDGFRA wild-type GIST and high expression of proteins involved in angiogenesis, including VEGF; therefore, potent VEGF inhibition may provide an important disease control mechanism.

Since cancer stem cells play a role in targeted drug resistance, using an alternating regimen of imatinib and regorafenib with short drug-free intervals may permit tumor stem cells to re-enter the cell cycle and become susceptible to therapy again, potentially overcoming resistance. Furthermore, targeting resistant mutations earlier may lead to improved outcomes. A phase 2, randomized trial (ALT GIST) is underway to determine whether alternating imatinib and regorafenib improves disease control in advanced GIST versus first-line imatinib alone.

HCC

Regorafenib was the first agent to show survival benefits in patients with HCC progressing on sorafenib in the phase 3 RESORCE trial, following several failed phase 3 trials. Regorafenib significantly improved OS versus placebo (median OS: 10.6 vs 7.8 months, respectively; HR = 0.62; P < 0.0001 [updated OS analysis]), reduced the risk of progression or death, prolonged median time-to-progression (TTP), and improved disease control rate (DCR; all P < 0.0001 vs placebo). Benefits were maintained across all stratified subgroups, including age, ECOG PS (0/1), Child–Pugh score (A5/A6), alpha-fetoprotein level (< 400/≥ 400 ng/mL), presence of extrahepatic disease and/or macrovascular invasion, hepatitis B or C, or history of alcohol use. No patient receiving regorafenib or placebo achieved complete response, while 7% versus 3% achieved partial response by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, respectively. The proportion of patients with stable disease for ≥ 6 weeks was 59% versus 32% (regorafenib vs placebo; RECIST v1.1). By comparison, as per modified RECIST (mRECIST), 11% of regorafenib-treated patients achieved an objective response rate (1% complete response; 10% partial response) and 54% achieved stable disease. Notably, PFS and TTP outcomes were similar when assessed by RECIST v1.1 or mRECIST. Exploratory subgroup analyses of RESORCE showed a consistent OS benefit for regorafenib, irrespective of prior sorafenib dose (including duration of sorafenib and median OS by last sorafenib dose [800 vs < 800 mg/day]), as well as pattern of progression under sorafenib, a factor identified as predictive of outcome. An exploratory analysis of RESORCE revealed a median OS of 26.0 months (regorafenib) versus 19.2 months (placebo) from time of sorafenib initiation. Differences in protein expression between regorafenib and sorafenib, including downregulation of proteins involved in angiogenesis, metabolism, cell cycle regulation, and apoptosis following exposure to sorafenib (but not regorafenib), may explain the anti-tumor effects of regorafenib in sorafenib-refractory patients. An exploratory analysis of predictive biomarkers suggested an association between expression patterns of plasma proteins and microRNAs and OS in patients with HCC following regorafenib in RESORCE, and showed that regorafenib treatment benefit for OS and TTP was independent of alpha-fetoprotein and c-Met levels.

References

[1] Evolving role of regorafenib for the treatment of advanced cancers. DOI:10.1016/j.ctrv.2020.101993

[2] Experience with regorafenib in the treatment of hepatocellular carcinoma. Therapeutic Advances in Gastroenterology. 2021;14.