Regorafenib: A narrative drug review : Cancer Research, Statistics, and Treatment

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Drug Review


A narrative drug review

Elamarthi, Prahalad

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Cancer Research, Statistics, and Treatment: Apr–Jun 2022 - Volume 5 - Issue 2 - p 293-301
doi: 10.4103/crst.crst_110_22
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Regorafenib is a multi-kinase inhibitor and targets multiple kinases involved in the pathways promoting tumor growth and angiogenesis.[1234] It has been approved by the United States Food and Drug Administration (US FDA) and the European Medicines Agency (EMA) for the treatment of refractory metastatic colorectal cancer that has progressed on 5-fluorouracil analogs, oxaliplatin, and irinotecan[5678910111213]; metastatic or locally advanced gastrointestinal stromal tumors[14] that have progressed on imatinib and sunitinib; and unresectable hepatocellular carcinoma that has progressed on sorafenib.[15] The purpose of this drug review is to discuss the approved indications of regorafenib as well as the ongoing trials in different cancer types. The review discusses the chemistry, pharmacokinetics, drug interactions, clinical indications, safety profile, and key clinical trials of regorafenib, thus enabling clinicians to get a clear understanding of the drug.


We referred to the data from the US FDA and the EMA drug manual,[1617] PubMed, and UpToDate. Articles published between 2011 and 2021 in English were selected. Out of a total of 65 studies identified, we included 46. The search terms “CRC,” “GIST,” “HCC,” “osteosarcoma,” and “regorafenib” were used. We also performed an extensive Google search for the ongoing trials of regorafenib. A flowchart of the search strategy adopted is presented in Figure 1.

Figure 1:
Flowchart illustrating the search methodology of articles for the regorafenib drug review


Regorafenib inhibits angiogenesis by the combined inhibition of vascular endothelial growth factor receptor 2 and angiopoietin-1 receptor tyrosine kinase (VEGFR2/Tie2). Starting from 2009, the drug has been studied in multiple tumor types. On September 27, 2012, the FDA first approved the use of regorafenib in advanced colorectal cancer and subsequently in advanced gastrointestinal stromal tumors on February 25, 2013. On April 27, 2017, the FDA approved regorafenib for the treatment of advanced hepatocellular carcinoma.


The structure of regorafenib is similar to that of sorafenib. Regorafenib is used as an oral tablet. The details of the chemistry of regorafenib are provided in Table 1. The chemical structure is depicted in Figure 2.

Figure 2:
Chemical structure of regorafenib (Reproduced from the National Center for Biotechnology Information. PubChem Database. Regorafenib, CID=11167602, [accessed on Jan 02, 2022])
Table 1:
Basic chemistry of regorafenib


Regorafenib is a monohydrate. It is insoluble in water and sparingly soluble in acetone. It is slightly soluble in acetonitrile, methanol, ethanol, and ethyl acetate.


Regorafenib inhibits VEGF receptors 1, 2, and 3; rearranged during transfection (RET); platelet-derived growth factor receptor (PDGFR-alpha, beta); receptor tyrosine kinase (KIT); fibroblast growth factor receptor (FGFR1 and 2); angiopoietin-1 receptor (Tie2); discoidin domain-containing receptor 2 (DDR2); Ephrin type-A receptor 2 (Eph 2A); tropomyosin receptor kinase A (TrkA); rapidly accelerated fibrosarcoma (RAF-1); v-RAF murine sarcoma viral oncogene homolog B1 (BRAF); stress-activated protein kinase-2 (SAPK2); protein tyrosine kinase 5 (PTK5); and Abelson murine leukemia virus (Abl).[1234]

It inhibits the colony-stimulating factor-1 receptor (CSF-1R) and reduces tumor-infiltrating macrophages (TAMs) which are a major component of tumor-infiltrating leukocytes and promotes tumor cell occurrence, development, and migration. The role of TAMs in carcinogenesis is documented in tumors such as colorectal cancer (CRC), gastric cancer, hepatocellular carcinoma, and sarcoma.[1819] In pre-clinical models of hepatocellular cancer, sorafenib and regorafenib, although structurally similar, had a different spectrum of activity.[20]



The peak plasma concentration (Tmax) of regorafenib is attained at 4 hours. The mean relative oral bioavailability of the tablet is 69–83%.[16]

Food effect

The drug should be taken as a whole tablet with water at the same time each day after a low-fat meal, that is, a meal containing less than 600 calories, and less than 30% of the calories of the meal should be from fat.[16]


The plasma protein binding of regorafenib is about 99.5%.[16]


Regorafenib is metabolized by the cytochrome P450 3A4 (CYP3A4) and the UDP Glucuronosyltransferase Family 1 Member A9 (UGT1A9) metabolic pathways. The metabolites are M-2 (N-oxide) and M-5 (N-oxide and N-desmethyl).[16]


The mean terminal half-life of regorafenib is 28 hours (range 14–58). The mean half-life of the M2 metabolite is 25 hours (range 14–32), and the mean half-life of the M5 metabolite is 51 hours (range 32–70).[16]


71% of regorafenib is excreted through feces, and 19% is excreted through urine.[16]


Regorafenib is available as an oral tablet dosed at 40 mg.


Regorafenib is orally administered. The tablet should be taken whole with water after a low-fat meal. The drug should preferably be taken every day at the same time. Regorafenib should not be taken twice on the same day for a missed dose from the day before. The FDA-approved dose of regorafenib in patients with colorectal cancer, gastrointestinal stromal tumor, and hepatocellular cancer is 160 mg orally (4 tablets of 40 mg each) daily on days 1–21, with the cycle repeated every 28 days.[51415]


Regorafenib should be avoided in patients who are on concomitant strong CYP3A4 inducers such as rifampin, phenobarbital, phenytoin, carbamazepine, and St. John's Wort and strong CYP3A4 inhibitors such as clarithromycin, itraconazole, ketoconazole, posaconazole, voriconazole, telithromycin, and those on grapefruit juice.[16]


Colorectal cancer

The “Regorafenib monotherapy for previously treated metastatic colorectal cancer” (CORRECT) trial evaluated patients with extensively pre-treated metastatic colorectal cancer who progressed during or within 3 months after completing the last standard therapy and were randomized to either regorafenib or placebo. The primary endpoint, the overall survival (OS), was improved by 1.4 months in the regorafenib arm; the median OS in the patients who received regorafenib was 6.4 months versus 5 months in those who received placebo [hazard ratio (HR), 0.77; 95% CI, 0.64–0.94, P = 0.0052]. The most common grade 3 and higher toxicities were hand–foot skin reaction (17%), weakness (10%), high blood pressure (7%), loose stools (7%), and rash (6%).[5] An alternative dosing schedule of the drug starting at a dose of 80 mg daily, with a weekly escalation of 40 mg, up to a final dose of 160 mg for 21 days, followed by 7 days of rest, resulted in similar efficacy, lower incidence of adverse effects, and a larger number of patients who were able to take cycle 3, compared to the usual regimen. In this trial, participants were randomly assigned (1:1:1:1) to four groups with two distinct regorafenib dosing strategies (standard dose vs escalated) and clobetasol usage (pre-emptive vs reactive). The OS was improved by 3.8 months (9.8 months for the dose-escalation group versus 6 months for the standard-dose group (HR = 0.72; 95% CI, 0.47–1.10; P = 0.12).[21]

Real-world studies in metastatic colorectal cancer

In the phase III study by Li et al.,[22] performed in a cohort of Asian patients with relapsed metastatic colorectal cancer, regorafenib improved the median progression-free survival as compared to placebo (PFS, 3.2 months in the patients who received regorafenib, versus 1.7 months in those who received placebo) and OS (8.8 months for regorafenib, versus 6.3 months for placebo) (HR, 0.55; 95% CI, 0.40–0.77; P, 0.00016). The survival benefits were similar between the Japanese and the non-Japanese patients.[23] The single-arm, phase IIIb CONSIGN study and several other studies performed in the real-world setting reconfirmed the safety and efficacy of regorafenib.[24252627] In the “Safety and Effectiveness of Regorafenib in Routine Clinical Practice Settings” (CORRELATE) study, 57% of the patients were started on regorafenib in the standard dose of 160 mg once daily for 21 days, with the cycle repeated every 28 days. The median OS and PFS were 7.7 months (95% CI, 7.2–8.3) and 2.9 months (95% CI, 2.8–3.0), respectively, and the toxicities were similar to those reported in the earlier studies.[26] The available evidence suggests that patients who have earlier received targeted therapies have poorer outcomes.[22] In patients with advanced colorectal cancer that is chemotherapy-refractory but anti-angiogenic-naïve, regorafenib resulted in a median PFS and OS of 3.5 months (95% CI, 1.8–3.6) and 7.4 months (95% CI, 5.3–8.9), respectively.[28] The benefit of starting regorafenib early in the treatment course was shown in the randomized, phase II REVERCE study in which the treatment sequence of regorafenib followed by cetuximab plus irinotecan resulted in a better survival compared to the reverse sequence of cetuximab followed by regorafenib.[29] The addition of regorafenib to chemotherapy [infusional 5-fluorouracil (5FU), leucovorin, and irinotecan (FOLFIRI)] resulted in a prolongation of the PFS in a phase II trial.[30] Similarly, regorafenib added to first-line chemotherapy [modified FOLFOX6 (infusional 5FU, leucovorin, oxaliplatin)] resulted in a prolonged time on treatment (>12 months) in a few patients, without any improvement in the objective response rate.[31]

Gastrointestinal stromal tumor

In the phase III GRID trial in patients with metastatic gastrointestinal stromal tumors who had relapsed after prior treatment with imatinib and sunitinib, regorafenib led to an absolute improvement in the median PFS by 3.9 months (the median PFS was 4.8 months in the regorafenib arm and 0.9 months in the placebo arm; HR, 0.27; 95% CI, 0.19–0.39; P < 0.0001). The most common grade 3 and higher toxicities were high blood pressure (23%), hand-foot skin reaction (20%), and diarrhea (5%).[14] Patients with KIT exon 11 mutation and succinate dehydrogenase (SDH)-deficient gastrointestinal stromal tumors benefited more than those with non-SDH-deficient and both KIT and PDGFRA wild-type tumors.[32] In the ongoing ALT-GIST phase II randomized non-comparative trial, patients with treatment-naïve gastrointestinal stromal tumors are being randomized to imatinib alone versus an alternating regimen of imatinib and regorafenib in an attempt to overcome cancer stem cell resistance.[33]

Hepatocellular carcinoma

The RESORCE study was a phase III trial in patients with metastatic hepatocellular cancer with a Child-Pugh A score who had progressed on sorafenib. Patients were randomized to regorafenib or placebo. The median OS was 10.6 months in the regorafenib arm, versus 7.8 months in those who received a placebo, with an absolute benefit of 2.8 months; HR, 0.63; 95% CI, 0.50–0.79; P < 0.0001. Grade 3 or 4 toxicities were high blood pressure (15%), hand-foot skin reaction (13%), weakness (9%), and diarrhea (3%).[15]


In the phase III randomized study of regorafenib versus placebo in patients with progressive metastatic osteosarcoma who had failed on at least one line of therapy, Davis et al.[34] reported that the median PFS improved from 1.7 months in the placebo arm to 3.6 months in the regorafenib arm, an absolute improvement of 1.9 months (HR, 0.42; 95% CI, 0.21–0.85; P =0.017). In another phase II study performed in progressive chemotherapy-refractory metastatic osteosarcoma, 65% of the patients randomized to regorafenib did not progress at 8 weeks, compared to none on the placebo arm. The grade ≥3 or greater toxicities were high blood pressure (24%), hand-foot skin reaction (10%), and weakness (10%).[35]

Other tumor types

Gastric/gastroesophageal cancer

In the multinational phase II “Regorafenib for the Treatment of Advanced Gastric Cancer” (INTEGRATE) trial in patients with advanced, refractory gastroesophageal carcinoma, regorafenib improved the median PFS (2.6 vs 0.9 months; HR, 0.40; 95% CI, 0.28–0.59; P < 0.001) and median OS (5.8 months vs 4.5 months; HR, 0.74; 95% CI, 0.51–1.08; P = 0.15) compared to placebo.[36]


In the “Safety and efficacy of regorafenib in patients with advanced soft tissue sarcoma” (REGOSARC) study conducted in patients with non-adipocytic soft tissue sarcomas (leiomyosarcoma and synovial sarcoma), regorafenib improved the PFS compared to placebo. In the patients with leiomyosarcoma, the median PFS was 3.7 months (95% CI, 2.5–5.0) with regorafenib versus 1.8 months (1.0–2.8) with placebo (HR, 0.46; 95% CI, 0.46–0.80; P = 0.0045). In the patients with synovial sarcoma, the median PFS was 5.6 months (95% CI, 1.4–11.6) with regorafenib versus 1.0 month (95% CI, 0.8–1.4) with placebo (HR, 0.10; 95% CI, 0.03–0.35; P < 0·0001). In the other sarcoma cohort, the median PFS was 2.9 months (95% CI, 1.0–7.8) with regorafenib versus 1.0 (95% CI, 0.9–1.9) with placebo (HR 0.46; 95% CI, 0.25–0.8; P = 0.0061). This benefit in PFS was not observed in patients with liposarcoma (HR, 0.89; 95% CI, 0.48–1.64; P, 0.70).[37] The lack of activity of regorafenib in treatment-refractory liposarcoma was confirmed in the SARC024 study, in which there was no observed PFS benefit in the patients treated with regorafenib; the median PFS in the regorafenib arm was 1.87 months, compared to 2.07 months in the placebo arm, HR, 0.85; 95% CI, 0.46–1.58; P = 0.62.[38] In patients with advanced Ewing's sarcoma, regorafenib improved the PFS by 3.6 months; 73% of the patients were progression-free at 8 weeks.[39]

Biliary tract cancer

Regorafenib improved the median PFS compared to placebo in patients with advanced biliary tract cancers after the failure of prior chemotherapies (3 vs 1.5 months; HR, 0.49; 95% CI, 0.29–0.81; P = 0.05), with a 70% disease control rate, as shown in the “Regorafenib after the failure of gemcitabine and platinum-based chemotherapy for locally advanced/metastatic biliary tumors” (REACHIN) study.[40]


In the randomized, phase II “Regorafenib compared with lomustine in patients with relapsed glioblastoma (REGOMA) trial,” regorafenib improved both the 6-month PFS compared to lomustine (16.9% vs 8.3%; HR, 0.65; 95% CI, 0.45–0.95; P = 0.022) and the median OS (7.4 vs 5.6 months; HR, 0.50; 95% CI, 0.33–0.75; P = 0.0009) with a higher disease control rate (44% vs 20%; P = 0.006).[41]

Table 2 summarizes the various trials that evaluated the efficacy of regorafenib in patients with colorectal cancer, gastrointestinal stromal tumors, hepatocellular carcinoma, and osteosarcoma. Table 3 presents the key features of regorafenib.

Table 2:
A summary of the trials of regorafenib in colorectal cancer, gastrointestinal stromal tumor, hepatocellular carcinoma, and osteosarcoma
Table 3:
Key features of regorafenib


1. Hepatotoxicity

Liver dysfunction may occur within 2 months of starting regorafenib. In the CORRECT and GRID studies, 1.6% and 0.8% of the patients, respectively, developed fatal hepatic failure.

2. Infections

Regorafenib may cause a higher incidence of infections in around 32% of patients. Grade 3 or higher infections are seen in around 9% of the patients.

3. Hemorrhage

Regorafenib increases the risk of hemorrhage. Grade 3 or higher hemorrhage is seen in around 3% of patients.

4. Gastrointestinal Perforation and Fistula

These may occur in approximately 0.6% and 0.8% of patients, respectively.

5. Dermatologic Toxicity

Dermatologic toxicity is seen in 71.9% of patients. The hand–foot skin reaction is seen in approximately 53% of the patients. The grade 3 hand–foot skin reaction rate is around 16%, and grade 3 rash occurs in approximately 3% of the patients. Asian patients have a higher incidence of hand–foot skin reaction with all grades occurring in approximately 72% of patients and grade 3 hand–foot skin reaction in approximately 18%.

6. Hypertension

Hypertensive crisis is seen in 0.2% of the patients. An increased incidence of hypertension was reported in various studies with rates of 30%, 59%, and 31% in the CORRECT, GRID, and RESORCE studies, respectively.[51415]

7. Myocardial Ischemia and Infarction

These cardiac toxicities may occur in around 0.9% of the patients.

8. Reversible posterior leukoencephalopathy syndrome:

Regorafenib has very rarely been reported to cause reversible posterior leukoencephalopathy syndrome.[44]

9. Wound Healing risk

In patients undergoing elective surgery, regorafenib should be withheld starting 2 weeks before surgery. It can be restarted 2 weeks after major surgery and after adequate wound healing has occurred.

10. Teratogenicity:

For women in the reproductive age group, pregnancy is to be ruled out before starting regorafenib. Regorafenib may cause fetal harm if administered during pregnancy based on animal reproduction studies. The drug has been shown to be embryolethal and teratogenic in rats and rabbits at exposures lower than human exposures at the recommended dose, with increased incidences of cardiovascular, genitourinary, and skeletal malformations. It is not known if regorafenib is excreted in the breast milk. Breastfeeding is not recommended while on treatment and for 2 weeks after its cessation.[16]


The lowest starting dose of regorafenib is 80 mg orally once daily.


  • Grade 2 – Withhold regorafenib for grade 2 symptomatic hypertension
  • Grade 3 or 4 – Withhold regorafenib and re-start at 120 mg once daily after recovery of the blood pressure to grade 1


  • Grade 2 transaminase elevation with concurrent grade 2 hyperbilirubinemia: Permanent discontinuation
  • Grade 3 transaminase elevation with normal bilirubin – Regorafenib may be restarted at a dose of 120 mg once daily if the benefit of treatment with regorafenib outweighs the risk of hepatotoxicity.
  • Recurring grade 3 transaminase elevation despite a dose reduction to 120 mg – Permanent discontinuation
  • Grade 4 transaminase elevation – Permanent discontinuation

Hand–foot skin reaction

  • Interrupt the dose of regorafenib for recurrent grade 2 hand–foot skin reaction or if there is no improvement within 7 days after dose reduction and for grade 3 or 4 reactions.
  • The dose of regorafenib is to be reduced to 120 mg once daily at the first onset of grade 2 hand–foot skin reaction that has lasted for any duration and after recovery from grade 3 or 4 hand–foot skin reactions that occurred at the 160 mg dose.
  • The dose of regorafenib is to be reduced to 80 mg once daily if there is a recurrence of grade 2 hand–foot skin reaction at the 120 mg dose and after recovery from grade 3 or 4 hand–foot skin reactions that occurred at the 120 mg dose.


  • Withhold for any grade infections
  • Grade 3 or 4 infections – Permanent discontinuation


  1. Liver function tests: At baseline and then every 2 weeks for the first 8 weeks, and then, at least once a month thereafter or more frequently, as clinically indicated
  2. Blood pressure (BP) monitoring: At baseline, check the BP every 1 week for the first 6 weeks, and then, every 28 days before every cycle
  3. International normalized ratio (INR) levels: The INR level should be monitored more frequently in those who are on warfarin
  4. Pregnancy status: To be checked before treatment initiation


The effect of regorafenib on quality of life (QoL) was evaluated in a pooled analysis of three different tumor types, that is, colorectal cancer, gastrointestinal stromal tumor, and hepatocellular carcinoma. Regorafenib significantly delayed the time until definitive deterioration (TUDD) of the QoL, defined as the patient's first minimal clinically important deterioration in QoL score from baseline, that did not resolve. The median delay in TUDD across the five scales ranged from 16.3 to 24.1 weeks for regorafenib and from 8.6 to 12.1 weeks for placebo across all three tumor types. The five scales included the European Organization for Research and Treatment of Cancer Core Quality-of-Life Questionnaire (EORTC QLQ-C30 summary score), EORTC QLQ-C30 global health status scale, physical functioning scale, EQ-5D Index, and the EQ-5D visual analog scale (VAS).[45]


Regorafenib improved the median survival of patients with metastatic colorectal cancer by 6 weeks. A study by Goldstein et al.[46] evaluated the cost-effectiveness of regorafenib. The health outcomes were measured in quality-adjusted life-years (QALYs), which showed an additional 0.04 QALYs (0.13 life-years) for $40,000, with an incremental cost-effectiveness ratio of $900,000 per QALY. In a study by Cho et al.,[47] the best supportive care was more cost-effective than regorafenib. Bekaii-Saab et al.[21] conducted the “Regorafenib dose-optimization in patients with refractory metastatic colorectal cancer (ReDOS)” study and reported that dose escalation (an initial dose of 80 mg/day regorafenib orally with dose escalation at 40 mg increments once a week to 160 mg/day) was more cost-effective, equi-efficacious, and less toxic than regorafenib at the standard dose of 160 mg/day orally for 21 days of a 28-day cycle.


The cost of regorafenib in India is approximately 1, 40, 000 per month ($1795), and the cost of the generic brand is approximately 37,000 per month ($474). In a study by Ramaswamy et al.[48] performed on patients with metastatic colorectal cancers, regorafenib was started at a lower dose (160 mg – 28.8%, 120 mg – 58.8%, and 80 mg – 12.5%). The median treatment duration was 3.1 months (range 0.5–18), and the median PFS was 3.48 months (range 2.6–4.3). The most common all grade toxicities were hand–foot syndrome (68.8%), fatigue (46.3%), mucositis (37.6%), and loose stools (31.3%).


Regorafenib is indicated and approved for patients with advanced colorectal cancer once all the standard therapies have failed, gastrointestinal stromal tumor after prior treatment with imatinib and sunitinib, hepatocellular carcinoma after progression on sorafenib, and advanced metastatic osteosarcoma after prior lines of therapy. In a few studies, regorafenib has been shown to have efficacy in advanced gastroesophageal cancers, biliary tract cancers, Ewing's sarcoma, non-adipocytic soft tissue sarcoma, and glioblastoma. It is usually an effective and well-tolerated drug. It can be used in patients who have exhausted all standard therapeutic options with improved PFS, overall OS, and QoL. Generic regorafenib is now available in India at a cost of approximately 37,000 ($474) per month using the dose of 160 mg once daily for 21 out of 28 days. Additional studies of dose optimization strategies and cost-effectiveness are needed. It is important to monitor the hepatic function, blood pressure, and skin reactions while on treatment. Further studies are needed to assess the role of regorafenib in other solid tumor malignancies.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.


I would like to thank the Department of Medical Oncology, Tata Memorial Hospital, Mumbai for giving me this opportunity.


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Colorectal cancer; GIST; HCC; osteosarcoma; regorafenib; VEGF

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