Think one step ahead for your HCC patients previously treated with sorafenib

Man is walking up three steps in a flower-filled meadow. The last step has a STIVARGA (regorafenib) logo on it.

The RESORCE trial evaluated the efficacy and safety of STIVARGA® (regorafenib)1,2

REgorafenib after SORafenib in patients with hepatoCEllular carcinoma (RESORCE) was an international, multicenter, randomized (2:1), double-blind, placebo-controlled phase 3 trial that evaluated the efficacy and safety of STIVARGA in HCC patients with progression following sorafenib (N=573).

  • Patients who permanently discontinued sorafenib due to toxicity or who were unable to tolerate sorafenib doses of 400 mg once daily were ineligible for the trial

RESORCE trial design1,2

Graphic outlining STIVARGA (regorafenib) RESORCE trial design. Patients were randomly (2:1 ratio) treated with Stivarga or Placebo. All patients received best supportive care and were treated until disease progression or unacceptable toxicity.

Primary endpoint1:

  • Overall survival (OS), analyzed by intention to treat

Secondary endpoints1,2:

  • Progression-free survival (PFS), time to progression, overall response rate (ORR; patients with complete response [CR] or partial response [PR]), disease control rate (DCR; patients with CR, PR, or stable disease [SD] for ≥6 weeks)
    • Analyzed by intention to treat; assessed using modified Response Evaluation Criteria In Solid Tumors (mRECIST) and RECIST 1.1

Tertiary endpoint2:

  • Duration of response

Patients in the RESORCE trial had good performance status and preserved liver function1,2

Baseline patient characteristics were similar between each arm1,2

Baseline characteristics1,2

 STIVARGA
(n=379) %		Placebo
(n=194) %
Sex  
Male8888
Female1212
Race  
White3635
Asian‡4140
Black21
Other/Not reported2124
Median age, years6462
Eastern Cooperative Oncology Group performance status (ECOG PS)  
06567
13533
Macrovascular invasion (MVI)2928
Extrahepatic disease (EHD)7076
MVI and/or EHD8084
Alpha-fetoprotein (AFP) ≥400 ng/mL4345
Child-Pugh§  
A9897
B13
BCLC stage  
A<10
B1411
C8689
Liver cirrhosis (investigator assessed)7574
Etiology of HCCII  
Hepatitis B3838
Alcohol use2428
Hepatitis C2121
Unknown1716
Nonalcoholic steatohepatitis77
Other75
Duration of sorafenib treatment, months7.8 (4.2-14.5)7.8 (4.4-14.7)

Results from RESORCE represent a significant advance in treatment for HCC patients previously treated with sorafenib1

10.6-month median OS achieved with STIVARGA vs 7.8 months with placebo1,2

Median OS in RESORCE1,2

Line graph showing OS results from STIVARGA (regorafenib) RESORCE trial and highlighting a 37% reduction in risk of death.

37% reduction in risk of
death with STIVARGA

HR: 0.63
(95% CI, 0.50-0.79)
P=<0.0001

37% reduction in risk of death with STIVARGA

HR: 0.63
(95% CI, 0.50-0.79)
P=<0.0001

STIVARGA OS based on exploratory, preplanned patient subgroup analyses1

Subgroup analysis in RESORCE1

Table outline analysis of subgroups participating in STIVARGA (regorafenib) RESORCE trial.

STIVARGA more than doubled PFS vs placebo1,2

3.1-month median PFS achieved with STIVARGA vs 1.5 months with placebo

PFS in RESORCE (mRECIST)1,2

Line graph showing PFS results from STIVARGA (regorafenib) RESORCE trial and highlighting a 54% reduction in risk of progression or death.

54% reduction in risk of
progression or death
with STIVARGA

HR: 0.46
(95% CI, 0.37-0.56)
P<0.0001

54% reduction in risk of
progression or death
with STIVARGA

HR: 0.46
(95% CI, 0.37-0.56)
P<0.0001

Reduction in risk of progression or death with STIVARGA was consistent when assessed by RECIST 1.12

  • 3.4-month (95% CI, 2.9-4.2) median PFS achieved with STIVARGA vs 1.5 months (95% CI, 1.4-1.5 with placebo (HR: 0.43; 95% CI, 0.35-0.52) (RECIST 1.1)
    • Number of progressions or deaths: 288 of 379 (76%) in the STIVARGA arm; 184 of 194 (95%) in the placebo arm

Break through response barriers with STIVARGA1-3

Tumor response rates in RESORCE1-3

 STIVARGA,
(n=379, %)		Placebo,
(n=194, %)
Assessed using mRECIST  
DCR6536
ORR (95% CI)11 (8-14)4 (2-8)
CR10
PR104
SD5432
Assessed using RECIST 1.1  
DCR6635
ORR (95% CI)7 (4-10)3 (1-6)
CR00
PR73
SD5932

DCR, CR + PR + SD; ORR, CR + PR.

Duration of disease response, assessed using mRECIST3

  • Median duration of response in patients with a complete or partial response was 3.5 months in the STIVARGA arm vs 2.7 months in the placebo arm3
  • Median duration of stable disease was 5.5 months in the STIVARGA arm vs 3.1 months in the placebo arm3

Indications

STIVARGA is indicated for the treatment of patients with metastatic colorectal cancer (CRC) who have been previously treated with fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, an anti-VEGF therapy, and, if RAS wild-type, an anti-EGFR therapy.

STIVARGA is indicated for the treatment of patients with locally advanced, unresectable or metastatic gastrointestinal stromal tumor (GIST) who have been previously treated with imatinib mesylate and sunitinib malate.

STIVARGA is indicated for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib.

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Important Safety Information

WARNING: HEPATOTOXICITY

  • Severe and sometimes fatal hepatotoxicity has occurred in clinical trials.
  • Monitor hepatic function prior to and during treatment.
  • Interrupt and then reduce or discontinue STIVARGA for hepatotoxicity as manifested by elevated liver function tests or hepatocellular necrosis, depending upon severity and persistence.

Hepatotoxicity: Severe drug-induced liver injury with fatal outcome occurred in STIVARGA-treated patients across all clinical trials. In most cases, liver dysfunction occurred within the first 2 months of therapy and was characterized by a hepatocellular pattern of injury. In metastatic colorectal cancer (mCRC), fatal hepatic failure occurred in 1.6% of patients in the STIVARGA arm and in 0.4% of patients in the placebo arm. In gastrointestinal stromal tumor (GIST), fatal hepatic failure occurred in 0.8% of patients in the STIVARGA arm. In hepatocellular carcinoma (HCC), there was no increase in the incidence of fatal hepatic failure as compared to placebo.

Liver Function Monitoring: Obtain liver function tests (ALT, AST, and bilirubin) before initiation of STIVARGA and monitor at least every 2 weeks during the first 2 months of treatment. Thereafter, monitor monthly or more frequently as clinically indicated. Monitor liver function tests weekly in patients experiencing elevated liver function tests until improvement to less than 3 times the upper limit of normal (ULN) or baseline values. Temporarily hold and then reduce or permanently discontinue STIVARGA, depending on the severity and persistence of hepatotoxicity as manifested by elevated liver function tests or hepatocellular necrosis.

Infections: STIVARGA caused an increased risk of infections. The overall incidence of infection (Grades 1-5) was higher (32% vs 17%) in 1142 STIVARGA-treated patients as compared to the control arm in randomized placebo-controlled trials. The incidence of grade 3 or greater infections in STIVARGA treated patients was 9%. The most common infections were urinary tract infections (5.7%), nasopharyngitis (4.0%), mucocutaneous and systemic fungal infections (3.3%) and pneumonia (2.6%). Fatal outcomes caused by infection occurred more often in patients treated with STIVARGA (1.0%) as compared to patients receiving placebo (0.3%); the most common fatal infections were respiratory (0.6% vs 0.2%). Withhold STIVARGA for Grade 3 or 4 infections, or worsening infection of any grade. Resume STIVARGA at the same dose following resolution of infection.

Hemorrhage: STIVARGA caused an increased incidence of hemorrhage. The overall incidence (Grades 1-5) was 18.2% in 1142 patients treated with STIVARGA vs 9.5% with placebo in randomized, placebo-controlled trials. The incidence of grade 3 or greater hemorrhage in patients treated with STIVARGA was 3.0%. The incidence of fatal hemorrhagic events was 0.7%, involving the central nervous system or the respiratory, gastrointestinal, or genitourinary tracts. Permanently discontinue STIVARGA in patients with severe or life-threatening hemorrhage and monitor INR levels more frequently in patients receiving warfarin.

Gastrointestinal Perforation or Fistula: Gastrointestinal perforation occurred in 0.6% of 4518 patients treated with STIVARGA across all clinical trials of STIVARGA administered as a single agent; this included eight fatal events. Gastrointestinal fistula occurred in 0.8% of patients treated with STIVARGA and in 0.2% of patients in the placebo arm across randomized, placebo-controlled trials. Permanently discontinue STIVARGA in patients who develop gastrointestinal perforation or fistula.

Dermatological Toxicity: In randomized, placebo-controlled trials, adverse skin reactions occurred in 71.9% of patients with STIVARGA arm and 25.5% of patients in the placebo arm including hand-foot skin reaction (HFSR) also known as palmar-plantar erythrodysesthesia syndrome (PPES) and severe rash, requiring dose modification. In the randomized, placebo-controlled trials, the overall incidence of HFSR was higher in 1142 STIVARGA-treated patients (53% vs 8%) than in the placebo-treated patients. Most cases of HFSR in STIVARGA-treated patients appeared during the first cycle of treatment. The incidences of Grade 3 HFSR (16% vs <1%), Grade 3 rash (3% vs <1%), serious adverse reactions of erythema multiforme (<0.1% vs 0%), and Stevens-Johnson syndrome (<0.1% vs 0%) were higher in STIVARGA-treated patients. Across all trials, a higher incidence of HFSR was observed in Asian patients treated with STIVARGA (all grades: 72%; Grade 3: 18%). Toxic epidermal necrolysis occurred in 0.02% of 4518 STIVARGA-treated patients across all clinical trials of STIVARGA administered as a single agent. Withhold STIVARGA, reduce the dose, or permanently discontinue depending on the severity and persistence of dermatologic toxicity.

Hypertension: Hypertensive crisis occurred in 0.2% in STIVARGA-treated patients and in none of the patients in placebo arm across all randomized, placebo-controlled trials. STIVARGA caused an increased incidence of hypertension (30% vs 8% in mCRC, 59% vs 27% in GIST, and 31% vs 6% in HCC). The onset of hypertension occurred during the first cycle of treatment in most patients who developed hypertension (67% in randomized, placebo controlled trials). Do not initiate STIVARGA until blood pressure is adequately controlled. Monitor blood pressure weekly for the first 6 weeks of treatment and then every cycle, or more frequently, as clinically indicated. Temporarily or permanently withhold STIVARGA for severe or uncontrolled hypertension.

Cardiac Ischemia and Infarction: STIVARGA increased the incidence of myocardial ischemia and infarction (0.9% with STIVARGA vs 0.2% with placebo) in randomized placebo-controlled trials. Withhold STIVARGA in patients who develop new or acute cardiac ischemia or infarction, and resume only after resolution of acute cardiac ischemic events if the potential benefits outweigh the risks of further cardiac ischemia.

Reversible Posterior Leukoencephalopathy Syndrome (RPLS): Reversible posterior leukoencephalopathy syndrome (RPLS), a syndrome of subcortical vasogenic edema diagnosed by characteristics finding on MRI, occurred in one of 4800 STIVARGA-treated patients across all clinical trials. Perform an evaluation for RPLS in any patient presenting with seizures, severe headache, visual disturbances, confusion, or altered mental function. Discontinue STIVARGA in patients who develop RPLS.

Wound Healing Complications: Impaired wound healing complications can occur in patients who receive drugs that inhibit the VEGF signaling pathway. Therefore, STIVARGA has the potential to adversely affect wound healing. Withhold STIVARGA for at least 2 weeks prior to elective surgery. Do not administer for at least 2 weeks following major surgery and until adequate wound healing. The safety of resumption of STIVARGA after resolution of wound healing complications has not been established.

Embryo-Fetal Toxicity: STIVARGA can cause fetal harm when administered to a pregnant woman. There are no available data on STIVARGA use in pregnant women. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential and males with female partners of reproductive potential to use effective contraception during treatment with STIVARGA and for 2 months after the final dose.

Nursing Mothers: Because of the potential for serious adverse reactions in breastfed infants from STIVARGA, do not breastfeed during treatment with STIVARGA and for 2 weeks after the final dose.

Most Frequently Observed Adverse Drug Reactions in mCRC (≥30%): The most frequently observed adverse drug reactions (≥30%) in STIVARGA-treated patients vs placebo-treated patients in mCRC, respectively, were: asthenia/fatigue (64% vs 46%), pain (59% vs 48%), decreased appetite and food intake (47% vs 28%), HFSR/PPE (45% vs 7%), diarrhea (43% vs 17%), mucositis (33% vs 5%), weight loss (32% vs 10%), infection (31% vs 17%), hypertension (30% vs 8%), and dysphonia (30% vs 6%).

Most Frequently Observed Adverse Drug Reactions in GIST (≥30%): The most frequently observed adverse drug reactions (≥30%) in STIVARGA-treated patients vs placebo-treated patients in GIST, respectively, were: HFSR/PPE (67% vs 12%), pain (60% vs 55%), hypertension (59% vs 27%), asthenia/fatigue (52% vs 39%), diarrhea (47% vs 9%), mucositis (40% vs 8%), dysphonia (39% vs 9%), infection (32% vs 5%), decreased appetite and food intake (31% vs 21%), and rash (30% vs 3%).

Most Frequently Observed Adverse Drug Reactions in HCC (≥30%): The most frequently observed adverse drug reactions (≥30%) in STIVARGA-treated patients vs placebo-treated patients in HCC, respectively, were: pain (55% vs 44%), HFSR/PPE (51% vs 7%), asthenia/fatigue (42% vs 33%), diarrhea (41% vs 15%), hypertension (31% vs 6%), infection (31% vs 18%), decreased appetite and food intake (31% vs 15%).

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*The mean daily STIVARGA dose was 144 mg.1

†Patients were followed up for radiological tumor assessments every 6 weeks up to 8 cycles, after which assessments were conducted every 12 weeks with scans that documented radiological progression.1

‡Includes patients from China, Japan, South Korea, Singapore, and Taiwan.1

§The Child-Pugh system describes liver disease severity: Patients are divided into classes from A to C, with class C representing the worst prognosis. Child-Pugh class was missing in 1 patient in the STIVARGA group. Those patients who progressed to Child-Pugh B after screening and before randomization were included.1

||Patients could have more than 1 etiology of HCC.1

CI, confidence interval; HR, hazard ratio.

References:

  • Bruix J, Qin S, Merle P, et al; on behalf of the RESORCE Investigators. Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2017;389(10064):56-66. Return to content
  • STIVARGA. Prescribing information. Whippany, NJ: Bayer HealthCare Pharmaceuticals Inc; December 2020. Return to content
  • Bruix J, Qin S, Merle P, et al; on behalf of the RESORCE Investigators. Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial [supplement published online December 5, 2016]. Lancet. http://dx.doi.org/10.1016/S0140-6736(16)32453-9 Return to content

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Last updated on May 2023