CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`
`203085Orig1s000
`
`OFFICE DIRECTOR MEMO
`
`
`
`
`

`

`Office Director Decisional Memo
`
`203085_Stivarga (regorafenib)
`
`Summary Review for Regulatory Action
`
`Electronic stam . date
`
`Richard Pazdur, MD
`Office Director Summa Review
`NBA 203085
`
`Applicant Name
`Bayer Healthcare Pharmaceuticals, Inc.
`
`Date of Submission
`April 27, 2012
`PDUFA Goal Date
`October 27, 2012
`
`Proprietary Name I
`Established
`SAN Name
`Dosa i e Forms I Stren h
`
`Proposed lndication(s)
`
`Recommended Action for NME:
`
`Stivarga Tablets]
`r- corafenib
`Tablets for oral administration/40 m
`
`For the treatment of patients with metastatic colorectal cancer
`(mCRC) who have been previously treated with,
`M“)
`fluoropyrimidine—based chemotherapy,
`an anti-VEGFR therapy, and, if KRAS wild type, an anti-EGFR
`therapy
`A I r oval
`
`
`
`Material Reviewed/Consulted
`
`0ND Action Packa-e, includinc:
`Division Director Summa Review
`CDTL Review
`
`Names of disci a line reviewers
`
`m—W_
`
`
`
`
`_—
`
`OND=Office of New Dnigs
`ONDQA=Office of New Dmgs Quality Assessment
`OPDP=Office of Prescription Dmg Promotion
`OSE= Office of Surveillance and Epidemiology
`DMEPA=Division of Medication Error Prevention and Analysis
`OSI=Office of Scientific Investigations
`DRISK=Divuion of Risk Management
`CDTL=Cross—Discipline Team Leader
`
`Reference ID: 3195162
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`Page 1 of 10
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`

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`Office Director Decisional Memo
`203085_Stivarga (regorafenib)
`
`
`
`Introduction
`1.
`On April 27, 2012, Bayer Pharmaceuticals submitted this NDA for Stivarga (regorafenib) tablets in the following
`proposed indication: “For the treatment of patients with metastatic colorectal cancer (mCRC) who have been
`previously treated with,
` fluoropyrimidine-based chemotherapy, an anti-
`VEGFR therapy, and, if KRAS wild type, an anti-EGFR therapy.” There are no FDA-approved therapies for the
`proposed indication.
`
`
`Regorafenib is an inhibitor of multiple membrane-bound and intracellular kinases (multi-kinase inhibitor) involved
`in a wide range of normal cellular functions and in pathologic processes, such as oncogenesis, tumor
`angiogenesis, and maintenance of the tumor microenvironment. The kinase inhibition profile of regorafenib affect
`the angiogenic (VEGFR 2/3, TIE2), stromal (PDGFR-ß, FGFR) and oncogenic (KIT, RET and B-RAF) cellular
`processes and pathways.
`
`This NDA was primarily supported by a single clinical trial (Protocol 14387; “CORRECT”), which enrolled 670
`patients with metastatic colorectal cancer with disease progression following all FDA-approved therapy.
`CORRECT was an international, multicenter, randomized (2:1), double-blind, placebo-controlled, trial comparing
`the effect of regorafenib at a dose of 160 mg once daily for 3 weeks (days 1-21) of a 28-day cycle plus best
`supportive care (BSC) (n=505) to matching placebo plus BSC (n=255) on OS (primary endpoint). Key secondary
`endpoints were PFS, objective response rate, and response duration.
`
`The CORRECT trial demonstrated statistically significant improvements in both OS and PFS for regorafenib
`treatment patients over those receiving best supportive care alone. There was no statistical difference in overall
`response rates between the arms of the study.
`
`The most frequently observed adverse drug reactions (≥30%) in regorafenib-treated patients are asthenia/fatigue,
`decreased appetite and food intake, palmar-plantar erythrodysesthesia (hand-foot syndrome), diarrhea, mucositis,
`weight loss, infection, hypertension and dysphonia. The most frequent laboratory abnormalities are cytopenias
`(anemia, thrombocytopenia, and lymphopenia), liver dysfunction (hyperbilirubinemia, transaminitis), and metabolic
`derangements (hypocalcemia, hypophosphatemia, and hypokalemia). The most serious adverse drug reactions of
`regorafenib in the CORRECT trial, occurring at an increased incidence in regorafenib-treated patients and
`placebo-treated patients, respectively, were Grade 3 palmar-plantar erythrodysesthesia (17% vs. 0), fatal
`hepatotoxicity (1.6% vs. 0.4%), myocardial ischemia and infarction (1.2% vs. 0.4%), and fatal hemorrhage (0.8%
`vs. 0).
`
`The absolute magnitude of the treatment effects on survival (difference of 1.4 months in median survival times)
`and PFS (difference of 1.2 weeks in median PFS times) are modest, but the ability of an agent to demonstrate
`efficacy in this heavily pre-treated population represents clinical benefit when considered in the context of serious
`adverse drug reactions occurring in fewer than 1% of patients and common toxicities already considered
`acceptable with other approved agents for the treatment of metastatic colorectal cancer.
`
`
`Background
`2.
`In 2012, there will be an estimated 103,170 new cases of colon cancer, 40,290 new cases of rectal cancer, and an
`estimated 51,690 deaths from colon or rectal cancers1. While the mortality from colorectal cancer has decreased
`in the past 50 years, approximately half the decline in mortality rates (from 28 deaths per 100,000 to 17 deaths per
`
`
`1 http://www.cancer.gov/cancertopics/types/colon-and-rectal
`
`
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`Reference ID: 3195162
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`Page 2 of 10
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`(b) (4)
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`

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`Office Director Decisional Memo
`203085_Stivarga (regorafenib)
`
`100,000) is attributed to screening and early diagnosis2. The identification of new systemic treatments for patients
`with metastatic disease has improved short-term outcomes but not long-term cure rates. The standard of care in
`the United States for the treatment of metastatic colorectal cancer includes first-line and second-line treatment
`with fluoropyrimidine-based combination chemotherapy (FOLFOX or FOLFIRI) administered with bevacizumab for
`the majority of patients. Cetuximab and panitumumab are indicated for the treatment of patients with metastatic
`colorectal cancer in which the tumor does not contain mutations in the c oncogene (K-Ras wild-type), either as an
`addition to combination chemotherapy for initial treatment (cetuximab) or as monotherapy in patients with
`recurrent, chemotherapy-refractory disease (cetuximab, panitumumab). The very elderly or those with co-morbid
`conditions which may render intensive treatment intolerable, are generally treated either with combinations of
`approved drugs (5-flurouracil and leucovorin, capecitabine, oxaliplatin, irinotecan, with or without anti-EGFR
`directed antibodies) or with single agent therapy.
`
`
`CMC
`3.
`There are no outstanding issues that preclude approval. Chemistry reviewers recommended an overall
`acceptability of the manufacturing of the drug product and drug substance. Manufacturing site inspections were
`acceptable. Stability testing supports an expiry of 36 months.
`
`
`Nonclinical Pharmacology/Toxicology
`4.
`There are no outstanding pharmacology/toxicology issues that preclude approval. This application did not contain
`carcinogenicity studies or a complete battery of reproductive toxicology studies; however, these studies are not
`required for products indicated for the treatment of advanced, incurable cancers. Similarly, the finding of potential
`mutagenic effects for a major metabolite (M2) did not require a specific Warning based on the indicated
`population.
`
`The NDA contained the reports for nonclinical primary pharmacology studies confirming the claimed effects of
`regorafenib and its two major metabolites (M2 and M5) on kinase inhibition, examining the phosphorylation of
`downstream targets to establish kinase inhibition at clinically achievable exposures in humans at the
`recommended dose for multiple kinase targets. Both the M2 and M5 metabolites showed inhibitory activity equal
`to or greater than the activity of the regorafenib. In addition, in vivo evaluation of anti-angiogenic effects were
`evaluated in rats and mice.
`
`The application also contained reports of repeat dose toxicology studies in rodents and dogs. Toxicologic findings
`demonstrated both rats and dogs which were also observed in patients with cancer involved the gastrointestinal
`tract (vomiting, diarrhea, decreased motility), hematopoietic/lymphoid system (marrow hypocellularity, neutropenia,
`thrombocytopenia, and lymphopenia), atrophy of lymphoid organs, the reproductive system (atrophy), hepatic
`enzyme elevation with histopathologic changes in the liver, cutaneous toxicity (dyskeratosis, hyperkeratosis,
`acanthosis, dermatitis, and alopecia), and skeletal system.
`
`Findings identified in animals that have not been confirmed in clinical trials of adults with cancer include renal
`toxicity (glomerulopathy, tubular degeneration/regeneration, tubular dilation, and interstitial fibrosis), skeletal
`changes (changes in dentin and epiphyseal growth plates), reproductive toxicity (increased necrotic corpus lutea
`and atrophy in the ovaries in females and decreased weight of the testes, prostate, and seminal vesicles and
`retarded maturation of the testes along with aspermia/oligospermia in the epididymides in males), histopathologic
`changes in the adrenal glands, and hypothyroidism.
`
` A
`
` report of a safety pharmacology study did not identify significant cardiotoxicity.
`
`
`2 http://www.cancer.gov/cancertopics/factsheet/cancer-advances-in-focus/colorectal
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`Reference ID: 3195162
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`Page 3 of 10
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`

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`Office Director Decisional Memo
`203085_Stivarga (regorafenib)
`
`
`Embryofetal studies conducted in Wistar rats and Himalayan rabbits demonstrated increased post-implantation
`loss and teratogenic effects including skeletal and cardiovascular malformations and renal findings of dilation of
`the renal pelvis or hydronephrosis at exposures significantly lower than the human exposure at the recommended
`daily dose. Based on these findings, and consistent with current practices in the Division of Hematology Oncology
`Toxicology, Pregnancy category D was recommended.
`
` distribution study in pregnant rats documented regorafenib exposure in the fetus, with greater regorafenib
`concentrations in fetal adrenal glands and brain as compared to the maternal blood and increased concentrations
`of regorafenib or its active metabolites in maternal mammary fluid as compared to the blood. Based on these
`studies, labeling directs lactating mothers to discontinue nursing while taking regorafenib.
`
`Product labeling identifies the potential risks of impaired fertility in both men and women based on embryofetal and
`teratogenic effects observed in general toxicology studies in which female rats were administered regorafenib at
`dose levels resulting in exposures similar to those observed in humans at the clinically recommended dose. Dr.
`Helms noted that these animals were not followed for a sufficient period to determine reversibility. Given the
`indicated population, the findings and limitations of the findings (i.e., based on animal data) will be conveyed in
`product labeling.
`
`
` A
`
` Clinical Pharmacology
`5.
`There are no outstanding clinical pharmacology issues that preclude approval.
`
`The NDA contained clinical pharmacology data from two dose-finding trials, evaluating continuous dosing and a
`three-week on/one-week off dosing schedule, three drug interaction studies, one food effect study and one
`bioequivalence trial comparing the pharmacokinetic of the tablet form used in the major efficacy trial with that of
`the “to-be-marketed” tablet.
`
`Following oral administration, regorafenib undergoes enterohepatic circulation. It is highly protein bound (99.5%),
`as are the two major metabolites (M2 and M5) of regorafenib, both of which are clinically active. Regorafenib is
`primarily metabolized by CYP3A4 and UGT1A9 and about 71% of a single radiolabeled dose (24% as
`metabolites) was excreted in feces. The mean elimination half-lives of regorafenib, M2, and M5 are 28 hours, 25
`hrs and 51 hrs, respectively. Hepatic elimination appears to be the major route of elimination for regorafenib.
`
`The bioavailability of regorafenib and its active metabolites are affected by the presence of food (fasted vs. fed)
`and the fat content (low vs. high-fat meal). Since the major efficacy trial which provides substantial evidence of
`effectiveness of regorafenib was performed with the direction to take regorafenib following a low-fat meal, and in
`light of the food-effects, product labeling recommends that regorafenib be administered following a low-fat meal.
`
`Pharmacokinetic data obtained in patients with mild renal impairment (n=10) or mild, Child-Pugh A (n=4) or
`moderate Child-Pugh B (n=10) hepatic impairment do not suggest altered clearance requiring dose adjustments.
`However, Bayer will be required to conduct trials assessing pharmacokinetics in patients with severe renal
`impairment and severe hepatic impairment.
`
`Pharmacokinetic studies were conducted to evaluate for interactions between regorafenib and irinotecan, between
`regorafenib and 5-fluorouracil, and between regorafenib and oxaliplatin. There was no evidence of a
`pharmacokinetic interaction with fluoropyrimidines. Regorafenib and its metabolites inhibited UGT1A9 and
`inhibited UGT1A1 in vitro; exposure to irinotecan and its major active metabolite, SN-38, were increased by 28%
`and 44%, respectively when irinotecan was administered following regorafenib. Exposure to oxaliplatin was
`increased by 39% when oxaliplatin was administered following regorafenib. The mechanism for this apparent
`
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`Reference ID: 3195162
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`Page 4 of 10
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`Office Director Decisional Memo
`203085_Stivarga (regorafenib)
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`interaction is unknown. Because regorafenib is indicated for use as a single agent, these interactions are not
`included in product labeling.
`
`Additional pharmacokinetic trials demonstrated interactions between regorafenib and ketoconazole and between
`regorafenib and rifampin. Administration of ketoconazole increased the exposure of regorafenib by 33% and
`decreased the mean AUC of M2 and M5 each by 93%. Information on drug interactions is described in product
`labeling based on the potential for co-administration with regorafenib of drugs that are strong inhibitors or strong
`inducers the CYP3A4 enzyme.
`
`Regorafenib or its active metabolites M2 or M5 inhibited CY2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or
`CYP3A4 in vitro. The effect of regorafenib on the PK of CYP2C8, CYP2C9, and CYP3A4 substrates are under
`evaluation in an ongoing study. Regorafenib did not induce cytochrome P450 activity in vitro.
`
`See action letter for PMRs and PMCs.
`
`
`Clinical Microbiology
`6.
`Not applicable.
`
`
`Clinical/Statistical-Efficacy
`7.
`The data supporting this NDA are from Protocol 14387 (CORRECT trial), titled “A randomized, double-blind,
`placebo-controlled phase III study of regorafenib plus best supportive care (BSC) versus placebo plus BSC in
`patients with metastatic colorectal cancer (CRC) who have progressed after standard therapy”.
`
`Key inclusion criteria were age 18 years or older, ECOG performance status of 0 or 1, metastatic adenocarcinoma
`of colon or rectum with disease progression during or within 3 months after the last administration of an FDA-
`approved drug(s) for colorectal cancer or intolerance to such drugs.
`
`Patients were randomized to regorafenib 160 mg or matching placebo, administered orally, once daily on days 1-
`21 of each 28-day treatment cycle. Study drug administration continued until objective disease progression (per
`RECIST), clinical progression, unacceptable toxicity, or death.
`
`The planned sample size of 690 patients was designed to detect a hazard ratio (HR) of 0.75 for OS after 582
`deaths, with a two-sided alpha of 0.05 and 90% power, given the 2:1 randomization ratio. This was based on the
`assumed median OS times of 6 months and 4.5 months for the regorafenib- and placebo-treated arms,
`respectively.
`
`Results
`Protocol 14387 enrolled 780 patients at 105 clinical sites across 15 countries; there were 505 patients randomized
`to regorafenib and 255 patients randomized to placebo. The trial was terminated at the first interim analysis of OS
`for efficacy, after 432 deaths (74% of the planned 582 deaths for the final analysis). Based on the O'Brien-
`Fleming-type error spending function, the boundary was considered to have been crossed (< p=0.018) at the
`interim analysis which yielded a hazard ratio of 0.77, p=0.0102 stratified log-rank test. Efficacy was tested for the
`secondary endpoints of PFS, which was also statistically significant, and for overall response rate, which was not
`significantly different between arms. The results of the key efficacy analyses are summarized in the table below.
`
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`Reference ID: 3195162
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`Page 5 of 10
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`Office Director Decisional Memo
`
`203085_Stivarga (regorafenib)
`
`Efficacy Results from the CORRECT Trial
`
`Efficacy Endpoint
`
`Overall Survival
`
`Regorafenib (n=505)
`
`Placebo (n=255)
`
`
`
`—-———1_
`
`—1'_——_
`Pro: ression-free Survival
`
`Overall Res nse Rate
`
`Overall resnse,n %
`
`1 0.4%
`
`95% CI
`
`0.3%, 2.3%
`
`0%, 2.2%
`
`In exploratory subset analyses based on demographic parameters (age, gender, race) and on prognostic factors
`(ECOG performance status, K-Ras mutation status, time from metastatic cancer diagnosis of less than 18 months
`or 18 months or longer, number of prior lines of chemotherapy), there was consistent evidence of a treatment
`effect favoring the regorafenib arm for OS.
`
`Kaplan—Meier curves for the two treatment arms for OS and for PFS, respectively, are below.
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`Reference ID: 3195162
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`Page 6 of 10
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`Office Director Decisional Memo
`203085_Stivarga (regorafenib)
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`
`Kaplan-Meier Curves for Overall Survival, by Treatment Arm, for the CORRECT trial
`
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`Kaplan-Meier Curves for Progression-Free Survival, by Treatment Arm, for the CORRECT trial
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`Page 7 of 10
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`Reference ID: 3195162
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`Office Director Decisional Memo
`203085_Stivarga (regorafenib)
`
`The results described above, demonstrate a statistically persuasive and clinically meaningful increase in OS in
`patients for whom there is no FDA-approved treatment. The effects were supported by consistent trends in
`improved OS in relevant patient subgroups and evidence of a significant improvement in PFS.
`
`
`Safety
`
`8.
`
`Safety evaluation across multiple trials
`
`There was adequate data in the application to assess the risks of regorafenib treatment. The evaluation of safety
`in this application was supported primarily by data from the CORRECT trial in which 500 patients with mCRC
`received regorafenib and safety was compared with the 253 patients with mCRC who received placebo.
`
`Evaluation of serious adverse reactions was evaluated across the 1,145 patients with cancer, which included 621
`regorafenib-treated patients with mCRC in Phase 1-2 and Phase 3 trials, a Phase 3 study (Protocol 11726) in
`patients with renal cell carcinoma, a Phase 2 study (Protocol 14596) in patients with hepatocellular carcinoma, and
`12 Phase 1 studies (7 studies in patients with advanced solid tumors and 5 studies enrolling 124 healthy
`volunteers).
`
`Across the pooled safety database, there were 138 deaths occurring during or within 30 days of drug treatment;
`the majority of these deaths (n=111) were attributed to disease progression by the medical reviewer after
`evaluation of the case narratives. The most common causes of death after disease progression in regorafenib-
`treated patients were hemorrhage (4 patients: upper GI hemorrhage; rectal and vaginal hemorrhage, pulmonary
`hemorrhage; and intracranial hemorrhage), cardiac arrest (3 patients), and pneumonia (3 patients).
`
`There were 13 patients (1 in the placebo group and 12 treated with regorafenib) in the safety database with
`evidence of hepatotoxicity [AST/ALT > 3 times the upper limit of normal (ULN), alkaline phosphatase < 2 times the
`ULN, and total bilirubin 2 times ULN]. Of the 12 regorafenib-treated patients, only 2 of the 13 met all of the Hy’s
`law criteria as the other eleven had underlying liver disease (hepatocellular carcinoma or liver metastases).
`
`
`Safety evaluation in the CORRECT trial
`
`In Protocol 14387, the evaluation of adverse reaction profile was based on 500 patients with mCRC received at
`least one dose of regorafenib and 253 patients with mCRC who received at least one dose of matching placebo.
`The demographic and baseline characteristics for this safety population were similar to that for the efficacy
`population. The mean duration of therapy was 12 weeks for patients receiving regorafenib and 8 weeks for
`patients receiving placebo; 16% of the regorafenib-treated patients (n=80) in the safety population received 6 or
`more cycles of protocol-specified treatment. Treatment-emergent adverse events resulted in dose interruptions in
`61% of the patients receiving regorafenib and 38% of the patients had their dose reduced. In placebo group, the
`incidences of dose interruption and dose reduction were 22% and 3%, respectively. Drug-related adverse
`reactions that resulted in treatment discontinuation were reported in 8.2% of regorafenib-treated patients
`compared to 1.2% of patients who received placebo. The most common adverse reactions leading to drug
`discontinuation were general health deterioration (4%) and palmar-plantar erythrodysesthesia, hepatic failure,
`decreased appetite, pneumonia and rash (1% for each). The most common adverse reactions leading to dose
`reduction were palmar-plantar erythrodysesthesia (18%), diarrhea (3.8%), hypertension (3.2%), fatigue (2%), rash
`(2%), mucositis (1.2%), abdominal pain (1%) and asthenia (1%).
`
`Most frequent treatment-emergent adverse drug reactions, i.e., occurring at a higher rate among regorafenib
`patients as compared to those receiving placebo, reported in CORRECT trial were: decreased appetite, palmar-
`plantar erythrodysesthesia (PPE), diarrhea, fatigue, decreased weight, hypertension, dysphonia, pyrexia, asthenia,
`
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`Reference ID: 3195162
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`Page 8 of 10
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`

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`Office Director Decisional Memo
`203085_Stivarga (regorafenib)
`
`constipation, and rash. The incidence of both Grade 3 (56% vs. 26.5%) and Grade 4 (8.6% vs. 7.9%) toxicities
`were higher among regorafenib-treated patients as compared to those receiving placebo in the CORRECT trial.
`The most common of grades 3 and 4 adverse drug reactions of regorafenib observed in the CORRECT trial were
`palmar-plantar erythrodysesthesia, fatigue, diarrhea, hypertension, asthenia, rash, and hyperbilirubinemia.
`
`Other adverse drug reactions of special interest, based on the toxicity spectrum of other agents with similar
`mechanism of action, which occurred at higher rate in regorafenib-treated patients in the CORRECT trial were:
`hemorrhage (regorafenib 13% vs. 4.3% placebo), cardiac ischemia (regorafenib 1.2% vs. 0.4% placebo), and
`hypertension (regorafenib 30% vs. 8% placebo).
`
`Based on evaluation of EKG findings obtained serially in the CORRECT trial, there was no evidence of QTc
`prolongation in regorafenib-treated patients. The final results of an ongoing dedicated cardiac safety study (study
`14814), are pending.
`
`
`Advisory Committee Meeting
`9.
`The NDA for this new molecular entity was not presented to the Oncologic Drugs Advisory Committee for all of the
`following reasons: the safety profile is similar to that of other drugs approved for this indication; the clinical study
`design was acceptable; the application did not raise significant safety or efficacy issues that were unexpected for a
`drug indicated for the treatment of metastatic colorectal cancer; the application did not raise significant public
`health questions on the role of regorafenib in the treatment of metastatic colorectal cancer; and there were no
`controversial issues that would benefit from advisory committee discussion.
`
`
`Pediatrics
`10.
`A full waiver is granted because the disease/condition (metastatic colorectal cancer) does not exist in children.
`
`
`Other Relevant Regulatory Issues
`11.
` There are no other unresolved relevant regulatory issues.
`
`
`Labeling
`12.
` Proprietary name:
`The proposed proprietary name, Stivarga, was found to be acceptable by the Office of Prescription Drug
`Promotion (OPDP), the Division of Medication Error and Prevention Analysis (DMEP), and the Office of
`Hematology and Oncology Products.
`
` Physician labeling, Carton & container, Patient Labeling: There are no outstanding issues that preclude
`approval.
`
` 
`
`
`
`13.
`
`
`
`
`
`
`Decision/Action/Risk Benefit Assessment
`
` Regulatory Action: Approval.
`
` Risk Benefit Assessment
`
`
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`Page 9 of 10
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`Reference ID: 3195162
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`

`

`Office Director Decisional Memo
`203085_Stivarga (regorafenib)
`
`
`The CORRECT trial demonstrated a statistically persuasive and clinically meaningful increase in OS in
`patients for whom there is no FDA-approved treatment. The effects were supported by consistent trends
`in improved OS in relevant patient subgroups and evidence of a significant improvement in PFS. While
`both effects are modest, judged in the context of the very short survival and PFS expected these
`improvements are clinically meaningful in this population for which there are currently no FDA-approved
`treatments. Furthermore, the clinical benefits are meaningful in light of the adverse drug reaction profile.
`The adverse drug reaction profile of regorafenib is qualitatively similar to that observed with drugs
`previously approved for the treatment of metastatic solid tumors and which have been deemed
`acceptable by the patient and medical community in light of the potential benefits. The risk-benefit
`profile, which was also discussed by Drs. Keegan, Lemery, Pradhan and Shastri, is acceptable. In
`addition, the review team recommends approval of this NDA, and I concur.
`
`
`
`
`
`
` Recommendation for Postmarketing Risk Evaluation and Mitigation Strategies
`A REMS is not needed to ensure safe and effective use of regorafenib.
`
`
` Recommendation for other Postmarketing Requirements and Commitments: See action letter.
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`Page 10 of 10
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`Reference ID: 3195162
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`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`TAMY E KIM
`09/26/2012
`
`RICHARD PAZDUR
`09/26/2012
`
`Reference ID: 3195162
`
`