NCCN CLINICAL PRACTICE GUIDELINES IN ONCOLOGY (NCCN GUIDELINES ) VERSION 3

Transcription

1 CABOMETYX (cabozantinib): PRODUCT MONOGRAPH NCCN CLINICAL PRACTICE GUIDELINES IN ONCOLOGY (NCCN GUIDELINES ) VERSION RECOMMEND CABOZANTINIB (CABOMETYX ) FOR THE TREATMENT OF ADVANCED RCC 1 FIRST-LINE TREATMENT RECOMMENDATION Cabozantinib (CABOMETYX ) has a Category 2A recommendation for poor- and intermediate-risk patients with relapse or stage IV and surgically unresectable predominant clear cell histology RCC. 1 SUBSEQUENT THERAPY RECOMMENDATIONS 1 Cabozantinib (CABOMETYX ) has a Category 1, preferred recommendation for patients with relapse or stage IV and surgically unresectable predominant clear cell histology RCC after prior treatment with an anti-angiogenic therapy.* Cabozantinib (CABOMETYX ) has a Category 2A recommendation for patients with relapse or stage IV and surgically unresectable non-clear cell histology after prior treatment with an anti-angiogenic therapy. *Eligible patients should preferentially receive CABOMETYX over everolimus. The National Comprehensive Cancer Network makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way. INDICATION CABOMETYX (cabozantinib) is a kinase inhibitor indicated for the treatment of patients with advanced renal cell carcinoma (RCC). IMPORTANT SAFETY INFORMATION WARNINGS AND PRECAUTIONS Hemorrhage: Severe and fatal hemorrhages have occurred with CABOMETYX. In RCC trials, the incidence of Grade 3 hemorrhagic events was 3% in CABOMETYX patients. Do not administer CABOMETYX to patients that have or are at risk for severe hemorrhage.

2 Table of Contents Introduction... 2 Disease State Overview... 3 Mechanism of Action... 7 CABOSUN... 8 Trial...8 Efficacy Safety METEOR...16 Trial...16 Efficacy...18 Safety...23 Dosing and Administration...25 Pharmacodynamics Pharmacokinetics Drug Interactions...30 Important Safety Information Introduction Kidney cancer is a malignant tumor originating in the kidneys. Kidney cancer includes renal cell carcinoma (RCC; cancer that forms in the lining of very small tubes in the kidney that filter the blood and remove waste products) and renal pelvis cancer (cancer that forms in the center of the kidney where urine collects). 2 Given that renal pelvis cancer is classified with kidney cancers by the Surveillance, Epidemiology, and End Results (SEER) program, this monograph reviews disease state information for RCC and renal pelvis cancer. 2 However, the clinical overview of CABOMETYX (cabozantinib) focuses on advanced RCC alone. The information contained within this monograph is intended for formulary decision makers at payers or institutions, including, but not limited to, pharmacy, medical, and quality directors; clinical pharmacists; and case managers. 2

3 Disease State Overview Epidemiology 3,4 Kidney and renal pelvis cancer is the 8th most common cancer in the United States. In 2018 an estimated 65,340 Americans will be diagnosed with kidney and renal pelvis cancer and 14,970 Americans will die from this disease. 3 RCC accounts for 90% of cases of kidney and renal pelvis cancer. 4 ESTIMATED NEW CASES OF CANCER IN Breast cancer (female) Lung and bronchus cancer 266, ,030 Prostate cancer Colon and rectum cancer Bladder cancer Non-Hodgkin lymphoma Kidney and renal pelvis cancer Uterine corpus cancer 164, ,250 Melanoma of the skin 91,270 81,190 74,680 65,340 63,230 Leukemia 60,300 3

4 Disease State Overview (cont d) Diagnosis and Prognosis 2 Thirty-two percent of kidney and renal pelvis cancer patients were diagnosed with regional or distant (metastatic) disease. Patients with metastatic disease have a poor prognosis compared with those with earlier stage disease. The 5-year relative survival rate for metastatic kidney and renal pelvis cancer is 11.7%, compared with 92.6% for patients with localized disease. DISEASE PROGRESSION AT DIAGNOSIS 2 32% of patients have regional or distant disease at diagnosis 16% 16% 3% 65% Localized (65%) Confined to primary site Regional (16%) Spread to regional lymph nodes Distant (16%) Cancer has metastasized Unknown (3%) Unstaged 5-YEAR RELATIVE SURVIVAL % Percent % 38.0% 11.7% Localized Regional Distant Unstaged The prognosis for patients with metastatic kidney and renal pelvis cancer remains poor, representing an unmet need for additional treatment options. Stage 4

5 Disease State Overview (cont d) Patient Population As more targeted treatment options come to market for advanced RCC, prognostic models have been developed in an effort to optimize patient outcomes. Although several models exist, the most widely used is the Memorial Sloan Kettering Cancer Center (MSKCC) model. 5 Based on this MSKCC model, over 80% of patients with advanced RCC are considered intermediate to poor risk. 5 DISTRIBUTION OF RISK GROUPS IN ADVANCED RCC 5 19% Favorable Intermediate 22% 59% Poor 5

6 Disease State Overview (cont d) Mechanism of Disease 6-9 Tumor progression in RCC is driven by more than the vascular endothelial growth factor (VEGF) pathway. Functional loss of the VHL upregulates proteins such as MET, AXL, VEGF, and others. Overexpression of these proteins promotes tumor angiogenesis, growth, invasiveness, and metastasis. VEGF, MET, and AXL receptors play a key role in the development and progression of advanced RCC. MET VEGF AXL AXL=growth arrest specific protein 6 receptor; MET=hepatocyte growth factor receptor; VHL=von Hippel-Lindau. 6

7 Mechanism of Action CABOMETYX Inhibits More Than the VEGF Pathway 6,8,10-12 CABOMETYX is a tyrosine kinase inhibitor (TKI) that inhibits key receptors, including VEGFR, MET, and AXL, which are involved in normal and pathologic processes such as tumor growth, invasiveness, angiogenesis, and metastasis. MET AXL VEGF CABOMETYX* *Mechanism of action shown is based on in vitro biochemical and/or cellular assay. 10 IMPORTANT SAFETY INFORMATION (CONT D) WARNINGS AND PRECAUTIONS (CONT D) Gastrointestinal (GI) Perforations and Fistulas: In RCC trials, GI perforations were reported in 1% of CABOMETYX patients. Fatal perforations occurred in patients treated with CABOMETYX. In RCC studies, fistulas were reported in 1% of CABOMETYX patients. Monitor patients for symptoms of perforations and fistulas, including abscess and sepsis. Discontinue CABOMETYX in patients who experience a GI perforation or a fistula that cannot be appropriately managed. Thrombotic Events: Thrombotic events increased with CABOMETYX. In RCC trials, venous thromboembolism occurred in 9% (including 5% pulmonary embolism) and arterial thromboembolism occurred in 1% of CABOMETYX patients. Fatal thrombotic events occurred in the cabozantinib clinical program. Discontinue CABOMETYX in patients who develop an acute myocardial infarction or any other arterial thromboembolic complication. 7

8 CABOSUN CABOSUN Trial CABOSUN: A US Cooperative Group Head-to-Head, Randomized Controlled Trial 13 A PHASE 2 TRIAL VS SUNITINIB IN FIRST-LINE ADVANCED RCC 10,13,14 1:1 Randomization (N=157) CABOMETYX 60 mg once daily (6-week cycle) (n=79) sunitinib 50 mg once daily Treatment continued Treatment until continued disease until disease progression progression or or unacceptable toxicity Primary endpoint Progression-free Primary endpoint survival (PFS)* Progression-free survival (PFS)* Secondary endpoints Overall survival (OS) Objective response rate (ORR)* Safety (N=78) (n=78) *PFS and ORR were assessed by a retrospective, blinded independent radiology review committee (IRRC). Tumor assessments were conducted every 12 weeks from randomization to disease progression. Inclusion criteria : Clear cell component Measurable disease as defined by RECIST v1.1 IMDC intermediate or poor risk (patients must have 1 or more of the following): Time from diagnosis of RCC to systemic treatment <1 year Hemoglobin < LLN Corrected calcium > ULN Karnofsky performance status <80% Neutrophil count > ULN Platelet count > ULN No prior systemic treatment ECOG PS of 0-2 Adequate end-organ and marrow function with no uncontrolled significant illness Brain metastases if adequately treated and stable for 3 months Stratification factors 10 : IMDC intermediate or poor Bone metastases: presence or absence ECOG=Eastern Cooperative Oncology Group; IMDC=International Metastatic Renal Cell Carcinoma Database Consortium; LLN=lower limit of normal; PS=performance status; RECIST=Response Evaluation Criteria in Solid Tumors; ULN=upper limit of normal. 8

9 CABOSUN CABOSUN Trial (cont d) CABOSUN Evaluated a Broad Range of First-Line Patients With Advanced RCC 13,14 BASELINE PATIENT CHARACTERISTICS CABOMETYX (n=79) No. (%) sunitinib (n=78) Age, years Median Range Sex Male 66 (83.5) 57 (73.1) Female 13 (16.5) 21 (26.9) Ethnic origin White 70 (88.6) 75 (96.2) Non-white 6 (7.6) 2 (2.6) Not reported/unknown (patient unsure) 3 (3.8) 1 (1.3) ECOG PS 0 36 (45.6) 36 (46.2) 1 33 (41.8) 32 (41.0) 2 10 (12.7) 10 (12.8) IMDC risk group Intermediate 64 (81.0) 63 (80.8) Poor 15 (19.0) 15 (19.2) Bone metastases Yes 29 (36.7) 28 (35.9) No 50 (63.3) 50 (64.1) Prior nephrectomy Yes 57 (72.2) 60 (76.9) No 22 (27.8) 18 (23.1) Number of metastatic sites per investigator, % Metastatic sites per investigator, % Nodal Lung Bone Liver

10 CABOSUN CABOSUN Efficacy CABOMETYX Is the First and Only TKI to Demonstrate Superior Efficacy vs Sunitinib in First-Line Advanced RCC 10 * The PFS benefit was consistent across prespecified stratification factors. 10,13 PRIMARY ENDPOINT: PFS Progression-free Survival (%) RAPID AND SUSTAINED DIFFERENCE 5.3 months 8.6 months 52 % reduction in risk 20 HR=0.48 (95% CI: ) P= CABOMETYX (n=79) sunitinib (n=78) Months Patients at Risk CABOMETYX sunitinib CABOMETYX demonstrated a statistically significant improvement in median PFS vs sunitinib. 10 There was a sustained separation of the PFS curve at 12 and 18 months (median follow-up of 25 months). 10,13 CI=confidence interval; HR=hazard ratio. *Patients had 1 IMDC risk factors. 10 PFS was assessed by a retrospective blinded IRRC. 10 IMPORTANT SAFETY INFORMATION (CONT D) WARNINGS AND PRECAUTIONS (CONT D) Hypertension and Hypertensive Crisis: Treatment-emergent hypertension, including hypertensive crisis, increased with CABOMETYX. In RCC trials, hypertension was reported in 44% (18% Grade 3) of CABOMETYX patients. Monitor blood pressure prior to initiation and regularly during CABOMETYX treatment. Withhold CABOMETYX for hypertension that is not adequately controlled with medical management; when controlled, resume CABOMETYX at a reduced dose. Discontinue CABOMETYX if there is evidence of hypertensive crisis or for severe hypertension that cannot be controlled with antihypertensive therapy or medical management. 10

11 CABOSUN CABOSUN Efficacy (cont d) Secondary Endpoint: OS 14 The trial did not have a prespecified hypothesis for OS, and statistical testing of this endpoint was not performed. 10,13,14 reduction in risk of death 20 % HR=0.80 (95% CI: ) 10 IMPORTANT SAFETY INFORMATION (CONT D) WARNINGS AND PRECAUTIONS (CONT D) Diarrhea: In RCC trials, diarrhea occurred in 74% of CABOMETYX patients. Grade 3 diarrhea occurred in 11% of CABOMETYX patients. Withhold CABOMETYX in patients who develop intolerable Grade 2 diarrhea or Grade 3-4 diarrhea that cannot be managed with standard antidiarrheal treatments until improvement to Grade 1; resume CABOMETYX at a reduced dose. Palmar-Plantar Erythrodysesthesia (PPE): In RCC trials, PPE occurred in 42% of CABOMETYX patients. Grade 3 PPE occurred in 8% of CABOMETYX patients. Withhold CABOMETYX in patients who develop intolerable Grade 2 PPE or Grade 3 PPE until improvement to Grade 1; resume CABOMETYX at a reduced dose. 11

12 CABOSUN CABOSUN Efficacy (cont d) Secondary Endpoint: ORR 14 CABOMETYX More Than Doubled ORR vs Sunitinib 10 As assessed by a retrospective blinded IRRC, all responses were partial responses. 10 The trial did not have a prespecified hypothesis for ORR, and statistical testing of this endpoint was not performed. 10,13 ORR 9% 20% (95% CI: 3.7%-17.6%) (95% CI: 12.0%-30.8%) 0 10 CABOMETYX (n=79) sunitinib (n=78) Patients (%) IMPORTANT SAFETY INFORMATION (CONT D) WARNINGS AND PRECAUTIONS (CONT D) Reversible Posterior Leukoencephalopathy Syndrome (RPLS): RPLS, a syndrome of subcortical vasogenic edema diagnosed by characteristic finding on MRI, occurred in the cabozantinib clinical program. Evaluate for RPLS in patients presenting with seizures, headache, visual disturbances, confusion, or altered mental function. Discontinue CABOMETYX in patients who develop RPLS. Embryo-fetal Toxicity: CABOMETYX can cause fetal harm. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during CABOMETYX treatment and for 4 months after the last dose. 12

13 CABOSUN CABOSUN Efficacy (cont d) 80% of Patients Experienced Tumor Shrinkage With CABOMETYX Compared to 50% With Sunitinib 13 * REDUCTION IN TARGET LESION FROM BASELINE +120 Change From Baseline (%) Change From Baseline (%) CABOMETYX (n=69) sunitinib (n=58) Each vertical line in the graphs below corresponds to 1 patient. The plot represents the best percentage change in tumor size from baseline in the ITT population as determined by IRRC. Patients had at least 1 baseline and postbaseline assessment. 13 CR=complete response; ITT=intent to treat; NPACT=non-protocol anticancer therapy; PD=progressive disease; UE=unable to evaluate. * Data for the following subjects are not included in this figure: 14 subjects (cabozantinib 2, sunitinib 12) did not have postbaseline data. In addition, 3 subjects (cabozantinib 2, sunitinib 1) had only non-target lesions (response of non-cr/ non-pd); 7 subjects (cabozantinib 3, sunitinib 4) were unevaluable due to NPACT; disease progression was assessed for 5 subjects (cabozantinib 2, sunitinib 3) on the basis of new lesions or progression in non-target lesions; target lesions did not contribute to the assessment. Additionally, 1 cabozantinib subject with an overall response of UE did not have any postbaseline target lesions measured. 13

14 CABOSUN CABOSUN Safety No New Safety Signals Were Observed With CABOMETYX in the CABOSUN Trial 10 The CABOSUN safety profile was generally consistent with that of the initial CABOMETYX product approval. 10 GRADE 3-4 ARs OCCURRING IN >1% PATIENTS WHO RECEIVED CABOMETYX* No. (%) CABOMETYX (n=78) sunitinib (n=72) PATIENTS WITH ANY GRADE 3-4 AR 53 (68) 47 (65) Gastrointestinal Disorders Diarrhea 8 (10) 8 (11) Stomatitis 4 (5) 4 (6) Nausea 2 (3) 3 (4) General Disorders and Administration Site Conditions Fatigue 5 (6) 12 (17) Pain 4 (5) 0 Metabolism and Nutrition Disorders Decreased appetite 4 (5) 1 (1) Dehydration 3 (4) 1 (1) Skin and Subcutaneous Skin Disorders PPE 6 (8) 3 (4) Skin ulcer 2 (3) 0 Vascular Disorders Hypertension 22 (28) 15 (21) Hypotension 4 (5) 1 (1) Investigations Weight decreased 3 (4) 0 Nervous System Disorders Syncope 4 (5) 0 Psychiatric Disorders Depression 3 (4) 0 Infections and Infestations Lung infection 3 (4) 0 Musculoskeletal and Connective Tissue Disorders Back pain 3 (4) 0 Bone pain 2 (3) 1 (1) Pain in extremity 2 (3) 0 Renal and Urinary Disorders Renal failure acute 3 (4) 1 (1) The following Grade 3-4 ARs were seen in 1% of patients receiving CABOMETYX: dyspnea (vs 6% with sunitinib), anemia (vs 3% with sunitinib), vomiting (vs 3% with sunitinib), angiopathy (vs 1% with sunitinib), confusional state (vs 1% with sunitinib), arthralgia (vs 0% with sunitinib), constipation (vs 0% with sunitinib), and dysphonia (vs 0% with sunitinib). 13 AR=adverse reaction; PPE=palmar-plantar erythrodysesthesia. *National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 (NCI-CTCAE v4.0). Includes preferred term hypertension. 14

15 CABOSUN CABOSUN Safety (cont d) LABORATORY-RELATED GRADE 3-4 ARs OCCURRING IN 1% PATIENTS WHO RECEIVED CABOMETYX 10 * No. (%) CABOMETYX (n=78) sunitinib (n=72) Metabolism and Nutrition Disorders Hyponatremia 7 (9) 6 (8) Hypophosphatemia 7 (9) 5 (7) Hypocalcemia 2 (3) 0 Hypomagnesemia 2 (3) 0 Hyperkalemia 1 (1) 2 (3) Investigations ALT increased 4 (5) 0 AST increased 2 (3) 2 (3) Blood creatinine increased 2 (3) 2 (3) Lymphocyte count decreased 1 (1) 4 (6) Platelet count decreased 1 (1) 8 (11) Renal and Urinary Disorders Proteinuria 2 (3) 1 (1) ALT=alanine aminotransferase; AST=aspartate aminotransferase. ARs were graded according to NCI CTCAE v4.0. *Laboratory abnormalities are reported as ARs and not based on shifts in laboratory values. HOLDING AND REDUCING THE DOSE CAN HELP TO MANAGE ARs WITH CABOMETYX 10 CABOMETYX (n=78) sunitinib (n=72) Dose withholds 73% 71% Dose reductions 46% 35% Discontinuations 21% 22% Discontinuation rates due to ARs were similar between CABOMETYX (21%) and sunitinib (22%). 10 The overall efficacy results in the CABOSUN trial were achieved in the context of dose reductions and interruptions. 10,13 15

16 METEOR METEOR Trial METEOR: A Pivotal, Phase 3, Head-to-Head, Randomized Controlled Trial 10,16,17 AN OPEN-LABEL TRIAL VS EVEROLIMUS IN ADVANCED RCC AFTER PRIOR THERAPY* 1:1 Randomization (N=658) CABOMETYX 60 mg once daily (n=330) everolimus 10 mg once daily (n=328) (N=78) Daily treatment until disease progression or unacceptable toxicity. Treatment was continued after disease progression at discretion of the investigator. Primary endpoint Progression-free survival (PFS) Secondary endpoint Overall survival (OS) Secondary endpoint Objective response rate (ORR) Tumor assessment every 8 weeks for the first 12 months; then every 12 weeks thereafter. 10 *Anti-angiogenic. Dose reductions were allowed in both arms. The primary PFS analysis was conducted in the first 375 patients randomized to treatment. The intent-to-treat (ITT) population included all 658 patients. Confirmed per IRRC. Inclusion criteria 10,13,16 : Clear cell component Measurable disease as defined by RECIST v1.1 Radiographic progression within 6 months of enrollment Radiographic progression during treatment with a VEGFR-tyrosine kinase inhibitor (TKI) or within 6 months of last dose No limit to the number of prior therapies Prior treatment with antibodies targeting PD-1/PD-L1/L2 allowed Brain metastases allowed if adequately treated and stable Karnofsky performance status 70% Prespecified stratification 10,16 : Memorial Sloan Kettering Cancer Center (MSKCC) risk groups: favorable, intermediate, poor Number of prior VEGFR-TKIs: 1, 2 PD-1=programmed cell death protein-1; PD-L1/L2=programmed death ligand-1/ligand 2. 16

17 METEOR METEOR Trial (cont d) METEOR Evaluated a Diverse Set of Patients Who Had Received Prior Therapy 10,16 CABOMETYX (n=330) No. (%) everolimus (n=328) Median age (range) 63 (56-68) 62 (55-68) Sex Male 253 (77) 241 (73) Female 77 (23) 86 (26) Geographic region Europe 167 (51) 153 (47) North America 118 (36) 122 (37) Asia-Pacific 39 (12) 47 (14) Latin America 6 (2) 6 (2) Race White 269 (82) 263 (80) Asian 21 (6) 26 (8) Black 6 (2) 3 (<1) Other 19 (6) 13 (4) Not reported 15 (5) 22 (7) ECOG PS (68) 217 (66) (32) 111 (34) MSKCC prognostic risk category Favorable 150 (45) 150 (46) Intermediate 139 (42) 135 (41) Poor 41 (12) 43 (13) Metastatic site per IRRC Lung 204 (62) 212 (65) Liver 88 (27) 103 (31) Bone 77 (23) 65 (20) Lymph node 206 (62) 199 (61) Brain 2 (<1) 1 (<1) Other 23 (7) 21 (6) Previous VEGFR-TKIs (71) 229 (70) 2 95 (29) 99 (30) Previous systemic therapy Sunitinib 210 (64) 205 (62) Pazopanib 144 (44) 136 (41) Axitinib 52 (16) 55 (17) Sorafenib 21 (6) 31 (9) Bevacizumab 5 (2) 11 (3) Interleukin 2 20 (6) 29 (9) Interferon α 19 (6) 24 (7) Nivolumab* 17 (5) 14 (4) Radiotherapy 110 (33) 108 (33) Nephrectomy 283 (86) 279 (85) Nearly half of patients in the METEOR trial had favorable-risk disease. 10 Data are n (%) or median (IQR). *One additional patient in the cabozantinib group received prior atezolizumab. 17

18 METEOR METEOR Efficacy CABOMETYX Is the First and Only TKI to Demonstrate Significant Improvement Across 3 Endpoints OS, PFS, and ORR in Advanced RCC After Prior Therapy* Significant Survival Advantage SECONDARY ENDPOINT: OS OS (%) months 34 % reduction in risk 21.4 months 20 HR=0.66 (95% CI: ) P= CABOMETYX (n=330) everolimus (n=328) Patients at Risk Months CABOMETYX everolimus CABOMETYX showed a nearly 5-month increase in median OS for patients taking CABOMETYX vs everolimus. 10 Note sustained separation of the OS curve at 12 and 18 months (follow-up of at least 13 months). 16 *Anti-angiogenic. IMPORTANT SAFETY INFORMATION (CONT D) ADVERSE REACTIONS The most commonly reported ( 25%) adverse reactions were: diarrhea, fatigue, nausea, decreased appetite, hypertension, PPE, weight decreased, vomiting, dysgeusia, and stomatitis. 18

19 METEOR METEOR Efficacy (cont d) Proven Control of Progression 10,17 PRIMARY ENDPOINT: PFS* PFS (%) EARLY SEPARATION Nearly double median PFS 7.4 months HR=0.58 (95% CI: ) P< CABOMETYX (n=187) everolimus (n=188) Patients at Risk CABOMETYX Months everolimus There was a 42% reduction in the risk of disease progression or death vs everolimus. 10,17 *PFS was confirmed by IRRC. IMPORTANT SAFETY INFORMATION (CONT D) DRUG INTERACTIONS Strong CYP3A4 Inhibitors: If concomitant use with strong CYP3A4 inhibitors cannot be avoided, reduce the CABOMETYX dosage. Strong CYP3A4 Inducers: If concomitant use with strong CYP3A4 inducers cannot be avoided, increase the CABOMETYX dosage. 19

20 METEOR METEOR Efficacy (cont d) Significantly Improved Tumor Control 10 CABOMETYX significantly improved ORR (17%) vs everolimus (3%), as assessed by independent radiology review. 10,17 SECONDARY ENDPOINT: ORR* ORR 17 % (95% CI: 13%-22%) 3 % (95% CI: 2%-6%) CABOMETYX (n=330) everolimus (n=328) P< *ORR was assessed by blinded IRRC using RECIST v Partial responses only. 10 Patients (%) IMPORTANT SAFETY INFORMATION (CONT D) USE IN SPECIFIC POPULATIONS Lactation: Advise women not to breastfeed while taking CABOMETYX and for 4 months after the final dose. Hepatic Impairment: In patients with mild to moderate hepatic impairment, reduce the CABOMETYX dosage. CABOMETYX is not recommended for use in patients with severe hepatic impairment. 20

21 METEOR METEOR Efficacy (cont d) OS and PFS Results Across Subgroups Were Consistent With the Overall Population 13,16 * Patients (CABOMETYX/ everolimus) OS Events (CABOMETYX/everolimus) HR (95% CI) PFS Events (CABOMETYX/everolimus) HR (95% CI) Overall 330/ / ( ) 180/ ( ) Age <65 years 196/198 86/ ( ) 109/ ( ) 65 years 134/130 54/ ( ) 71/ ( ) Sex Female 77/86 37/ ( ) 48/ ( ) Male 253/ / ( ) 132/ ( ) Race Non-white 46/42 22/ ( ) 27/ ( ) White 269/ / ( ) 142/ ( ) MSKCC risk group Favorable 150/150 48/ ( ) 79/ ( ) Intermediate 139/135 64/ ( ) 74/ ( ) Poor 41/43 28/ ( ) 27/ ( ) IMDC risk group Favorable 66/62 14/ ( ) 34/ ( ) Intermediate 210/214 89/ ( ) 107/ ( ) Poor 54/52 37/ ( ) 39/ ( ) Previous nephrectomy No 47/49 24/ ( ) 25/ ( ) Yes 283/ / ( ) 155/ ( ) ECOG PS 0 226/216 81/ ( ) 114/ ( ) 1 104/112 59/ ( ) 66/ ( ) Diagnosis to randomization <1 year 59/76 35/ ( ) 37/ ( ) 1 year 271/ / ( ) 143/ ( ) Tumor MET status High 51/50 20/ ( ) 26/ ( ) Low 150/162 63/ ( ) 79/ ( ) Unknown 129/116 57/ ( ) 75/ ( ) Number of organs with metastases 1 59/56 18/ ( ) 33/ ( ) 2 101/77 38/ ( ) 52/ ( ) 3 168/190 84/ ( ) 95/ ( ) SoD < median 165/163 57/ ( ) 87/ ( ) median 165/164 83/ ( ) 93/ ( ) Bone metastases No 253/ / ( ) 140/ ( ) Yes 77/65 35/ ( ) 40/ ( ) Visceral metastases No 89/83 32/ ( ) 44/ ( ) Yes 241/ / ( ) 136/ ( ) Visceral and bone metastases No 270/ / ( ) 145/ ( ) Yes 60/52 29/ ( ) 35/ ( ) Number of previous VEGFR-TKIs 1 235/229 98/ ( ) 131/ ( ) 2 95/99 42/ ( ) 49/ ( ) Duration of first VEGFR-TKI 6 months 88/102 42/ ( ) 56/ ( ) >6 months 242/224 98/ ( ) 124/ ( ) Progression after start of most recent VEGFR-TKI <3 months 44/68 25/ ( ) 29/ ( ) 3 months 283/ / ( ) 148/ ( ) Previous PD-1 or PD-L1 treatment No 312/ / ( ) 174/ ( ) Yes 18/14 7/ ( ) 6/ ( ) Only previous VEGFR-TKI Sunitinib 135/132 59/ ( ) 74/ ( ) Pazopanib 88/83 34/ ( ) 51/ ( ) Favors CABOMETYX Favors everolimus Favors CABOMETYX Favors everolimus MET=hepatocyte growth factor receptor; SoD=sum of target lesion diameters. * The analysis of OS and PFS included all 658 patients from the ITT population. Subgroups were prespecified unless otherwise noted. Some populations were small. Subgroups are not considered substantial evidence and should only be considered hypothesis generating. These subgroups were not prespecified. 21

22 METEOR METEOR Efficacy (cont d) Improved Tumor Control 10,18 TUMOR RESPONSE AS ASSESSED BY IRRC 18 ORR (95% CI)* Best overall response, n (%) CABOMETYX (n=330) everolimus (n=328) 17% (13%-22%) 3% (2%-6%) Secondary endpoint 13 P< Confirmed complete response (CR) 0 0 Confirmed partial response (PR) 57 (17%) 11 (3%) Stable disease (SD) 216 (65%) 203 (62%) Progressive disease (PD) 41 (12%) 88 (27%) Not evaluable or missing II 16 (5%) 26 (8%) *The proportion of patients achieving an overall response of confirmed CR or PR per RECIST v PR is defined by RECIST v1.1 as 30% decrease in tumor size following study treatment. 19 SD is defined by RECIST v1.1 as neither sufficient increase nor decrease in tumor size to qualify as PD or PR, respectively, following study treatment. 19 PD is defined by RECIST v1.1 as 20% relative increase and 5 mm absolute increase in tumor size following study treatment. The appearance of 1 or more new lesions is also considered progression. 19 No qualifying postbaseline assessment for overall response

23 METEOR METEOR Safety CABOMETYX Safety in the METEOR Study ARs OCCURRING IN 10% OF PATIENTS IN THE CABOMETYX ARM 10,13 CABOMETYX (n=331) Percentage (%) of Patients everolimus (n=322) ARs* All Grades Grades 3-4 All Grades Grades 3-4 GI disorders Diarrhea Nausea <1 Vomiting <1 Stomatitis Constipation 25 <1 19 <1 Abdominal pain Dyspepsia 12 <1 5 0 General disorders and administration site conditions Fatigue Mucosal inflammation 19 < Asthenia Metabolism and nutrition disorders Decreased appetite <1 Skin and subcutaneous tissue disorders PPE <1 Rash 23 <1 43 <1 Dry skin Vascular disorders Hypertension Investigations Weight decreased Nervous system disorders Dysgeusia Headache 11 <1 12 <1 Dizziness Endocrine disorders Hypothyroidism 21 0 <1 <1 Respiratory, thoracic, and mediastinal disorders Dysphonia 20 <1 4 0 Dyspnea Cough 18 <1 33 <1 Blood and lymphatic disorders Anemia Musculoskeletal and connective tissue disorders Pain in extremity <1 Muscle spasms Arthralgia 11 < Renal and urinary disorders Proteinuria <1 GI=gastrointestinal. *Percentages are treatment-emergent, all-causality events. One subject randomized to everolimus received CABOMETYX. National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0. These adverse reactions are grouped terms. For details, please see full Prescribing Information. 23

24 METEOR METEOR Safety (cont d) CABOMETYX Safety in the METEOR Study (cont d) LABORATORY ABNORMALITIES OCCURRING IN 25% OF PATIENTS IN THE CABOMETYX ARM 10 CABOMETYX (n=331)* ALP=alkaline phosphatase; GGT=gamma-glutamyltransferase. *One subject randomized to everolimus received CABOMETYX. NCI CTCAE. Percentage (%) of Patients everolimus (n=322) Test All Grades Grades 3-4 All Grades Grades 3-4 Chemistry AST increased <1 ALT increased <1 Creatinine increased 58 < Triglycerides increased Hypophosphatemia Hyperglycemia Hypoalbuminemia <1 ALP increased Hypomagnesemia <1 Hyponatremia GGT increased Hematology White blood cells decreased 35 <1 31 <1 Absolute neutrophil count decreased <1 Hemoglobin decreased Lymphocytes decreased Platelets decreased 25 <1 27 <1 Dose Withholds, Reductions, Discontinuations and Duration of Treatment During the METEOR Trial Discontinuation rates due to ARs were similar between CABOMETYX (10%) and everolimus (10%). 10 Dose adjustments were allowed in the METEOR trial, resulting in a mean daily dose of CABOMETYX of 45 mg. 13 The overall efficacy results in the METEOR trial were achieved in the context of dose reductions and interruptions. 10,13 HOLDING AND REDUCING THE DOSE CAN HELP TO MANAGE ARs WITH CABOMETYX 10 CABOMETYX (n=331) everolimus (n=322) Dose withholds 70% 59% Dose reductions 60% 24% Discontinuations 10% 10%

25 Dosing and Administration 10 Recommended starting dose 60 mg daily First reduction 40 mg daily Second reduction 20 mg daily Tablets shown are not actual size. Do not substitute CABOMETYX tablets with cabozantinib capsules The recommended oral daily dose of CABOMETYX is 60 mg. Do not administer CABOMETYX with food. Instruct patients not to eat for at least 2 hours before and at least 1 hour after taking CABOMETYX. Continue treatment until patient no longer experiences clinical benefit or experiences unacceptable toxicity Swallow CABOMETYX tablets whole. Do not crush CABOMETYX tablets Do not take a missed dose within 12 hours of the next dose Do not ingest foods (eg, grapefruit, grapefruit juice) or nutritional supplements that are known to inhibit cytochrome P450 during CABOMETYX treatment 25

26 Dosing and Administration (cont d) CABOMETYX Dose May Need to Be Adjusted Based on Individual Patient Safety and Tolerability 10 FOR GRADE 4 OR INTOLERABLE GRADE 3 ARS THAT REQUIRE A DOSE REDUCTION Withhold CABOMETYX Wait until improvement or resolution (return to baseline or resolution to Grade 1) Restart For patients who previously received 60 mg or 40 mg: RESTART CABOMETYX at a dose reduced by 20 mg Resume For patients who previously received 20 mg: RESUME CABOMETYX at 20 mg if tolerated; otherwise, DISCONTINUE Permanently discontinue CABOMETYX for development of unmanageable fistula or GI perforation, severe hemorrhage, arterial thromboembolic event, hypertensive crisis or severe hypertension despite optimal medical management, nephrotic syndrome, or reversible posterior leukoencephalopathy syndrome. 10 The overall efficacy results in the CABOMETYX trials were achieved in the context of dose adjustments and reduction. If ARs occur, consider supportive care and/or adjust the dose. 26

27 Dosing and Administration (cont d) Dosage Adjustments 10 For Patients Undergoing Surgery Stop treatment with CABOMETYX at least 28 days prior to scheduled surgery, including dental surgery. For Adverse Reactions Management of Grade 3 adverse reactions may require dose modifications and/or supportive care. If dose reduction is required, a 20-mg decrease from the previously administered dose is recommended. If Grade 3 adverse reaction is intolerable, withhold CABOMETYX. Withhold CABOMETYX for NCI CTCAE Grade 4 adverse reactions. If the dose was withheld, upon resolution/improvement (ie, return to baseline or resolution to Grade 1) of an adverse reaction, reduce the dose as follows: If previously receiving 60-mg daily dose, resume treatment at 40 mg daily If previously receiving 40-mg daily dose, resume treatment at 20 mg daily If previously receiving 20-mg daily dose, resume at 20 mg if tolerated, otherwise discontinue CABOMETYX Permanently discontinue CABOMETYX for any of the following: Development of unmanageable fistula or GI perforation Severe hemorrhage Arterial thromboembolic event (eg, myocardial infarction, cerebral infarction) Hypertensive crisis or severe hypertension despite optimal medical management Nephrotic syndrome Reversible posterior leukoencephalopathy syndrome In Patients Concurrently Taking a Strong CYP3A4 Inhibitor Reduce the daily CABOMETYX dose by 20 mg (for example, from 60 mg to 40 mg daily or from 40 mg to 20 mg daily). Resume the dose that was used prior to initiating the CYP3A4 inhibitor 2 to 3 days after discontinuation of the strong inhibitor. In Patients Concurrently Taking a Strong CYP3A4 Inducer Increase the daily CABOMETYX dose by 20 mg (for example, from 60 mg to 80 mg daily or from 40 mg to 60 mg daily) as tolerated. Resume the dose that was used prior to initiating the CYP3A4 inducer 2 to 3 days after discontinuation of the strong inducer. The daily dose of CABOMETYX should not exceed 80 mg. In Patients With Hepatic Impairment Reduce the starting dose of CABOMETYX to 40 mg once daily in patients with mild or moderate hepatic impairment. CABOMETYX is not recommended for use in patients with severe hepatic impairment. 27

28 Dosing and Administration (cont d) How Supplied10 CABOMETYX is available as 60-mg, 40-mg, and 20-mg tablets. Strength National Drug Code (NDC)* CABOMETYX 60 mg CABOMETYX 40 mg CABOMETYX 20 mg Tablets and bottles not actual size. * FDA standard NDC has been zero-filled to ensure creation of an 11-digit code that meets Health Insurance Portability and Accountability Act (HIPAA) standards. The zero-fill location is indicated in bold. Storage Requirements10 Store CABOMETYX at 20 C to 25 C (68 F to 77 F) Excursions are permitted from 15 C to 30 C (59 F to 86 F) 28

29 Pharmacodynamics The exposure-response or safety relationship for cabozantinib is unknown. 10 Cardiac Electrophysiology 10 The effect of orally administered cabozantinib on QTc interval was evaluated in a randomized, double-blinded, placebo-controlled study in patients with medullary thyroid cancer administered a dose of 140 mg. A mean increase in QTcF of 10 ms to 15 ms was observed at 4 weeks after initiating cabozantinib. A concentration-qtc relationship could not be definitively established. Changes in cardiac wave form morphology or new rhythms were not observed. No cabozantinibtreated patients in this study had a confirmed QTcF >500 ms, nor did any cabozantinib-treated patients in the RCC study (at a dose of 60 mg). Pharmacokinetics Repeat daily dosing of cabozantinib at 140 mg for 19 days resulted in 4- to 5-fold mean cabozantinib accumulation (based on AUC) compared to a single dose administration; steadystate was achieved by day Absorption 10 Following oral administration of cabozantinib, median time to peak cabozantinib plasma concentrations (T max ) ranged from 3 to 4 hours postdose. A 19% increase in the C max of the tablet formulation (CABOMETYX) compared to the capsule formulation (COMETRIQ ) was observed following a single 140-mg dose. A <10% difference in the AUC was observed between the cabozantinib tablet (CABOMETYX) and capsule (COMETRIQ) formulations. Cabozantinib C max and AUC values increased by 41% and 57%, respectively, following a high-fat meal relative to fasted conditions in healthy subjects administered a single 140-mg oral dose of an investigational cabozantinib capsule formulation. Distribution 10 The oral volume of distribution (V z /F) of cabozantinib is approximately 319 L. Cabozantinib is highly protein bound in human plasma ( 99.7%). Elimination 10 The predicted terminal half-life is approximately 99 hours and the clearance (CL/F) at steady state is estimated to be 2.2 L/hour. Metabolism 10 Cabozantinib is a substrate of CYP3A4 in vitro. Excretion 10 Approximately 81% of the total administered radioactivity was recovered within a 48-day collection period following a single 140-mg dose of an investigational 14 C-cabozantinib formulation in healthy subjects. Approximately 54% was recovered in feces and 27% in urine. Unchanged cabozantinib accounted for 43% of the total radioactivity in feces and was not detectable in urine following a 72-hour collection. 29

30 Pharmacokinetics (cont d) Specific Populations 10 The following patient characteristics did not result in a clinically relevant difference in the pharmacokinetics of cabozantinib: age (32-86 years), sex, race (whites and non-whites), or mild to moderate renal impairment (egfr greater than or equal to 30 ml/min/1.73 m 2 as estimated by MDRD [modification of diet in renal disease] equation). The pharmacokinetics of cabozantinib is unknown in patients with worse than moderate renal impairment (egfr less than 29 ml/min/1.73 m 2 ) as estimated by MDRD equation or renal impairment requiring dialysis. Hepatic Impairment Cabozantinib exposure (AUC 0-inf ) increased by 81% and 63%, respectively, in patients with mild (C-P A) and moderate (C-P B) hepatic impairment. Patients with severe hepatic impairment have not been studied. Pediatric Population The pharmacokinetics of cabozantinib has not been studied in the pediatric population. Drug Interactions Clinically Significant Drug Interactions Involving Drugs That Affect Cabozantinib 10 STRONG CYP3A4 INHIBITORS 10 Clinical implications Prevention or management Examples Concomitant use of CABOMETYX with a strong CYP3A4 inhibitor increased the exposure of cabozantinib compared to the use of CABOMETYX alone Increased cabozantinib exposure may increase the risk of exposurerelated toxicity Reduce the dosage of CABOMETYX if concomitant use with strong CYP3A4 inhibitors cannot be avoided Boceprevir, clarithromycin, conivaptan, grapefruit juice,* indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telithromycin, and voriconazole STRONG CYP3A4 INDUCERS 10 Clinical implications Prevention or management Examples Concomitant use of CABOMETYX with a strong CYP3A4 inducer decreased the exposure of cabozantinib compared with the use of CABOMETYX alone Decreased cabozantinib exposure may lead to reduced efficacy Increase the dosage of CABOMETYX if concomitant use with strong CYP3A4 inducers cannot be avoided (please see Dosing and Administration section for appropriate dose adjustments) Rifampin, phenytoin, carbamazepine, phenobarbital, rifabutin, rifapentine, and St. John s wort *The effect of grapefruit juice varies widely among brands and is concentration-, dose-, and preparation-dependent. Studies have shown that it can be classified as a strong CYP3A inhibitor when a certain preparation was used (eg, high dose, double strength) or as a moderate CYP3A inhibitor when another preparation was used (eg, low dose, single strength). The effect of St. John s wort varies widely and is preparation-dependent. 30

31 Important Safety Information WARNINGS AND PRECAUTIONS Hemorrhage: Severe and fatal hemorrhages have occurred with CABOMETYX. In RCC trials, the incidence of Grade 3 hemorrhagic events was 3% in CABOMETYX patients. Do not administer CABOMETYX to patients that have or are at risk for severe hemorrhage. Gastrointestinal (GI) Perforations and Fistulas: In RCC trials, GI perforations were reported in 1% of CABOMETYX patients. Fatal perforations occurred in patients treated with CABOMETYX. In RCC studies, fistulas were reported in 1% of CABOMETYX patients. Monitor patients for symptoms of perforations and fistulas, including abscess and sepsis. Discontinue CABOMETYX in patients who experience a GI perforation or a fistula that cannot be appropriately managed. Thrombotic Events: Thrombotic events increased with CABOMETYX. In RCC trials, venous thromboembolism occurred in 9% (including 5% pulmonary embolism) and arterial thromboembolism occurred in 1% of CABOMETYX patients. Fatal thrombotic events occurred in the cabozantinib clinical program. Discontinue CABOMETYX in patients who develop an acute myocardial infarction or any other arterial thromboembolic complication. Hypertension and Hypertensive Crisis: Treatment-emergent hypertension, including hypertensive crisis, increased with CABOMETYX. In RCC trials, hypertension was reported in 44% (18% Grade 3) of CABOMETYX patients. Monitor blood pressure prior to initiation and regularly during CABOMETYX treatment. Withhold CABOMETYX for hypertension that is not adequately controlled with medical management; when controlled, resume CABOMETYX at a reduced dose. Discontinue CABOMETYX if there is evidence of hypertensive crisis or for severe hypertension that cannot be controlled with antihypertensive therapy or medical management. Diarrhea: In RCC trials, diarrhea occurred in 74% of CABOMETYX patients. Grade 3 diarrhea occurred in 11% of CABOMETYX patients. Withhold CABOMETYX in patients who develop intolerable Grade 2 diarrhea or Grade 3-4 diarrhea that cannot be managed with standard antidiarrheal treatments until improvement to Grade 1; resume CABOMETYX at a reduced dose. Palmar-Plantar Erythrodysesthesia (PPE): In RCC trials, PPE occurred in 42% of CABOMETYX patients. Grade 3 PPE occurred in 8% of CABOMETYX patients. Withhold CABOMETYX in patients who develop intolerable Grade 2 PPE or Grade 3 PPE until improvement to Grade 1; resume CABOMETYX at a reduced dose. Reversible Posterior Leukoencephalopathy Syndrome (RPLS): RPLS, a syndrome of subcortical vasogenic edema diagnosed by characteristic finding on MRI, occurred in the cabozantinib clinical program. Evaluate for RPLS in patients presenting with seizures, headache, visual disturbances, confusion, or altered mental function. Discontinue CABOMETYX in patients who develop RPLS. Embryo-fetal Toxicity: CABOMETYX can cause fetal harm. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during CABOMETYX treatment and for 4 months after the last dose. page 32 and full Prescribing Information by clicking here. 31

32 Important Safety Information (cont d) ADVERSE REACTIONS The most commonly reported ( 25%) adverse reactions were: diarrhea, fatigue, nausea, decreased appetite, hypertension, PPE, weight decreased, vomiting, dysgeusia, and stomatitis. DRUG INTERACTIONS Strong CYP3A4 Inhibitors: If concomitant use with strong CYP3A4 inhibitors cannot be avoided, reduce the CABOMETYX dosage. Strong CYP3A4 Inducers: If concomitant use with strong CYP3A4 inducers cannot be avoided, increase the CABOMETYX dosage. USE IN SPECIFIC POPULATIONS Lactation: Advise women not to breastfeed while taking CABOMETYX and for 4 months after the final dose. Hepatic Impairment: In patients with mild to moderate hepatic impairment, reduce the CABOMETYX dosage. CABOMETYX is not recommended for use in patients with severe hepatic impairment. page 31 and full Prescribing Information by clicking here. References: 1. Referenced with permission from The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ) for Kidney Cancer. V National Comprehensive Cancer Network, Inc All rights reserved. Accessed February 12, To view the most recent and complete version of the guidelines, go online to NATIONAL COMPREHENSIVE CANCER NETWORK, NCCN, NCCN GUIDELINES, and all other NCCN content are trademarks owned by the National Comprehensive Cancer Network, Inc. 2. National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) Program. Stat fact sheets: kidney and renal pelvis cancer. html/kidrp.html. February 2, American Cancer Society. Cancer Facts & Figures Atlanta: American Cancer Society; Available at: Accessed February 2, American Cancer Society. Kidney cancer (adult) renal cell carcinoma. Accessed February 2, Heng DY, Xie W, Regan MM, et al. External validation and comparison with other models of the International Metastatic Renal-Cell Carcinoma Database Consortium prognostic model: a population-based study. Lancet Oncol. 2013;14(2): Koochekpour S, Jeffers M, Wang PH, et al. The von Hippel-Lindau tumor suppressor gene inhibits hepatocyte growth factor/scatter factor-induced invasion and branching morphogenesis in renal carcinoma cells. Mol Cell Biol. 1999;19: Rankin EB, Fuh KC, Castellini L, et al. Direct regulation of GAS6/AXL signaling by HIF promotes renal metastasis through SRC and MET. Proc Natl Acad Sci USA. 2014;111: Zhou L, Liu X-D, Sun M, et al. Targeting MET and AXL overcomes resistance to sunitinib therapy in renal cell carcinoma. Oncogene. 2016;35: doi: / onc Wiesener MS, Münchenhagen PM, Berger I, et al. Constitutive activation of hypoxia-inducible genes related to overexpression of hypoxia-inducible factor-1α in clear cell renal carcinomas. Cancer Res. 2001;61: CABOMETYX (cabozantinib) Prescribing Information. Exelixis, Inc., Bukowski RM. Third generation tyrosine kinase inhibitors and their development in advanced renal cell carcinoma. Front Oncol. 2012;2(13): Kwilas AR, Ardiani A, Donahue RN, et al. Dual effects of a targeted small-molecule inhibitor (cabozantinib) on immune-mediated killing of tumor cells and immune tumor microenvironment permissiveness when combined with a cancer vaccine. J Transl Med. 2014;12: Data on file. Exelixis, Inc. 14. Choueiri TK, Halabi S, Sanford BL, et al. Cabozantinib versus sunitinib as initial targeted therapy for patients with metastatic renal cell carcinoma of poor or intermediate risk: the Alliance A CABOSUN trial. J Clin Oncol. 2017;35(6): Heng DY, Xie W, Regan MM, et al. Prognostic factors for overall survival in patients with metastatic renal cell carcinoma treated with vascular endothelial growth factor-targeted agents: results from a large, multicenter study. J Clin Oncol. 2009;27(34): Choueiri TK, Escudier B, Powles T, et al. Cabozantinib versus everolimus in advanced renal cell carcinoma (METEOR): final results from a randomised, open-label, phase 3 trial. Lancet Oncol. 2016;17(7): doi: /s (16) Choueiri TK, Escudier B, Powles T, et al. Cabozantinib versus everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015;373(19): doi: /nejmoa Supplement to: Choueiri TK, Escudier B, Powles T, et al. Cabozantinib versus everolimus in advanced renal cell carcinoma (METEOR): final results from a randomised, openlabel, phase 3 trial. Lancet Oncol. 2016;17(7): doi: /s (16) Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation in solid tumors: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):

33 2018 Exelixis, Inc. CA /18