Move Forward in RCC by OEM65

Because it’s not only where his treatment will take him— it’s where he will take his treatment

New VOTRIENT— Move Forward in Advanced RCC

Introducing a new multitargeted tyrosine kinase inhibitor (TKI) that is indicated for the treatment of advanced renal cell carcinoma (RCC)1 WARNING: HEPATOTOXICITY See full prescribing information for complete boxed warning. Severe and fatal hepatotoxicity has been observed in clinical studies. Monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended. Please see additional Important Safety Information on pages 10 and 11 and accompanying full Prescribing Information, including BOXED WARNING.

pazopanib tablets (200 mg)

MOA/Study Design

New VOTRIENT—Move Forward in Advanced RCC

VOTRIENT Is a New Selective Multitargeted Tyrosine Kinase Inhibitor (TKI) for Advanced RCC1

Randomized, Double-Blind, Placebo-Controlled Phase 3 Trial1,3

VOTRIENT is a small-molecule TKI that speciﬁcally targets growth factor receptors associated with angiogenesis and tumor cell proliferation1,2

Trial included treatment-naïve and cytokine-pretreated patients (n=435) with advanced RCC1,3

• VOTRIENT exhibited inhibition of1,2:

STUDY DESIGN1,3

— Vascular endothelial growth factor receptors (VEGFR -1, -2, and -3)

Eligibility Criteria

— Platelet-derived growth factor receptors (PDGFR -α and -β) — Fibroblast growth factor receptors (FGFR -1 and -3) — Stem cell factor receptor (c-Kit)

• Failure of 1 prior cytokinebased treatment • Treatment-naïve patients

— Interleukin-2 receptor inducible T-cell kinase (Itk) — Leukocyte-speciﬁc protein tyrosine kinase (Lck) — Transmembrane glycoprotein receptor tyrosine kinase (c-Fms)

• Predominant clear cell • Response evaluation criteria in solid tumors (measurable)

Stratiﬁcation • Treatment naïve • Failure of 1 prior cytokine-based treatment* • ECOG PS 0 vs 1 • Prior nephrectomy

RANDOMIZED (2:1)

VOTRIENT (n=290) 800 mg once daily

Treatment Naïve (n=155) Cytokine Pretreated (n=135)

Placebo† (n=145) Treatment Naïve (n=78) Cytokine Pretreated (n=67)

Upon progression, patients in the placebo group were eligible to receive VOTRIENT in an extension study

• The primary endpoint of the study was progression-free survival (PFS)1,3 — Study was powered prospectively to detect differences in treatment-naïve and cytokine-pretreated subpopulations WARNING: HEPATOTOXICITY See full prescribing information for complete boxed warning. Severe and fatal hepatotoxicity has been observed in clinical studies. Monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended.

— ≥90% power to detect 80% difference for integrated population • Secondary endpoint of the study was overall survival (OS)1,3 — OS data were not mature at the time of the interim survival analysis

VOTRIENT is indicated for the treatment of patients with advanced renal cell carcinoma. Please see additional Important Safety Information on pages 10 and 11 and accompanying full Prescribing Information, including BOXED WARNING.

*Prior cytokine-based treated = IFNα (interferon alpha) and IL-2 (interleukin-2). † Placebo plus best supportive care was used as the comparator due to limited availability of other multikinase inhibitors at the time of study initiation.

New VOTRIENT—Move Forward in Advanced RCC

VOTRIENT Provides Signiﬁcant Improvement in PFS in Patients With Advanced RCC 1

Patient Demographics3

• 9.2 months (95% CI, 7.4-12.9) overall median PFS with VOTRIENT vs 4.2 months (95% CI, 2.8-4.2) with placebo (P<0.0000001)1,3

Parameters

• 30% overall response rate with VOTRIENT vs 3% with placebo (P<0.001)1,3

Male, n (%)

VOTRIENT (n=290)

Placebo (n=145)

59 (28-85)

60 (25-81)

198 (68)

109 (75)

White

252 (87)

122 (84)

Asian

36 (12)

23 (16)

Black

1 (<1)

Other

1 (<1)

264 (91)

129 (89)

Median age, years (range) Race, n (%)

• 58.7-week median duration of response as per independent review1

Median PFS in 435 patients with advanced RCC1 Proportion Progression Free

Efﬁcacy/ Patient Demographics

Patient demographics and disease characteristics3

According to independent assessment1

Histology, n (%)

1.0 VOTRIENT (n=290) Placebo (n=145)

0.8

P<0.0000001 0.6 0.4 0.2

54% HR 0.46 (0.34, 0.62) reduced risk of progression with New VOTRIENT 1

0.0 0

Clear cell Predominantly clear cell

25 (9)

16 (11)

15.7 (0-184)

13.8 (1.0-152)

Lung

214 (74)

Lymph nodes

157 (54)

106 (73) 86 (59)

Bone

81 (28)

Median time since initial diagnosis, months, (range) Most common sites of metastasis, n (%)

Liver

75 (26)

32 (22)

Kidney

66 (23)

36 (25)

53 (18)

20 (14)

78 (27)

50 (34)

≥3

159 (55)

75 (52)

123 (42)

60 (41)

167 (58)

85 (59)

Favorable risk

113 (39)

57 (39)

Intermediate risk

159 (55)

77 (53)

Poor risk

9 (3)

5 (3)

Unknown

9 (3)

6 (4)

258 (89)

127 (88)

Number of organs involved, n (%)

Months

VOTRIENT demonstrated signiﬁcant improvement in PFS in treatment-naïve and cytokine-pretreated patients1,3 Treatment-naïve patients

Cytokine-pretreated patients

11.1 months

7.4 months

(95% CI, 7.4-14.8) median PFS with VOTRIENT (n=155) vs 2.8 months (95% CI, 1.9-5.6) with placebo (n=78) (P<0.0000001)1,3

(95% CI, 5.6-12.9) median PFS with VOTRIENT (n=135) vs 4.2 months (95% CI, 2.8-5.6) with placebo (n=67) (P<0.001)1,3

60% [HR 0.40 (0.27, 0.60)] reduced risk of progression with VOTRIENT vs placebo

38 (26)

46% [HR 0.54 (0.35, 0.84)] reduced risk of progression with VOTRIENT vs placebo

ECOG performance status, n (%)

MSKCC risk category, n (%)

Prior nephrectomy, n (%) Prior systemic treatment, n (%)

Hepatic Effects: Patients with pre-existing hepatic impairment should use VOTRIENT with caution. Increases in serum transaminase levels (ALT, AST) and bilirubin were observed. Severe and fatal hepatotoxicity have occurred. Before the initiation of treatment and regularly during treatment, monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended.

Treatment naïve

155 (53)

78 (54)

Cytokine pretreated

135 (47)

67 (46) 5

Abbreviations: ITT, intent to treat; ECOG, Eastern Cooperative Oncology Group; MSKCC, Memorial Sloan-Kettering Cancer Center.

New VOTRIENT—Move Forward in Advanced RCC

VOTRIENT Signiﬁcantly Improved PFS in Treatment-Naïve Patients1

VOTRIENT Signiﬁcantly Improved PFS in Cytokine-Pretreated Patients1

• 11.1 months (95% CI, 7.4-14.8) median PFS with VOTRIENT vs 2.8 months (95% CI, 1.9-5.6) with placebo (P<0.0000001)1,3

• 7.4 months (95% CI, 5.6-12.9) median PFS with VOTRIENT vs 4.2 months (95% CI, 2.8-5.6) with placebo (P<0.001)1,3 Median PFS by independent assessment in 202 cytokine-pretreated patients with advanced RCC3

VOTRIENT (n=155) Placebo (n=78)

0.8

60%

P<0.0000001

HR 0.40 (0.27, 0.60) reduced risk of progression with New VOTRIENT 1

0.6 0.4 0.2 0.0

1.0 VOTRIENT (n=135) Placebo (n=67)

0.8

46%

P<0.001

HR 0.54 (0.35, 0.84) reduced risk of progression with New VOTRIENT 1

0.6 0.4 0.2 0.0

Months

Proportion Progression Free

1.0

Efﬁcacy

Proportion Progression Free

Median PFS by independent assessment in 233 treatment-naive patients with advanced RCC3

Months

Randomized, double-blind, placebo-controlled, multicenter study to evaluate the efﬁcacy and safety of VOTRIENT in patients (N=435) with advanced RCC. Patients with locally advanced or metastatic RCC were randomized (2:1) to receive either VOTRIENT 800 mg once daily or placebo.

32% overall response with VOTRIENT in treatment-naïve patients vs 4% with placebo 3

29% overall response with VOTRIENT in cytokine-pretreated patients vs 3% with placebo 3

QT Prolongation and Torsades de Pointes: Arrhythmias, including torsades de pointes, have been observed with VOTRIENT. Use with caution in patients at higher risk of developing QT interval prolongation, in patients taking antiarrhythmics or other medications that may prolong QT interval, and those with relevant pre-existing cardiac disease. Monitoring electrocardiograms and electrolytes should be performed.

Gastrointestinal Perforation and Fistula: Gastrointestinal perforation or ﬁstula has occurred. Fatal perforation events have occurred. Use with caution in patients at risk for gastrointestinal perforation or ﬁstula.

Hemorrhagic Events: Fatal hemorrhagic events have been reported. VOTRIENT has not been studied in patients who have a history of hemoptysis, cerebral, or clinically signiﬁcant gastrointestinal hemorrhage in the past 6 months and should not be used in those patients.

Hypertension: Hypertension has been observed. Blood pressure should be well-controlled prior to initiating VOTRIENT. Monitor for hypertension and treat as needed. If hypertension persists despite antihypertensive therapy, the dose of VOTRIENT may be reduced or discontinued as appropriate.

Arterial Thrombotic Events: Arterial thrombotic events have been observed and can be fatal. Use with caution in patients who are at increased risk for these events.

Wound Healing: VOTRIENT may impair wound healing. Temporary interruption of therapy with VOTRIENT is recommended in patients undergoing surgical procedures.

New VOTRIENT—Move Forward in Advanced RCC

VOTRIENT Adverse Events Proﬁle1,3

VOTRIENT Laboratory Abnormalities Proﬁle1

Most common adverse events observed with VOTRIENT were diarrhea, hypertension, hair color changes, nausea, anorexia, and vomiting1

Most common grade 3/4 laboratory abnormalities observed with VOTRIENT were ALT and AST increases1

All adverse reactions occurring in ≥10% of patients who received VOTRIENT1 VOTRIENT (n=290)

Placebo (n=145)

Grade*

Adverse Reaction

3 (%)

4 (%)

All (%)

3 (%)

4 (%)

All (%)

Parameter

Diarrhea

Chemistry

Hypertension

Hair color changes

Nausea

Anorexia

Vomiting

Fatigue

Asthenia

VOTRIENT (n=290)

Placebo (n=145)

Grade*

4 (%)

All (%)

3 (%)

4 (%)

All (%)

ALT increased

AST increased

Glucose increased

Total bilirubin increased

Phosphorus decreased

Sodium decreased

Magnesium decreased

Abdominal pain

Glucose decreased

Headache

Hematologic Leukopenia

Neutropenia

Thrombocytopenia

Lymphocytopenia

Generally well tolerated with a low incidence of grade 3/4 adverse events1,3 • Fatigue occurred in 2% of patients; all grades,19% • Asthenia occurred in 3% of patients; all grades,14% • Hand-foot syndrome occurred in <1% of patients; all grades, 6% • Stomatitis and mucositis each occurred in 0% of patients; all grades, 4% each • All grade 3/4 adverse reactions occurred in ≤4% of patients in the VOTRIENT arm

Discontinuation rates in the VOTRIENT and placebo groups3: • 12% discontinuation due to adverse events among treatment-naive patients • 19% discontinuation due to adverse events among cytokine-pretreated patients • In the placebo group, discontinuation rate was 6% Hypothyroidism: Hypothyroidism may occur. Monitoring of thyroid function tests is recommended.

*National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.

Hepatic effects occurred in clinical trials with VOTRIENT and require monitoring • In clinical trials, 92.5% of all transaminase elevations of any grade occurred in the ﬁrst 18 weeks of treatment with VOTRIENT • Monitor serum liver tests before initiation of treatment with VOTRIENT and at least once every 4 weeks for at least the ﬁrst 4 months of treatment or as clinically indicated. Periodic monitoring should then continue after this time period

The occurrence of other grade 3/4 laboratory abnormalities was generally low with VOTRIENT vs placebo1 9

Proteinuria: Monitor urine protein. Discontinue for Grade 4 proteinuria.

Safety & Tolerability

3 (%)

*National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.

Laboratory abnormalities in >10% of patients who received VOTRIENT and more commonly (≥5%) versus placebo1

Indication VOTRIENT is indicated for the treatment of patients with advanced renal cell carcinoma (RCC).

Important Safety Information WARNING: HEPATOTOXICITY See full prescribing information for complete boxed warning. Severe and fatal hepatotoxicity has been observed in clinical studies. Monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended. Hepatic Effects Patients with pre-existing hepatic impairment should use VOTRIENT with caution. Increases in serum transaminase levels (ALT, AST) and bilirubin were observed. Severe and fatal hepatotoxicity has occurred. Before the initiation of treatment and regularly during treatment, monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended. QT Prolongation and Torsades de Pointes Prolonged QT intervals and arrhythmias, including torsades de pointes, have been observed with VOTRIENT. Use with caution in patients at higher risk of developing QT interval prolongation, in patients taking antiarrhythmics or other medications that may prolong QT interval, and those with relevant pre-existing cardiac disease. Monitoring electrocardiograms and electrolytes should be performed. Hemorrhagic Events Fatal hemorrhagic events have been reported. VOTRIENT has not been studied in patients who have a history of hemoptysis, cerebral, or clinically signiﬁcant gastrointestinal hemorrhage in the past 6 months and should not be used in those patients.

Gastrointestinal Perforation and Fistula Gastrointestinal perforation or ﬁstula has occurred. Fatal perforation events have occurred. Use with caution in patients at risk for gastrointestinal perforation or ﬁstula.

Wound Healing VOTRIENT may impair wound healing. Temporary interruption of therapy with VOTRIENT is recommended in patients undergoing surgical procedures. Hypothyroidism Hypothyroidism may occur. Monitoring of thyroid function tests is recommended. Proteinuria Monitor urine protein. Discontinue for Grade 4 proteinuria. Pregnancy Category D VOTRIENT can cause fetal harm when administered to a pregnant woman. Women of childbearing potential should be advised of the potential hazard to the fetus and to avoid becoming pregnant while taking VOTRIENT. Drug Interactions CYP3A4 Inhibitors: Avoid use of strong inhibitors. Consider dose reduction of VOTRIENT when administered with strong CYP3A4 inhibitors. CYP3A4 Inducers: Consider an alternate concomitant medication with no or minimal enzyme induction potential or avoid VOTRIENT. CYP Substrates: Concomitant use of VOTRIENT with agents with narrow therapeutic windows that are metabolized by CYP3A4, CYP2D6, or CYP2C8 is not recommended. Adverse Reactions The most common adverse reactions (≥20%) were diarrhea, hypertension, hair color changes (depigmentation), nausea, anorexia, and vomiting.

Important Safety Information

Arterial Thrombotic Events Arterial thrombotic events have been observed and can be fatal. Use with caution in patients who are at increased risk for these events.

Hypertension Hypertension has been observed. Blood pressure should be well-controlled prior to initiating VOTRIENT. Monitor for hypertension and treat as needed. If hypertension persists despite antihypertensive therapy, the dose of VOTRIENT may be reduced or discontinued as appropriate.

Please see full Prescribing Information for VOTRIENT, including BOXED WARNING.

References: 1. VOTRIENT Prescribing Information. Research Triangle Park, NC: GlaxoSmithKline; 2009. 2. Sloan B, Scheinfeld NS. Pazopanib, a VEGF receptor tyrosine kinase inhibitor for cancer therapy. Curr Opin Investig Drugs. 2008;9(12):1324-1335. 3. Data on ﬁle. GlaxoSmithKline.

New VOTRIENT—Move Forward in Advanced RCC

VOTRIENT Offers Convenient Once-Daily Oral Dosing The recommended dosage of VOTRIENT is 800 mg once daily1

Dosing Modiﬁcation and Monitoring Guidelines for Hepatic Effects1

800 mg once daily VOTRIENT is available in 200 mg tablets

Monitor serum liver tests before initiation of treatment with VOTRIENT and at least once every 4 weeks for at least the ﬁrst 4 months of treatment or as clinically indicated. Periodic monitoring should then continue after this time period

Tablets are shown actual size.

• Daily dose should not exceed 800 mg • VOTRIENT must be taken without food at least 1 hour before or 2 hours after a meal • Do not crush tablets due to the potential for increased rate of absorption • Initial dose reduction should be 400 mg, and additional dose decrease or increase should be in 200 mg steps based on individual tolerability • If a dose is missed, it should not be taken if it is less than 12 hours until the next dose

Isolated ALT levels between 3X ULN and 8X ULN Continue treatment with VOTRIENT and monitor liver function tests weekly until ALT levels return to Grade 1 or baseline ALT = alanine aminotransferase; ULN = upper limit of normal.

See full Prescribing Information for more detail.

Isolated ALT levels >8X ULN Interrupt VOTRIENT until ALT levels return to Grade 1 or baseline. Consider reintroducing VOTRIENT at a reduced dose of no more than 400 mg once daily if the potential beneﬁt outweighs the risk for hepatotoxicity. Monitor liver function tests weekly for 8 weeks. If ALT elevations >3X ULN recur, permanently discontinue VOTRIENT

ALT levels >3X ULN concurrently with bilirubin levels >2X ULN If ALT elevations >3X ULN occur concurrently with bilirubin elevations >2X ULN, VOTRIENT should be permanently discontinued. Patients should be monitored until resolution. Please see full Prescribing Information for more detail

Across all monotherapy studies with VOTRIENT (n=977)1 • Isolated ALT levels ranging from >3X ULN to 8X ULN were reported in 10% of patients • Isolated ALT levels >8X ULN were reported in 4% of patients • Concurrent elevation in ALT >3X ULN and bilirubin >2X ULN in the absence of signiﬁcant alkaline phosphatase elevation occurred in 1% of patients

Pregnancy Category D: VOTRIENT can cause fetal harm when administered to a pregnant woman. Women of childbearing potential should be advised of the potential hazard to the fetus and to avoid becoming pregnant while taking VOTRIENT.

• The safety of VOTRIENT in patients with pre-existing severe hepatic impairment, deﬁned as total bilirubin >3X ULN with any levels of ALT, is unknown. Treatment with VOTRIENT is not recommended in patients with severe hepatic impairment

Drug Interactions: CYP3A4 Inhibitors: Avoid use of strong inhibitors. Consider dose reduction of VOTRIENT when administered with strong CYP3A4 inhibitors. CYP3A4 Inducers: Consider an alternate concomitant medication with no or minimal enzyme induction potential or avoid VOTRIENT. CYP Substrates: Concomitant use of VOTRIENT with agents with narrow therapeutic windows that are metabolized by CYP3A4, CYP2D6, or CYP2C8 is not recommended.

Dosing/Modiﬁcations

Because it’s not only where his treatment will take him— it’s where he will take his treatment

Move Forward in Advanced RCC With New VOTRIENT VOTRIENT provides signiﬁcant improvement in PFS in both treatment-naïve and cytokine-pretreated patients with advanced RCC1 All patients

9.2 months overall median PFS with VOTRIENT (n=290) vs 4.2 months with placebo (n=145) (P<0.0000001)1,3

Treatment-naïve patients

Cytokine-pretreated patients

11.1 months

7.4 months

median PFS with VOTRIENT (n=155) vs 2.8 months with placebo (n=78) (P<0.0000001)1,3

median PFS with VOTRIENT (n=135) vs 4.2 months with placebo (n=67) (P<0.001)1,3

Proven Safety Proﬁle1 • VOTRIENT was generally well tolerated with grade 3/4 adverse reactions occurring in ≤4% of patients • Most common adverse events observed with VOTRIENT were diarrhea, hypertension, hair color changes, nausea, anorexia, and vomiting — Grade 3/4 fatigue occurred in 2% of patients; all grades, 19% — Grade 3/4 asthenia occurred in 3% of patients; all grades, 14% • Most common laboratory abnormalities observed with VOTRIENT were ALT and AST increases • In clinical trials, 92.5% of all transaminase elevations of any grade occurred in the ﬁrst 18 weeks of treatment with VOTRIENT

Convenient once-daily oral dosing1 • The recommended dosage of VOTRIENT is 800 mg once daily (4 x 200 mg tablets) — Daily dose should not exceed 800 mg • Monitor serum liver tests before initiation of treatment with VOTRIENT and at least once every 4 weeks for at least the ﬁrst 4 months of treatment or as clinically indicated. Periodic monitoring should then continue after this time period

WARNING: HEPATOTOXICITY See full prescribing information for complete boxed warning. Severe and fatal hepatotoxicity has been observed in clinical studies. Monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended. Please see additional Important Safety Information on pages 10 and 11 and accompanying full Prescribing Information, including BOXED WARNING. Not to be left with physicians. When this material is shown to physicians, complete Prescribing Information must be presented.