Still Outliving His Cancer, Still Out Living His Life by OEM65

New The first and only FDA-approved oral chemotherapy for relapsed small cell lung cancer (SCLC) in patients with a prior complete or partial response and who are at least 45 days from the end of first-line chemotherapy

Hycamtin Capsules—proven to significantly increase overall survival vs best supportive care (BSC)1,2

Still Outliving His Cancer1,2

Still living His LIFE1,2

Hycamtin Capsules are indicated for the treatment of relapsed SCLC in patients with a prior complete or partial response and who are at least 45 days from the end of first-line chemotherapy.

WARNING: BONE MARROW SUPPRESSION See full Prescribing Information for complete boxed warning Hycamtin Capsules should be administered only to patients with baseline neutrophil counts of ≥1,500 cells/mm3 and a platelet count ≥100,000 cells/mm3. In order to monitor the occurrence of bone marrow suppression, blood cell counts should be monitored. Please see accompanying full Prescribing Information, including BOXED WARNING.

New

Hycamtin Capsules—proven to significantly increase overall survival vs BSC1,2

Broad Range of Patients, Including Those With Sensitive and Resistant Disease, Good and Poor Performance Status, and Limited and Extensive Disease1

• Randomized, open-label, multicenter trial of 141 patients with relapsed SCLC1

Hycamtin Capsules + BSC (n=71)

—Majority of patients received prior therapy with either cisplatin or carboplatin and etoposide —Patients were considered not suitable for further intravenous (IV) chemotherapy*

Characteristics

• The primary end point was overall survival (all-cause mortality)1

BSC (n=70)

No. of patients

52 19

73 27

51 19

73 27

Sex Male Female

—Analysis with Kaplan-Meier method and comparisons using log-rank test

Age, Years Mean (range) SD

TOTAL PATIENT POPULATION1,2 N=141 <65 years, n=97; ≥65 years, n=44

58.6 (43-79) 8.2

Performance Status

Initial inclusion criteria1 • • • • • •

59.8 (37-76) 9.0

Extensive or limited relapsed SCLC Unsuitable for further IV chemotherapy* Refused further IV chemotherapy 1 prior chemotherapy regimen Treatment-free interval (TFI) ≤90 days Relapsed at least 45 days from the end of first-line chemotherapy

2.3 mg/m2/day for 5 consecutive days, every 21 days + BSC

8 44 19

11 62 27

6 41 23

9 59 33

23 48

32 68

27 43

39 61

51 20

72 28

56 14

80 20

22 49 41 30

31 69 58 42

20 50 35 35

29 71 50 50

Disease Stage Limited Extensive

Randomized

Liver Metastases

Expanded inclusion criteria

BSC Alone (n=70)

• Sensitive SCLC (TFI >90 days) —Patients who refused further IV chemotherapy —Patients prohibited from further IV chemotherapy due to comorbidities

• Analgesics • RBC transfusions • Antibiotics •D eep relaxation • Corticosteroids therapy • Appetite stimulants • Palliative radiotherapy • Antidepressants or surgical procedures

0 1 2

Hycamtin Capsules + BSC1 (n=71)

No Yes

TFI, Days† ≤60 >60 ≤90 >90 Median (range)

84 (34-1996)

90 (14 to 1409)

SD=standard deviation. Defined as time to progression since completion of first-line chemotherapy.

†

[ Questions for Consideration ] What role does treatment-free interval play in selecting a second-line agent? In what situations do you provide patients with BSC alone as an option? What do you consider to be poor prognostic factors?

* Unsuitability was based on local policy concerning the unproven risk and benefit in patients with resistant (short TFI) SCLC and assessed on an individual basis by the attending oncologist.

New

Please see accompanying full Prescribing Information, including BOXED WARNING.

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Study Design/ Patient Characteristics

Overall Survival Advantage Achieved in a Phase III Clinical Trial of Hycamtin Capsules Plus BSC vs BSC Alone1

Hycamtin Capsules—proven to significantly increase overall survival vs BSC1,2 Hycamtin Capsules Almost Doubled Overall Median Survival When Added to BSC1,2

Approximately longer median survival time1,2

Significant Overall Survival Advantage With Hycamtin Capsules Plus BSC1,2 • Unadjusted hazard ratio for overall survival with Hycamtin Capsules was 0.64 (95% CI, 0.45 to 0.90) relative to BSC alone, indicating a 36% lower risk of death (P=0.01)1,2

BSC alone 13.9 weeks Hycamtin Capsules + BSC

25.9 weeks

Kaplan-Meier Estimates for Overall Survival: Hycamtin Capsules Plus BSC vs BSC Alone1,2

• 25.9 weeks median survival with Hycamtin Capsules plus BSC (95% CI, 18.3 to 31.6) vs 13.9 weeks with BSC alone (95% CI, 11.1 to 18.6) (P=0.01)1,2 Hycamtin Capsules Increased 6-Month Survival Rates When Added to BSC 1 • 49% survival at 6 months with Hycamtin Capsules plus BSC vs 26% with BSC alone1 6-Month Survival Rates

Patients (%)

0.8

36%

0.6

0.4

Lower risk of death with Hycamtin Capsules

0.2

49%

Hycamtin Capsules (n=71) BSC (n=70)

120

144

168

192

Time (weeks) Study randomly assigned patients with relapsed SCLC not considered as candidates for standard IV therapy to BSC alone (n=70) or Hycamtin Capsules (2.3 mg/m2/day, days 1 through 5, every 21 days) plus BSC (n=71).

26%

Survival Benefit in Elderly Patients With Hycamtin Capsules Plus BSC2

• Among elderly patients (≥65 years), those receiving Hycamtin Capsules plus BSC showed a survival benefit compared with those receiving BSC alone2

Hycamtin Capsules plus BSC

BSC alone

—D rug-related diarrhea was more frequent in patients ≥65 years of age (28%) compared with those <65 years of age (19%)2

Study randomly assigned patients with relapsed SCLC not considered as candidates for standard IV therapy to BSC alone (n=70) or Hycamtin Capsules (2.3 mg/m2/day, days 1 through 5, every 21 days) plus BSC (n=71).

[ Questions for Consideration ] What outcome is most important to you when treating relapsed SCLC? Of the data presented from this Phase III trial, which do you find most compelling? Will these results influence how you treat relapsed SCLC? Do you have any concerns about treating elderly SCLC patients (≥65 years of age)?

New Please see accompanying full Prescribing Information, including BOXED WARNING.

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Overall Survival Advantage

Cumulative Proportion Alive

1.0

Hycamtin Capsules—proven to significantly increase overall survival vs BSC1,2

Hematologic Adverse Events2

Nonhematologic Adverse Events2

Incidence (≥5%) of Adverse Reactions in SCLC Patients Treated With Hycamtin Capsules Plus BSC and in 4 Thoracic Cancer Studies2*†

Incidence (≥5%) of Adverse Reactions in SCLC Patients Treated With Hycamtin Capsules Plus BSC and in 4 Thoracic Cancer Studies2§ll

Adverse Reactions

Hycamtin Capsules + BSC Hycamtin Capsules SCLC Population Thoracic Cancer Population (N‡=682) (N‡=70) All Grades

Grade 3

Grade 4

All Grades

Grade 3

Grade 4

Anemia

94%

15%

10%

98%

18%

Leukopenia

90%

25%

16%

86%

29%

Neutropenia

91%

28%

33%

83%

Thrombocytopenia

81%

30%

81%

Adverse Reactions

Hycamtin Capsules + BSC Hycamtin Capsules SCLC Population Thoracic Cancer Population (N¶=682) (N¶=70) Grade 3

Grade 4

All Grades

Grade 3

Grade 4

Nausea

27%

33%

15%

Diarrhea

14%

22%

0.4%

24%

32%

Vomiting

19%

21%

0.4%

29%

Alopecia

10%

20%

0.1%

Fatigue

11%

19%

0.1%

Anorexia

14%

Asthenia

Pyrexia

* The safety of Hycamtin Capsules has been evaluated in 682 patients with thoracic cancer (3 recurrent SCLC studies and 1 recurrent non-small cell lung cancer [NSCLC] study) who received at least 1 dose of Hycamtin Capsules. † Adverse reactions were graded using National Cancer Institute (NCI) Common Toxicity Criteria. ‡ N=total number of patients treated.

• Febrile neutropenia occurred in 4% of patients receiving Hycamtin Capsules in the 4 thoracic malignancy studies2 Dose Modifications (SCLC study population)1

he safety of Hycamtin Capsules has been evaluated in 682 patients with thoracic cancer (3 recurrent SCLC studies and 1 recurrent T NSCLC study) who received at least 1 dose of Hycamtin Capsules. ll Adverse reactions were graded using NCI Common Toxicity Criteria. ¶ N=total number of patients treated. §

• Dose reduction of Hycamtin Capsules occurred in 8% of courses (16)—most reductions were due to hematologic toxicity (13 courses, 6%) • Dose delays of Hycamtin Capsules occurred in 20% of courses (41)—most commonly from hematologic toxicity (25 courses, 12%)

Adverse Events

All Grades

References: 1. O’Brien MER, Ciuleanu T-E, Tsekov H, et al. Phase III trial comparing supportive care alone with supportive care with oral topotecan in patients with relapsed small-cell lung cancer. J Clin Oncol. 2006;24(34):5441-5447. 2. Hycamtin Capsules [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2008. 3. O’Brien M, Eckardt J, Ramlau R. Recent advances with topotecan in the treatment of lung cancer. Oncologist. 2007;12:1194-1204.

• Dose escalation of Hycamtin Capsules occurred in 14% of courses (39)

New Please see accompanying full Prescribing Information, including BOXED WARNING.

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Hycamtin Capsules—proven to significantly increase overall survival vs BSC1,2 Important Safety Information Indication Hycamtin Capsules are indicated for the treatment of relapsed small cell lung cancer in patients with a prior complete or partial response and who are at least 45 days from the end of first-line chemotherapy. WARNING: BONE MARROW SUPPRESSION See full Prescribing Information for complete boxed warning Hycamtin Capsules should be administered only to patients with baseline neutrophil counts of ≥1,500 cells/mm3 and a platelet count ≥100,000 cells/mm3. In order to monitor the occurrence of bone marrow suppression, blood cell counts should be monitored. Contraindications: Hycamtin Capsules are contraindicated in patients who have a history of severe hypersensitivity reactions (e.g., anaphylactoid reactions) to topotecan or to any of its ingredients. Hycamtin Capsules should not be used in patients who are pregnant or breastfeeding, or in patients with severe bone marrow depression. Warnings and Precautions: Bone marrow suppression (primarily neutropenia) is a dose-limiting toxicity of Hycamtin Capsules. Neutropenia is not cumulative over time. The following data on myelosuppression are based on an integrated safety database from 4 thoracic malignancy studies (N = 682) using Hycamtin Capsules at 2.3 mg/m2/day for 5 consecutive days. The median day for neutrophil, red blood cell, and platelet nadirs occurred on day 15. Neutropenia: Grade 4 neutropenia (<500 cells/mm3) occurred in 32% of patients with a median duration of 7 days and was most common during course 1 of treatment (20% of patients). Infection, sepsis, and febrile neutropenia occurred in 17%, 2%, and 4% of patients, respectively. Death due to sepsis occurred in 1% of patients. Pancytopenia has been reported. Topotecan-induced neutropenia can lead to neutropenic colitis. Fatalities due to neutropenic colitis have been reported. In patients presenting with fever, neutropenia, and a compatible pattern of abdominal pain, the possibility of neutropenic colitis should be considered. Thrombocytopenia: Grade 4 thrombocytopenia (<10,000 cells/mm3) occurred in 6% of patients, with a median duration of 3 days. Anemia: Grade 3 or 4 anemia (<8 g/dL) occurred in 25% of patients.

For patients who experience Grade 3 or 4 diarrhea, the Hycamtin Capsules dose should be reduced by 0.4 mg/m2/day for subsequent courses. Patients with Grade 2 diarrhea may need to follow the same dose modification guidelines. Pregnancy – Pregnancy D: Hycamtin Capsules may cause fetal harm when administered to a pregnant woman. Women of childbearing potential should be advised to avoid becoming pregnant during therapy with Hycamtin Capsules. Clinical Trials Experience: In the 682 patients who received Hycamtin Capsules in the 4 thoracic cancer studies, 39 deaths occurred within 30 days after the last dose of study medication for a reason other than progressive disease; 13 of these deaths were attributed to hematologic toxicity, 5 were attributed to nonhematologic toxicity, and 21 were attributed to other causes. One patient death (68 years of age) was attributed to treatment-related diarrhea and one death (68 years of age) attributed diarrhea as a contributory event; both patients received Hycamtin Capsules. Drug Interactions: P-glycoprotein inhibitors (e.g., cyclosporine A, elacridar, ketoconazole, ritonavir, and saquinavir) can cause significant increases in topotecan exposure. The concomitant use of P-glycoprotein inhibitors with Hycamtin Capsules should be avoided. Elacridar (inhibitor of ABCB1 and ABCG2) administered with Hycamtin Capsules increased topotecan exposure to approximately 2.5-fold of control. Cyclosporine A (inhibitor of ABCB1, ABCC1 [MRP-1], and CYP3A4) with Hycamtin Capsules increased topotecan exposure to 2- to 3-fold of control. Patients should be carefully monitored for adverse reactions when Hycamtin Capsules are administered with a drug known to inhibit these transporters. Adverse Events: The most common serious adverse event is myelosuppression. The most common Grade 3 or 4 hematologic adverse reactions with Hycamtin Capsules were neutropenia (61%), leukopenia (41%), thrombocytopenia (37%) and anemia (25%). The most common (≥10%) non-hematologic adverse reactions (all grades) were nausea (27%), vomiting (19%), diarrhea (14%), fatigue (11%), and alopecia (10%). These adverse reactions are reported only for the Hycamtin Capsules + BSC group, N=70.

Patients should not be treated with subsequent courses of Hycamtin Capsules until neutrophils recover to >1,000 cells/mm3, platelets recover to >100,000 cells/mm3, and hemoglobin levels recover to ≥9.0 g/dL (with transfusion if necessary). For patients who experience severe neutropenia (neutrophils <500 cells/mm3 associated with fever or infection or lasting for 7 days or more) or neutropenia (neutrophils 500 to 1,000 cells/mm3 lasting beyond day 21 of the treatment course), the Hycamtin Capsules dose should be reduced by 0.4 mg/m2/day for subsequent courses. Doses should be similarly reduced if the platelet count falls below 25,000 cells/mm3.

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Safety

Monitoring of Bone Marrow Function: Hycamtin Capsules should be administered only in patients with adequate bone marrow reserves, including a baseline neutrophil count of ≥1,500 cells/mm3 and a platelet count ≥100,000 cells/mm3. Frequent monitoring of peripheral blood cell counts should be instituted during treatment with Hycamtin Capsules.

Diarrhea: Diarrhea, including severe diarrhea requiring hospitalization, has been reported during treatment with Hycamtin Capsules. Communication with patients prior to drug administration regarding these side effects and proactive management of early and all signs and symptoms of diarrhea is important. Treatment-related diarrhea is associated with significant morbidity and may be life-threatening. Should diarrhea occur during treatment with Hycamtin Capsules, physicians are advised to aggressively manage diarrhea. Drug-related diarrhea was more frequent in patients ≥65 years of age (28%) compared to those <65 years of age (19%).

Hycamtin Capsules—proven to significantly increase overall survival vs BSC1,2

Convenient Oral Dosing2 Recommended Dosing2

• May be taken with or without food2 • Must be swallowed whole (do not chew, crush, or divide)2

2.3 mg/m2/day once daily* for 5 consecutive days, repeated every 21 days

Days 1 2 3 4 5

• If the patient vomits after taking the dose of Hycamtin Capsules, the patient should not take a replacement dose2

21 Repeat

* The calculated oral daily dose should be rounded to the nearest 0.25 mg. Prescribe the minimum number of 1 mg and 0.25 mg capsules. The same number of capsules should be prescribed for each of the 5 dosing days.

Dosage Adjustments2 Hycamtin Capsules is known to be excreted by the kidney, and the risk of toxic reactions to Hycamtin Capsules may be greater in patients with impaired renal function. Renal Function Impairment: a dose adjustment of Hycamtin Capsules to 1.8 mg/m2/day is predicted to adjust the area under the curve (AUC) to the normal range for patients with moderate renal impairment (CLcr = 30-49 mL/min). Insufficient data are available in patients with severe renal impairment (CLcr <30 mL/min) to provide a dosage recommendation for Hycamtin Capsules.2 Patients should not be treated with subsequent courses of Hycamtin until neutrophils recover to >1,000 cells/mm3, platelets recover to >100,000 cells/mm3, and hemoglobin levels recover to ≥9.0 g/dL (with transfusion if necessary).2 For patients who experience severe neutropenia (neutrophils <500 cells/mm3 associated with fever or infection or lasting for 7 days or more) or neutropenia (neutrophils 500 to 1,000 cells/mm3 lasting beyond day 21 of the treatment course), the Hycamtin Capsules dose should be reduced by 0.4 mg/m2/day for subsequent courses. Doses should be similarly reduced if the platelet count falls below 25,000 cells/mm3.2 Grade 3 or 4 Diarrhea: the Hycamtin Capsules dose should be reduced by 0.4 mg/m2/day for subsequent courses. Patients with grade 2 diarrhea may need to follow the same dose modification guidelines.2

Please see accompanying full Prescribing Information, including BOXED WARNING.

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