Tyverb Slide Kit

[object Object],[object Object],TYV/SLK/08/39072/1 Date of preparation: Nov 2008 Prescribing information can be found at the end of the full slide set

ErbB2-positive breast cancer 1.Cancer Research UK. UK breast cancer incidence and mortality statistics. www.cancerresearchuk.org (accessed May 2008) 2. Penault-Llorca F, Vincent-Salomon A, Mathieu MC et al. J Clin Oncol 2005; 23 (16S):764. 3. NICE. Technology Appraisal Guidance Number 34. London: NICE, 2002 ,[object Object],[object Object],[object Object],[object Object],[object Object]

Treatment of ErbB2-positive breast cancer (BC) ,[object Object],[object Object],[object Object],[object Object],[object Object],1. Vogel CL et al. J Clin Oncol 2002; 2. Marty M et al. J Clin Oncol 2005; 3. Slamon DJ et al. N Engl J Med 2001; 4. Tsao MN et al. Clin Oncol (R Coll Radiol) 2003; 5. Palmieri D et al. Breast Dis 2006

Tyverb ® (lapatinib) is licensed ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]

Tyverb ® (lapatinib): Mode of Action TYV/SLK/08/39072/1 Date of preparation: Nov 2008 Prescribing information can be found at the end of the full slide set

Tyverb is an oral, small-molecule, dual-targeted agent

Antibody versus small-molecule ErbB2-targeted agents ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],1. Plosker GL et al. Drugs 2006; 2. Rusnak DW et al. Mol Cancer Ther 2001; 3. Hegde PS et al. Mol Cancer Ther 2007; 4 Xia W et al. Oncogene 2002

Tyverb ® (lapatinib): EGF100151 Study (Pivotal Registration Study) TYV/SLK/08/39072/1 Date of preparation: Nov 2008 Prescribing information can be found at the end of the full slide set

EGF100151 study design 1,2 Treatment continued until progression or unacceptable toxicity Patients with ErbB2-positive locally advanced or metastatic breast cancer that progressed after prior anthracycline, taxane and trastuzumab (N=399 ) RANDOMISATION 1. Cameron D et al. Breast Cancer Res Treat 2008 ; 2. Geyer GE et al. N Engl J Med 2006 Tyverb 1250 mg po od continuously + capecitabine 2000 mg/m 2 /d po days 1-14 q 3 wk Capecitabine 2500 mg/m 2 /day po days 1-14 q 3 wk po = oral; od = once daily; q 3 wk = once every 3 weeks

EGF100151: Inclusion and exclusion criteria Geyer GE et al. N Engl J Med 2006 IHC = immunohistochemistry; FISH = Fluorescence in situ Hybridization; GI = gastro-intestinal; RECIST = response evaluation criteria in solid tumours; ECOG = Eastern Cooperative Oncology Group Key inclusion criteria Key exclusion criteria ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]

EGF100151: Study overview ,[object Object],[object Object],[object Object],[object Object],[object Object],Geyer GE et al. N Engl J Med 2006

EGF100151: Patient and tumour characteristics Cameron D et al. Breast Cancer Res Treat 2008 Characteristic Tyverb + capecitabine n=198 Capecitabine n=201 ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],48% 50% 2% 96% 49% 31% 20% 17% 61% 23% 97% 46% 53% <1% 96% 48% 30% 21% 18% 61% 21% 98%

EGF100151: prior therapy Cameron D et al. Breast Cancer Res Treat 2008 Tyverb + capecitabine (N=198) Capecitabine (N=201) Anthracyclines 194 (98) 199 (>99) Taxanes 198 (100) 199 (>99) Trastuzumab Metastatic Adjuvant Neoadjuvant 196 (99) 187 (95) 9 (5) 0 197 (98) 189 (94) 7 (4) 1 (<1) Median duration of trastuzumab, weeks (range) 44 (3-296) 45 (0-329) Time from discontinuation of trastuzumab to randomisation – no. < 4 weeks 4 - 8 weeks > 8 weeks Missing 196 55 (28) 62 (32) 79 (40) 0 197 52 (27) 65 (33) 77 (39) 3 (2)

EGF100151: independently assessed time to progression 1

EGF100151: key efficacy results 1 a Primary endpoint of the study 1 ; CI = confidence interval; TTP = time to progression; ORR = overall response rate (PR or CR); CR = complete response; PR = partial response Investigator assessment 2,3 Independent assessment 1 1. Cameron D et al. Breast Cancer Res Treat 2008; 2. Tyverb Summary of Product Characteristics; 3. GSK data on file (TYV/DOF/08/34764/1) Outcome Tyverb + capecitabine (N=198) Capecitabine (N=201) Hazard ratio (95% CI) Odds ratio (95% CI) p - value Median TTP [weeks (months)] a 27.1 (6.2) 18.6 (4.3) 0.57 (0.43, 0.77) – 0.00013 ORR (%) 23.7 13.9 – 1.9 (1.1, 3.4) 0.017 Outcome Tyverb + capecitabine (N=198) Capecitabine (N=201) Hazard ratio (95% CI) Odds ratio (95% CI) p - value Median TTP [weeks (months)] 23.9 (5.5) 18.3 (4.2) 0.72 (0.56, 0.92) – 0.008 ORR (%) 31.8 17.4 - 2.2 (1.3, 3.6) 0.002

EGF100151: overall survival by independent assessment 1. Cameron D et al. Breast Cancer Res Treat 2008 ; 2. Tyverb Summary of Product Characteristics September 2007 cut-off – after cross-over 2 April 2006 cut-off – before cross-over 1 Tyverb + capecitabine Capecitabine No. of patients 198 201 Median overall survival (weeks [months]) 67.7 (15.6) 66.6 (15.4) Hazard ratio (95% CI) 0.78 (0.55, 1.12) p-value 0.177 Tyverb + capecitabine Capecitabine No. of patients 207 201 Median overall survival (weeks [months]) 74.0 (17.1) 65.9 (15.2) Hazard ratio (95% CI) 0.9 (0.71, 1.12) p-value 0.3

EGF100151: effect of interval from last administration of trastuzumab to randomization on TTP Cameron D et al. Breast Cancer Res Treat 2008 Interval between last trastuzumab dose and randomization Tyverb + capecitabine Capecitabine alone Hazard ratio (95% CI) P value No. of pts Median TTP, wk No. of pts Median TTP, wk < 8 weeks 117 27.1 117 18.6 0.59 (0.40, 0.86) 0.004 > 8 weeks 79 26.1 77 14.6 0.56 (0.35, 0.91) 0.012

EGF100151 Relapse of brain metastases (BM) with Tyverb plus capecitabine ,[object Object],[object Object],[object Object],[object Object],1. Bendell JC et al. Cancer 2003; 2. Cameron D et al. Breast Cancer Res Treat 2008 3. Kaufman B et al. EBCC 2008 a Lapatinib (Tyverb) Expanded Access Programme Outcome Tyverb + capecitabine (n=198) Capecitabine alone (n=201) Patients with symptomatic CNS progression as part of first progression event, n (%) 4 (2) 13 (6) p=0.045

EGF100151: overview of safety 1 ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],1. Cameron D et al. Breast Cancer Res Treat 2008

EGF100151: six most common adverse events (all grades)

Recommendations for diarrhoea management 1,2 ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],1. Benson AB et al. J Clin Oncol 2004; 2. Tyverb Summary of Product Characteristics, June 2008

Recommendations for managing skin events associated with Tyverb ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],1. Moy B, Goss P . Oncologist 2007; 2. Lacouture ME et al. Breast Cancer Res Treat 2008

EGF100151: impact on LVEF ,[object Object],[object Object],[object Object],[object Object],[object Object],1. Ewer MS, O’Shaughnessey JA. Clin Breast Cancer 2007; 2. Seidman A et al. J Clin Oncol 2002; 3. Geyer GE et al. N Engl J Med 2006; 4. Tyverb Summary of Product Characteristics; 5. Cameron D et al. Breast Cancer Res Treat 2008 a Defined as symptomatic regardless of degree of decline or Asymptomatic ↓ LVEF ( relative decrease  20% from baseline and below the LLN) 3

[object Object],[object Object],EGF100151: Quality of Life 1. Zhou X et al. EBCC 2008 Adjusted change from baseline in FACT-B scores 1 Adjusted change from baseline Baseline – 2 – 1 0 1 2 3 4 5 6 7 8 Week 6 Week 12 Week 18 Week 24 T + C minus C: p value: 0.7 (–1.4, 2.6) 0.505 1.5 (–0.7, 3.7) 0.186 2.2 (–0.1, 4.4) 0.057 1.7 (–0.6, 3.9) 0.157 Capecitabine 2,000 mg/m2 (n = 166) Tyverb 1,250 mg + capecitabine 2,000 mg/m 2 (n = 163) FACT-B total scores

EGF100151: overall conclusions ,[object Object],[object Object],[object Object],[object Object],[object Object]

Tyverb ® (lapatinib): Practical considerations TYV/SLK/08/37076/1 Date of preparation: Nov 2008 Prescribing information can be found at the end of the full slide set

Tyverb ® (lapatinib): Dosage and administration TYV/SLK/08/39072/1 Date of preparation: Nov 2008 Prescribing information can be found at the end of the full slide set

Tyverb (lapatinib) 250mg tablets

General presentation ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]

Tyverb dosage and administration 1 ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],1. Tyverb Summary of Product Characteristics, June 2008

Capecitabine dosage and administration (in combination with Tyverb) ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],1. Tyverb Summary of Product Characteristics, June 2008; 2. Xeloda Summary of Product Characteristics

Tyverb ® (lapatinib): Information for patients Practical advice on administering/dosing TYV/SLK/08/39072/1 Date of preparation: Nov 2008 Prescribing information can be found at the end of the full slide set

[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],Questions your patient may ask (1)

Questions your patient may ask (2) ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]

[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],Questions your patient may ask (3)

[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],Questions your patient may ask (4)

Prescribing Information (Refer to full SmPC before prescribing ) ,[object Object],Adverse events should be reported. Reporting forms and information can be found at: www.yellowcard.gov.uk Adverse events should also be reported to GlaxoSmithKline on 0800 221 441. Further information is available from Customer Contact Centre, GlaxoSmithKline, Stockley Park West, Uxbridge, Middlesex UB11 1BT [email_address] ; Freephone: 0800 221 441. Tyverb is a registered trademark of the GlaxoSmithKline group of companies. Monitor liver function before initiation of treatment and monthly thereafter or as clinically indicated; Pulmonary toxicity including interstitial lung disease reported. Monitor for symptoms of pulmonary toxicity; Diarrhoea including severe diarrhoea reported. Proactive management of diarrhoea with anti-diarrhoeal agents is important. Severe cases may require oral or i.v. electrolytes and fluids, and interruption/discontinuation of therapy. . Interactions Avoid grapefruit juice during lapatinib treatment; Avoid concomitant treatment with inducers (incl. St. John’s Wort) and strong inhibitors of CYP3A4, and with medical products with narrow therapeutic windows that are substrates of CYP3A4 or CYP2C8; Avoid concomitant use of substances that increase gastric pH as lapatinib solubility and absorption may decrease. Pregnancy and lactation No adequate data on use in pregnant women. Not to be used unless clearly necessary. Contraception advised; Not known whether lapatinib excreted in human milk. Breastfeeding should be discontinued. Effects on ability to drive and use machines No studies conducted. Detrimental effect cannot be predicted from pharmacology of lapatinib. Undesirable effects Following adverse reactions reported in association with lapatinib + capecitabine therapy: Very common : Diarrhoea (may lead to dehydration), nausea, vomiting, dyspepsia, stomatitis, constipation, abdominal pain; Rash (including dermatitis acneiform), dry skin, PPE; Anorexia; Fatigue, mucosal inflammation; Pain in extremity; back pain. Insomnia. Common : Decreased LVEF; Headache; Hyperbilirubinaemia, hepatotoxicity. Uncommon: interstitial lung disease/pnuemonitis. Specific events: Decreased LVEF : Reported in ~1% of all patients receiving lapatinib across clinical programme and asymptomatic in > 90% cases. Symptomatic LVEF decreases observed in ~ 0.1% of patients on lapatinib monotherapy. Symptoms included dyspnoea, cardiac failure, palpitations. LVEF decreases reported in 2.5% of patients on lapatinib + capecitabine vs. 1% for capecitabine alone. Diarrhoea : Occurred in ~ 65% of patients on lapatinib + capecitabine. Most cases grade 1 or 2 and did not result in discontinuation of lapatinib. Rash : Occurred in ~ 28% of patients on lapatinib + capecitabine. Generally low grade and did not result in discontinuation of lapatinib. Overdose No specific antidote. Haemodialysis not expected to be effective method of elimination as lapatinib is not significantly renally excreted and is highly bound to plasma proteins. Basic NHS Cost 70 tablet pack £804.30. Marketing authorisation (MA) no . EU/1/07/440/001 MA holder Glaxo Group Limited, Berkeley Avenue, Greenford, Middlesex UB6 ONN. Legal category POM. TYV/PRI/08/36896/1. June 2008

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Tyverb Slide Kit