Tyverb Slide Kit

Tyverb ® (lapatinib):
Introduction and Background
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
Most common malignancy in women in UK
44,000 new cases and 12,509 deaths in UK in 2003 1
Approximately 20-30% have tumours that overexpress ErbB2 2,3
ErbB2-positive disease tends to be more aggressive and has a poorer prognosis
Average survival time, with treatment, from diagnosis of advanced or metastatic disease is 18-24 months; reduced by up to 50% if ErbB2-positive 3

Treatment of ErbB2-positive breast cancer (BC)
Trastuzumab was previously the only licensed ErbB2-targeted agent available in UK
Significant activity in first-line metastatic setting 1-3
Majority of patients receiving trastuzumab for metastatic disease progress within 12 months of starting treatment 1-3
Management of brain metastases in BC patients is a challenging clinical problem 4-5
Few treatment options were previously available for patients who progress on or following trastuzumab and there has been no alternative ErbB2-targeted agent
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
Conditional marketing authorisation was granted by EMEA in June 2008 for use in combination with capecitabine (Xeloda ® ) for treatment of ErbB2+ve advanced or metastatic breast cancer (MBC) in patients with progressive disease following received prior therapy including:
Anthracyclines
Taxanes
Trastuzumab for metastatic disease
Once-daily oral treatment
Targets both the ErbB1 (EGFR) and ErbB2 (HER2) receptors
Small molecule, works ‘inside’ the cancer cells

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
Small molecule – Tyverb 2-4
Directed toward kinase domain (intracellular target)
Can directly and efficiently inhibit phosphorylation and activation of downstream signalling pathways
Monoclonal antibody – trastuzumab 1
Directed toward extracellular portion of receptor
Works mainly by triggering antibody-dependent cellular cytotoxicity
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
Women aged ≥18 years with life expectancy ≥12 weeks
Progressive ErbB2-positve (IHC 3+ or IHC 2+ with FISH confirmation) locally advanced or metastatic breast cancer
Prior treatment with an anthracycline or taxane in either adjuvant or metastatic setting
Prior treatment with trastuzumab for at least 6 weeks in metastatic setting
Measurable disease by RECIST
ECOG performance status 1 or 0
Stable brain metastases
Prior capecitabine treatment
Pre-existing heart disease
Pre-existing conditions that may affect GI absorption

EGF100151: Study overview
The primary endpoint of the study was time to progression (TTP) by independent review
Secondary endpoints included:
Progression free survival, overall response rate, overall survival, clinical benefit rate and adverse events
The planned interim analysis (15 November 2005 cut-off) demonstrated a clinically meaningful and statistically significant improvement in TTP
Independent Data Monitoring Committee recommended that enrolment to the study should be halted early ( 3 April 2006)
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
Hormone receptor status ER+ and/or PR+ ER- and PR- Unknown
Stage IV disease
Number of metastatic sites
> 3
2
1
Metastatic sites
Visceral only
Visceral/ Non-visceral
Non-visceral only
Progressed on trastuzumab
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
Patients with ErbB2-positive MBC are at increased risk of relapsing with BM 1
Retrospective exploratory analysis in Study EGF100151 demonstrated that Tyverb + capecitabine may reduce the incidence of BM as the first site of recurrence 2
Preliminary results from the LEAP a suggest that Tyverb + capecitabine is active in ErbB2-positive BM previously treated with trastuzumab and whole brain radiotherapy 3
Further studies are warranted
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
Adverse event (AE) rates were similar in both arms for:
All adverse events
Serious adverse events
AEs leading to discontinuation of study medication were the same (14%) in both arms
Most common AEs: diarrhoea, nausea, vomiting, fatigue, rash & PPE
Diarrhoea and rash were more common with Tyverb + capecitabine than with capecitabine alone
The majority of adverse events were Grade 1 or 2
The incidence of Grade 3 & 4 AEs was low and similar in both treatment arms
1. Cameron D et al. Breast Cancer Res Treat 2008

EGF100151: six most common adverse events (all grades)

Recommendations for diarrhoea management 1,2
Grades 1 & 2
Avoid all lactose-containing products
Stay well hydrated (8–10 large glasses/day)
Eat frequent small meals
Administer standard doses of loperamide
Grade 2: Consider Tyverb dose reduction / interruption; consider reducing / withholding capecitabine
Grade 3+
IV fluids
Hospitalisation if at risk of life-threatening complications
Discontinue Tyverb and/or capecitabine permanently, or until patient recovers and re-start at reduced dose
Continue loperamide
Consider prophylactic antibiotics
Consider second-line agents (e.g. codeine)
Follow local treatment guidelines
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
No clear evidence-based treatment options for management of lapatinib-associated rash 1
Guidance based on experience from Tyverb clinical trials and from managing rash associated with ErbB1 inhibitors 1,2
Emollients (e.g. aqueous cream) where dry skin component
Topical antibiotics (e.g. clindamycin gel) or oral antibiotics (e.g. tetracycline, minocyline) where pustular component
Mild-to-moderate topical steroids
Short course of oral steroids for severe (≥50% BSA) maculopapular rash
Antihistamines may be useful if pruritic component
Note: Topical / oral retinoids not recommended
Interrupt Tyverb treatment
Severe/persistent cases – reduce dose or interrupt Tyverb treatment, refer to dermatologist
1. Moy B, Goss P . Oncologist 2007; 2. Lacouture ME et al. Breast Cancer Res Treat 2008

EGF100151: impact on LVEF
ErbB2-targeted therapies have been associated with reports of decreased LVEF 1,2
Cardiac function a monitored closely during trial
Decrease in LVEF reported in 2.5% of patients in Tyverb + capecitabine group vs 1% for capecitabine alone 4
No withdrawals due to decrease in LVEF 5
No decline in mean LVEF in either treatment group 5
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

QoL scores were generally higher for Tyverb + capecitabine vs. capecitabine alone but differences were not statistically significant 1
There was no detriment to QoL in patients receiving Tyverb + capecitabine 1
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
First RCT to have examined continued ErbB2 suppression in patients with ErbB2-positive MBC who have progressed on trastuzumab
Tyverb + capecitabine significantly extended TTP and improved response rates vs capecitabine alone
Tyverb + capecitabine was generally well tolerated
Declines in LVEF were infrequent, asymptomatic and reversible
Tyverb + capecitabine is a rational and evidence- based option for patients with ErbB2-positve MBC who have progressed on trastuzumab

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
Tyverb is an oral (tablet) treatment
Tyverb is taken in combination with the chemotherapy agent capecitabine, also an oral treatment
Tyverb and capecitabine are dispensed in separate packs
Tyverb is available in packs of 70 tablets, packed in aluminium foil blisters
Capecitabine tablets are available in two strengths:
150mg and 500mg

Tyverb dosage and administration 1
Recommended dosage of Tyverb: 1,250mg (5 tablets)
Once daily
Continuously throughout treatment
Standardised, i.e. always before or always after the same meal
Take at least 1h before or 1h after a meal
Swallow tablets whole with water
1. Tyverb Summary of Product Characteristics, June 2008

Capecitabine dosage and administration (in combination with Tyverb)
Capecitabine dosage (when given in combination with Tyverb) is: 1
2000mg/m 2 per day in two divided doses
12 hours apart (morning and evening) for first 14 days of each 21-day treatment cycle
Taken with food or within 30 min of food 2
Capecitabine dose when taken with Tyverb is lower than recommended in the capecitabine SmPC 2
Tyverb plus capecitabine is therefore an all-oral regimen
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

What should I do if forget to take my Tyverb or capecitabine tablets?
Answers:
If it is still the same day, take your Tyverb tablets as soon as you remember
If capecitabine dose is missed (e.g. morning dose), take next dose as usual (do not double up)
Remember to inform the cancer unit
What if I missed a whole day?
Answers:
Take the usual dose of Tyverb (or capecitabine) on the day after the missed day at the usual time(s)
Remember to inform the cancer unit
Questions your patient may ask (1)

What if I am sick after taking Tyverb or capecitabine?
Answers:
Do not take a second dose to make up for the vomited dose
Take next dose as normal when due
If vomiting continues, contact the cancer unit
Can I crush, split or dissolve the tablets?
Answers:
Tyverb tablets should be swallowed whole with a drink of water
Crushing, splitting, chewing and dissolving the tablets are not recommended
Talk to the breast cancer/chemotherapy nurse if experiencing difficulty taking tablets

What should I do if I get diarrhoea while taking Tyverb?
Answers:
If diarrhoea occurs it usually happens during the first week or so but can happen at any time during treatment
It is usually mild or moderate, but can be severe in some cases
Most people with diarrhoea should be able to continue their treatment with Tyverb with appropriate management
If experiencing diarrhoea or a change in your normal bowel pattern, inform the cancer unit

What should I do if I get a rash while taking Tyverb?
Answers:
Rash is a very common side-effect of taking Tyverb
It usually develops within the first 2 weeks of treatment
The rash will usually improve or disappear after a few weeks.
Most people who develop a rash are able to continue their treatment with Tyverb
If a rash develops, or if your skin feels dry, itchy or painful, inform your doctor or nurse

Prescribing Information (Refer to full SmPC before prescribing )
Tyverb ® ▼(lapatinib) 250mg film-coated tablets. Each tablet contains 250mg lapatinib as ditosylate monohydrate. Indications In combination with capecitabine for treatment of patients with advanced or metastatic breast cancer whose tumours overexpress ErbB2 (HER2). Patients should have progressive disease following prior therapy which must include anthracyclines and taxanes and therapy with trastuzumab in the metastatic setting. Dosage and administration Only to be initiated by physician experienced in use of anti-cancer agents. Lapatinib: 1250mg (5 tablets) once daily continuously. Taken at least one hour before, or at least one hour after food. Standardise administration in relation to food intake. Capecitabine: 2000 mg/m2 /day taken in 2 doses 12 hours apart on days 1-14 in a 21-day cycle. Taken with food or within 30 mins after food. Renal impairment : No lapatinib dose adjustment necessary in mild to moderate renal impairment. Caution advised in severe renal impairment as no experience of lapatinib in this population. Hepatic impairment : Discontinue lapatinib if changes in liver function are severe and do not retreat patients. Insufficient data available to provide a dose adjustment recommendation. Use with caution in moderate to severe hepatic impairment due to increased exposure to product. Elderly : Limited data in patients > 65 years. Paediatrics : Not recommended. Dose delay and dose reduction Cardiac events : Discontinue lapatinib in patients with symptoms associated with decreased LVEF that are NCI CTCAE grade > 3 or if LVEF drops below institution’s LLN. May be restarted at 1000mg/day after > 2 weeks and if LVEF recovers to normal and patient is asymptomatic. Interstitial lung disease/pneumonitis : Discontinue lapatinib in patients who experience pulmonary symptoms that are NCI CTCAE grade > 3. Other toxicities : Consider discontinuation or interruption of lapatinib dosing if patient develops toxicity that is NCI CTCAE grade > 2. Can be restarted at 1250mg/day when toxicity improves to < grade 1. If recurs, restart lapatinib at 1000mg/day. Consult capecitabine SmPC for guidance on dose delay and dose reduction recommendations for capecitabine. Contra-indications Hypersensitivity to active substance or excipients. Refer to capecitabine SmPC for relevant contraindications and safety information. Special Warnings and Precautions Decreases in LVEF reported. Caution advised if lapatinib given to patients with conditions that could impair LVEF. Evaluate LVEF in all patients prior to starting treatment to ensure baseline LVEF within institution’s normal limits. Evaluate LVEF during treatment to ensure it does not decline to unacceptable level; Hepatotoxicity has occurred (may rarely be fatal).
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

Tyverb Slide Kit

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Tyverb Slide Kit — Presentation Transcript

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