A paradigm shift in the treatment of advanced lung cancer: survival and symptom benefits with TarcevaTudor-Eliade CiuleanuCancer Institute Ion Chiricuta and University of Medicine and Pharmacy Iuliu Hatieganu Cluj-Napoca, Romania

What are our therapeutic objectives in advanced NSCLC?To prolong lifeimproved survivallengthened time to disease progressionTo maintain QoLimproved disease-related symptoms/QoLTo develop better-tolerated treatment regimens QoL = quality of life

More effective and better tolerated second-line therapeutic strategies are neededIncreasing need for second-line treatment due to greater use of first-line, platinum-based chemotherapyMany patients (e.g. elderly, poor PS) are unsuitable to receive chemotherapy due to significant toxicitiesPatients progressing on first-line chemotherapy may benefit from an agent with a different mechanism of action As single agents, docetaxel and pemetrexed have proven benefits in second-line NSCLC, but are limited by significant toxicities

Tarceva: preliminary evidence of antitumour effects and clinical benefitsObjective RR = 12.3% (5.123.7)Median OS = 8.4 months (4.813.9)1-year survival rate = 40% (2854)Survival distribution functionTime (months)0510152025301.000.750.500.250Prez-Soler R, et al. J Clin Oncol 2004;22:323847Phase II trial in relapsed NSCLC: overall survivalOS = overall survival RR = response rateTarceva 150mg/day

BR.21, a randomised phase III trial of Tarceva (erlotinib; OSI-774) as treatment following chemotherapy in patients with advanced NSCLC:an NCIC CTG trialNCIC CTG = National Cancer Institute of Canada Clinical Trials Group

BR.21: study designPS = performance status; CR = complete response; PR = partial response SD = stable disease; PD = progressive disease Stratified by: Centre PS (0/1 vs 2/3) Response to prior treatment (CR/PR:SD:PD) Prior regimens (1 vs 2) Prior platinum (yes vs no)Tarceva 150mg dailyPlacebo21RANDOM I SE

BR.21: patient characteristics

Characteristic

Tarceva(n=488)

Placebo(n=243)

Median age (years)

62

59

Female (%)

35

34

PS 0, 1 (%)

13, 52

14, 54

PS 2, 3 (%)

26, 9

23, 9

Adenocarcinoma (%)

50

49

Prior regimens 1, 2, 3 (%)

Prior platinum (%)

50, 49, 1

93

50, 49, 1

92

Response to prior chemotherapy (%)

CR/PR

SD

PD

40

39

21

40

39

21

Measurable disease (%)

88

87

NCIC CTG BR.21: best response (n=638)*CI = confidence interval*Measurable disease was not an entry criterion

Tarceva(n=427)

Placebo(n=211)

Complete response (%)

1

BR.21: improvement in overall survival with Tarceva*HR and p (log-rank test) adjusted for stratificationfactors at randomisation and HER1/EGFR status42.5% improvement in median survivalSurvival distribution functionSurvival time (months)HR=0.73, p

Forest plot of survival by subsetsD-R = diagnosis to randomisationHR

Survival benefit with erlotinib according to HER1/EGFR biomarker status*p value for subgroup compared with placebop value for interaction0.97Tsao M-S, et al. N Engl J Med 2005;353:133440.250.10

nHRCIp*pMutation statusWild-type1370.730.491.100.13Mutant 400.770.401.500.45EGFR expression (IHC)IHC+1840.680.490.950.02IHC1410.930.631.360.70Gene copy Number (FISH)Low690.860.481.510.59High560.440.20.82 0.008

Progression-free survivalHR=0.61, p

Efficacy of current treatment options in the second-line setting**Survival cannot be compared directly because of different patient populationsn=156 (T) and 82 (BSC); n=2531Tarceva product information; 2OSI and Roche data on file 3Pemetrexed product information; 4Docetaxel product information 5Hanna N, et al. J Clin Oncol 2004;22:158997 Tarceva vs BSC1,2 Docetaxel (75mg/m2) vs pemetrexed3 Docetaxel (75mg/m2) vs BSC4 T (n=488) BSC (n=243) D (n=288) P (n=283) D (n=55) BSC (n=100) PS (%) 0/1 2 3 65 26 9 68 23 9 88 12 0 89 11 0 75 25 0 75 25 0 Prior regimens (%) 1 2 50 50 50 50 100 0 100 0 80 20 76 24 Median survival (months)* 6.7 4.7 7.9 8.3 7.5 4.6 1-year survival (%) 31.2 21.5 29.7 29.7 37 19 Median survival in PS 0/1 patients with one prior regimen 9.42 6.72 9.15 9.455

BR.21: QoL impairments at baseline mainly due to fatigue, cough, dyspnoea and painScoreBezjak A, et al. J Clin Oncol 2005;23(Suppl. 16 Pt I):625s (Abs. 7018)100

80

60

40

20

0GlobalRolePhysicalFatigueCoughDyspnoeaPain

BR.21: time to deterioration of QoL symptoms*Median Adjusted log-rankBezjak A, et al. J Clin Oncol 2005;23(Suppl. 16 Pt I):625s (Abs. 7018)

Tarceva

Placebo

n

Time, months*(95% CI)

n

Time, months*(95% CI)

p

Cough

298

4.9(3.87.4)

153

3.7(24.9)

0.04

Dyspnoea

353

4.7(3.86.2)

179

2.9(24.8)

0.03

Pain

348

2.8(2.43)

179

1.9(1.82.8)

0.04

BR.21: change in symptoms*10 point change from baseline at any time 2Bezjak A, et al. J Clin Oncol 2005;23(Suppl. 16 Pt I):625s (Abs. 7018)

Improved (%)*

Stable (%)

Worse (%)*

Symptom

Tarceva

Placebo

Tarceva

Placebo

Tarceva

Placebo

p value

Pain

42

28

15

20

43

51

0.01

Dyspnoea

34

23

27

33

40

44

0.03

Cough

44

27

24

31

32

41

BR.21: change in QoL domains (EORTC QLQ-C30) *10 point change from baseline at any time (clinically significant)p

BR.21: adverse events (%)

Tarceva (n=485)Placebo (n=242)AnyGrade 3, 4AnyGrade 3, 4Rash75 917 0Diarrhoea54 618

Tolerability of second-line therapies: haematological toxicitiesShepherd F, et al. N Engl J Med 2005;353:12332 Hanna N, et al. J Clin Oncol 2004;22:158997Serious haematological toxicities may require hospitalisation and blood transfusions The most common non-haematological side effects were rash and diarrhoea (mainly mild to moderate)

Patients (%)

Adverse event(grade 3/4)

Tarceva(150mg/day)

Docetaxel(75mg/m2)

Pemetrexed(500mg/m2)

Neutropenia

(1

40.2

5.3

Febrile neutropenia

(1

12.7

1.9

Anaemia

(1

4.3

4.2

Thrombocytopenia

(1

0.4

1.9

Conclusions: Tarceva in NSCLCNSCLC has a high incidence and mortality Standard cytotoxic regimens offer clinical benefits, but are limited by substantial toxicities Tarceva is a new treatment option that has equivalent efficacy to approved chemotherapy options for second-line treatment, but is not associated with the side effects of chemotherapyTarceva is a valuable new treatment option for patients with advanced NSCLC