Transcript BR.21 schema - Amazon Web Services
BR.21 schema
Stratified by Centre PS (0/1 vs 2/3) Response prior Rx (CR/PR:SD:PD) Prior regimens (1 vs 2) Prior platinum (Yes vs no) R A N D O M I S E *
Tarceva Placebo
TM
150mg daily ‘150mg’ daily
PS = performance status; CR = complete response PR = partial response SD = stable disease; PD = progressive disease; *2:1 randomisation
Study endpoints
• Primary – overall survival • Secondary – progression-free survival (PFS) – time to deterioration of cough, dyspnoea, pain as per EORTC QLQ-C30 + QLQ-LC13 – response rates, duration – toxicity and tolerability – tissue HER1/EGFR versus outcome and safety – TarcevaTM trough pharmacokinetics
HER/EGFR = epidermal growth factor receptor
Key eligibility criteria
• Confirmed NSCLC, Stage IIIB or IV • Age ³18 years • PS 0, 1, 2 or 3 • Measurable or non-measurable disease • One or two prior chemotherapy regimens • Adequate organ function • HER1/EGFR+ not required • No prior HER1/EGFR inhibitors • No prior malignancies or uncontrolled CNS M1 • Written informed consent
NSCLC = non-small-cell lung cancer; CNS M1 = symptomatic central nervous system metastasis
BR.21 patient characteristics
Characteristic Median age (years) Tarceva TM (n=488) 62 Placebo (n=243) 59 Female (%) PS 0, 1 (%) PS 2, 3 (%) Adenocarcinoma (%) Prior regimens 1, 2, 3 (%) Prior platinum (%) Response to prior chemotherapy (%) CR/PR SD 35 13, 52 26, 9 50 50, 49, 1 93 40 39 34 14, 54 23, 9 49 50, 49, 1 92 40 39 PD Measurable disease (%) 21 88 21 87
Overall survival: all patients
1.00
0.75
0.50
42.5% improvement in median survival Median survival (months) 1-year survival (%) HR* = 0.73, p<0.001
Tarceva TM (n=488) 6.7 31 Placebo (n=243) 4.7 21 0.25
Tarceva TM Placebo 0 0 5 10 15 Survival time (months) 20 25 30 *HR and p-value adjusted for stratification factors at randomisation + HER1/EGFR status
Survival after eliminating CR/PRs
• Exploratory analyses in BR.21 dataset SD/PD/NE SD/PD n Tarceva TM Median 449 367 5.7
7.4
n Placebo Median 241 204 4.7
6.7
HR 0.86
0.82
p-value 0.073
0.037
• The TarcevaTM benefit is still present after eliminating CRs and PRs
Efficacy data for docetaxel, pemetrexed & erlotinib
Ramalingam, S. et al. Oncologist 2006;11:655-665
BR.21: summary of significant clinical predictors of response
Gender Female (146) Male (281) Histology Ethnicity Adenocarcinoma (209) Other (218) Asian (53) Other (374) Ever smoked Yes (311) No (93) Unknown (23)
*Significance between subgroups
Erlotinib Patients (%) (n=427) 14.4
6.1
13.9
4.1
18.9
7.5
3.8
24.7
13.0
p* 0.006
<0.001
0.02
<0.001
BR.21: Survival Across Subgroups
Subset n Tarceva: Placebo 731 PS 0-1 PS 2-3 Male Female <65 y
65 y Adenocarcinoma Squamous cell carcinoma Other histology Prior weight loss <5% Prior wt loss 5%-10% Prior wt loss >10% Never smoked Current/ex-smoker 1 prior regimen
2 prior regimens 486 245 475 256 452 279 365 222 144 486 132 81 146 545 364 367
HR = hash mark on horizontal bar.
95% CI = length of horizontal bar.
TARCEVA™ (erlotinib) PI.
0 0.5
Decreased risk of death
1.0
1.5
2.0
Increased risk of death
2.5
BR.21: Survival Across Subgroups Cont’d
Subset Tarceva: Placebo Prior platinum No prior platinum Prior taxane No prior taxane Best prior response: CR/PR Best prior response: SD Best prior response: PD <6 mo since diagnosis 6-12 mo since diagnosis >12 mo since diagnosis EGFR-positive EGFR-negative EGFR unmeasured Caucasian Asian Stage IV at diagnosis Stage
HR = hash mark on horizontal bar.
95% CI = length of horizontal bar.
TARCEVA™ (erlotinib) PI.
n 731 678 53 267 464 292 287 152 97 242 392 127 111 493 567 91 329 402 0 0.5
Decreased risk of death
1.0
1.5
2.0
Increased risk of death
2.5
Clinical Benefit of Erlotinib in Male Smokers with SCC Clark, Abstract #7166, Poster
NCIC CTG BR.21
:
Survival for Male, Ever Smokers with SCC
Clark GM et al. ASCO 2006, Abs #7166.
BR.21 Symptom Benefit
Parameter Tarceva TM Cough Dyspnoea Pain Median time to deterioration (weeks) † 28.14
20.43
12.14
Placebo 15.71
12.14
8.14
Adjusted * p-value 0.041
0.031
0.040
*Adjustment for multiple testing † Patients were considered to have deteriorated symptoms if the change in score from baseline for each symptom was 10 points or higher at any time point after baseline assessment
QoL outcomes for second-line therapy
Agent
Tarceva 1
Tool
EORTC: QLQ-C30 QLQ-LC13
QoL outcomes
Significant improvement in global, physical, and emotional QoL versus BSC
Symptom outcomes
Significant increase in time to deterioration of symptoms (cough, dyspnoea, pain) versus BSC Docetaxel 2 Pemetrexed 3 Lung Cancer Symptom Scale (LCSS) LCSS – – No significant improvement for docetaxel 75mg/m 2 compared with BSC No significant difference compared with docetaxel 75mg/m 2 1 Bezjak A, et al. J Clin Oncol 2006;24:3831–7; 2 Dancey J, et al. Lung Cancer 2004;43:183–94; 3 Hanna N, et al. J Clin Oncol 2004;22:1589–97
BR.21 adverse events (%)
Rash Diarrhoea Nausea Vomiting Stomatitis Fatigue Ocular (all) Anorexia Infection Any 75 54 33 23 17 52 27 52 24 Tarceva TM (n=485) Grade 3, 4 9 6 3 2 <1 18 1 9 4 Any 17 18 24 19 3 45 9 38 15 Placebo (n=242) Grade 3, 4 0 <1 2 2 0 20 <1 5 2
Comparison of phase III trials in relapsed NSCLC: haematological toxicity
Adverse event (grade 3/4) Neutropenia Febrile neutropenia Anaemia Thrombocytopenia Tarceva (150mg/day)
<
1
<
1
<
1
<
1 Patients (%) Docetaxel (75mg/m 2 ) 40.2
12.7
4.3
0.4
Pemetrexed (500mg/m 2 ) 5.3
1.9
4.2
1.9
Shepherd F, et al. N Engl J Med 2005;353:123 –32 Hanna N, et al. J Clin Oncol 2004;22:1589 –97
ASCO 2006 Abstracts
1
st
-line Erlotinib in Elderly Patients with Advanced NSCLC Jackman, Abstract #7168
Study Design Non-randomized, open label, Phase II trial
• • • •
Key inclusion criteria
Age > 70 years Stage IIIb/IV ECOG PS 0 – 2 >3 wks since RT or major surgery
Endpoints
• • Primary: survival Secondary include RR, TTP, toxicity, QoL, symptom response
Treatment
• • Erlotinib 150 mg/day until PD or unacceptable toxicity Dose reductions (100 mg; 50 mg) permitted for AE’s Jackman DM et al. ASCO 2006, Abs #7168.
1 st -line Erlotinib in Elderly Patients with Advanced NSCLC Jackman, Abstract #7168 Survival 1.0
Median Survival 41 weeks 52-week survival 40.4% 0.75
0.50
0.25
0.0
0 26
Jackman DM et al. ASCO 2006, Abs #7168.
Jackman DM et al. 11th WCLC 2005, Abstract #O-188.
52 78 104
1 st -line Erlotinib in Elderly Patients with Advanced NSCLC Jackman, Abstract #7168
Poster
Symptom Response
100% 80% 60% 15 15 70 40% 20% 0% Dyspnea (n=47) 11 24 64 Cough (n=45) Improved 20 22 58 Fatigue (n=50) Stable 18 9 73 15 15 70 Pain (n=22) Worse Loss of appetite (n=37)
1st-line Erlotinib in Elderly Patients with Advanced NSCLC Jackman, Abstract #7168 Results
• For the 64 patients eligible for QoL analysis, there was no statistically significant improvement in overall LCSS score.
• Patients who achieved PR or SD had statistically significant improvements in their overall score QoL as measured by LCSS.
Conclusions
• Patients over the age of 70 years had a median survival of 10.9 months when treated with erlotinib in the first-line.
• Erlotinib in this population was also associated with improvements in key symptoms of dyspnea, cough, fatigue, pain and loss of appetite.
• Improvements in overall LCSS score were noted in patients who achieved disease control (PR or SD).
Jackman DM et al. ASCO 2006, Abs #7168.
1
st
-line Erlotinib in Advanced NSCLC with Good Prognosis Akerley, Abstract #7178
Study Design
Stage IIIb or IV NSCLC No prior chemotherapy for metastatic disease • • • • • Good prognosis defined as: No brain metastases <10% weight loss O 2 use not due to malignancy
PS 0 or 1
No immediate need for chemotherapy Erlotinib 150 mg/day Objective or symptomatic progression Switch to chemotherapy
Primary Objective
Achieve 6-month chemotherapy-progression-free survival rate that is significantly higher than the historically observed 31% Akerley W et al. ASCO 2006, Abs #7178.
1 st -line Erlotinib in Advanced NSCLC with Good Prognosis Akerley, Abstract #7178
Response to Erlotinib PR SD PD n (%) 6 (15) 11 (28) 23 (58)
Response
Rash Correlates with Duration of Therapy Grade of Rash Median duration of Tx 0 – 1 3 – 4 7.8 weeks 17.7 weeks Progression-free Survival* 6-month PFS 56% *Chemotherapy-progression-free survival: time from study entry to progression on chemotherapy or erlotinib if patient refused chemotherapy.
Subsequent Chemotherapy and Outcomes Too early to assess Never received chemo PR SD PD n (%) 5 (14) 11 (31) 9 (26) 11 (31) 4 (11) Akerley W et al. ASCO 2006, Abs #7178.
1 st -line Erlotinib in Advanced NSCLC with Good Prognosis Akerley, Abstract #7178 Overall Survival
Akerley W et al. ASCO 2006, Abs #7178.
1
st
-line Erlotinib in Elderly Patients with Advanced NSCLC Akerley, Abstract #7178
• • • • •
Conclusions The overall response rate was 15%; the 6-month PFS rate is 56%.
Rash predicts the duration of erlotinib effectiveness.
Never smokers show a better survival outcome than ever smokers.
Survival and PFS in this population of minimally selected patients appear comparable to that with chemotherapy.
A randomized trial is warranted to further investigate the results of this trial.
Akerley W et al. ASCO 2006, Abs #7178.