c.p. belani 1 , t. brodowicz 2 , p. peterson 3 , w. john 3 , g. scagliotti 4
DESCRIPTION
C.P. Belani 1 , T. Brodowicz 2 , P. Peterson 3 , W. John 3 , G. Scagliotti 4 1 Penn State Cancer Institute, Hershey, PA USA; 2 Medical University, Vienna, Austria; 3 Eli Lilly and Co., IN, USA; 4 University of Torino, Orbassano, Italy. - PowerPoint PPT PresentationTRANSCRIPT
C.P. Belani1, T. Brodowicz2, P. Peterson3, W. John3, G. Scagliotti 4
1Penn State Cancer Institute, Hershey, PA USA;
2Medical University, Vienna, Austria; 3Eli Lilly and Co., IN, USA; 4University of Torino, Orbassano, Italy
Nonsquamous Histology: A Predictor of Efficacy for Pemetrexed Treatment. An Analysis of Phase III Trials
Using Treatment-by-Histology Interaction (THI) in Advanced NSCLC
The identification of predictive factors may allow a The identification of predictive factors may allow a tailored- approach to the treatment of patientstailored- approach to the treatment of patients
Treatment-by-histology interaction (THI) analyses Treatment-by-histology interaction (THI) analyses predicts the relative efficacy of a specific treatment predicts the relative efficacy of a specific treatment versus a comparatorversus a comparator
Randomized phase III study of pemetrexed vs. docetaxel Randomized phase III study of pemetrexed vs. docetaxel indicated a predictive role for histology in NSCLC, as indicated a predictive role for histology in NSCLC, as well as a differential treatment effect by histology for well as a differential treatment effect by histology for pemetrexedpemetrexed11
We report the results of THI analyses performed on two We report the results of THI analyses performed on two large randomized trials evaluating the effects of large randomized trials evaluating the effects of pemetrexed.pemetrexed.
11 Peterson, et al. WCLC. 2007; P2-328, Seoul, Korea.Peterson, et al. WCLC. 2007; P2-328, Seoul, Korea.
Role of Histology as a Predictive Factor
Study Design – Pemetrexed/Cisplatin vs. Gemcitabine/CisplatinStudy Design – Pemetrexed/Cisplatin vs. Gemcitabine/Cisplatin
Randomization factors: • Stage • PS • Gender • Histo vs. cyto dx • Brain mets. hx
Cisplatin 75 mg/m2 d1 +Pemetrexed 500 mg/m2 d1(N=862)
Median OS Cis Pemetrexed 10.3 mos Cis Gemcitabine 10.3 mos
HR=0.94(95% CI: 0.84–0.1.05 )Cis/Pem noninferior vs Cis/Gem
Cisplatin 75 mg/m2 d 1 +Gem 1.25 mg/m2 d 1 & 8(N=863)
B12, folate, and dexamethasone given in both arms
1:1 Randomization
Double-blind, Placebo-controlled, Multicenter, Phase III Trial
# Nonsquamous pts : CisPem 71.7%, CisGem 72.4%
Each cycle repeated q3weeks up to 6 cycles
Study Design – Maintenance Pemetrexed vs. PlaceboStudy Design – Maintenance Pemetrexed vs. Placebo
Stage IIIB/IV NSCLC PS 0-1 4 prior cycles of gem,
doc, or tax + cis or carb, with CR, PR, or SD
Randomization factors: gender PS stage best tumor response to
induction non-platinum induction
drug brain mets
Pemetrexed 500 mg/m2 (q21d) + BSC (N=441)
Median PFS Pemetrexed 4.04 mos Placebo 1.97 mos
HR=0.599 (95% CI: 0.49–0.73)p <0.00001
Placebo (d1, q21d) + BSC (N=222)
B12, folate, and dexamethasone given in both arms
2:1 Randomization
Double-blind, Placebo-controlled, Multicenter, Phase III Trial
# Nonsquamous pts : Pemetrexed 74%, Placebo 70.3%
Treatment-by-Histology AnalysisTreatment-by-Histology Analysis
Presence of THI implies that histologic- subtype will be predictive of the treatment effect
Analysis of the 2 studies performed to determine the treatment effect for pemetrexed relative to the control arm (non-squamous histology vs. those with squamous histology)
THI analyses, prospectively planned for both the studies utilized adjusted Cox proportional hazard models of PFS & OS
The interaction parameter Exp (B3) is a ratio of two hazard ratios:
HR for non-squamous over squamous (for Pemetrexed patients) ---------------------------------------------------------------------------------------------------------- HR for non-squamous over squamous (for Comparator arm patients)
Exp (B3) can also be re-written as the following ratio:
HR for Pemetrexed over the Comparator (for Non-squamous patients) -------------------------------------------------------------------------------------------------------- HR for Pemetrexed over the Comparator (for Squamous patients)
So the interaction HR Exp (B3) is the treatment effect for the non-squamous subgroup divided by the treatment effect for the squamous subgroup.
The test for interaction has null hypothesis “H0: Exp (B3) = 1.00”.
When we say that there is a "treatment by histology interaction", we are saying that the treatment effect varies significantly between the subgroups, i.e. that Exp (B3) differs significantly from 1.00.
The Interaction Test
Treatment-by-Histology InteractionsTreatment-by-Histology Interactions
Pemetrexed/Cisplatin vs Gemcitabine/Cisplatin
Pemetrexed versus Placebo*
Efficacy Parameter
Nonsquamous
n=1252
Squamous
n=473
Nonsquamous
n=482
Squamous
n=181
PFS adjusted HR (95% CI)
0.95
(0.84, 1.06)
1.36
(1.12, 1.65)
0.47
(0.37, 0.60)
1.03
(0.71, 1.49)THI HR
(95% CI)
p-value
0.70
(0.56, 0.88)
0.002
0.46
(0.30, 0.72)
0.001OS adjusted HR (95% CI)
0.84
(0.74, 0.96)
1.23
(1.00, 1.51)
0.66
(0.49, 0.88)
1.28
( 0.85, 1.93) THI HR
(95% CI)
p-value
0.69
(0.54, 0.87)
0.002
0.52
(0.31, 0.86)
0.011
* PFS data independently reviewed; OS data is preliminary
Median PFS, mos Median OS, mos
Pemetrexed plus Cisplatin versus Gemcitabine plus Cisplatin
Pem/Cis Gem/Cis p-value Pem/Cis Gem/Cis p-valueNonsquamous
N=12525.3 5.0 0.349 11.0 10.1 0.011
Squamous N=473
4.4 5.5 0.002 9.4 10.8 0.050
Pemetrexed vs Placebo*
Pem Placebo p-value Pem Placebo p-valueNonsquamous
N=4824.4 1.8 <0.00001 14.4 9.4 0.005
Squamous
N=1812.4 2.5 0.896 9.6 11.9 0.231
Efficacy by HistologyEfficacy by Histology
* PFS data independently reviewed (N=430 nonsquamous; N=151 squamous); OS data is preliminary
ConclusionsConclusions
These two large, randomized, phase III studies, provide evidence of significant interaction between NSCLC histology and a pemetrexed treatment effect, regardless of the control arm treatment
The consistency of these results across studies confirms that the treatment advantage for pemetrexed in patients with non-squamous histology is reproducible
Non-squamous histology is predictive of the improved efficacy of pemetrexed in patients with NSCLC