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 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 tailored- approach to the treatment of patients  Treatment-by-histology interaction (THI) analyses predicts the relative efficacy of a specific treatment versus a comparator  Randomized phase III study of pemetrexed vs. docetaxel indicated a predictive role for histology in NSCLC, as well as a differential treatment effect by histology for pemetrexed 1  We report the results of THI analyses performed on two large randomized trials evaluating the effects of pemetrexed. 1 Peterson, et al. WCLC. 2007; P2-328, Seoul, Korea. Role of Histology as a Predictive Factor

Study Design – Pemetrexed/Cisplatin vs. Gemcitabine/Cisplatin Randomization factors: Stage PS Gender Histo vs. cyto dx Brain mets. hx Cisplatin 75 mg/m 2 d1 + Pemetrexed 500 mg/m 2 d1 (N=862) Median OS Cis Pemetrexed 10.3 mos Cis Gemcitabine 10.3 mos HR=0.94(95% CI: 0.84– ) Cis/Pem noninferior vs Cis/Gem Cisplatin 75 mg/m 2 d 1 + Gem 1.25 mg/m 2 d 1 & 8 (N=863) B 12, 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. 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/m 2 (q21d) + BSC (N=441) Median PFS Pemetrexed 4.04 mos Placebo 1.97 mos HR=0.599 (95% CI: 0.49–0.73) p < Placebo (d1, q21d) + BSC (N=222) B 12, 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 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 (B 3 ) 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 (B 3 ) 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 (B 3 ) 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 “H 0 : Exp (B 3 ) = 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 (B 3 ) differs significantly from The Interaction Test

Treatment-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) (0.30, 0.72) OS 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) (0.31, 0.86) * PFS data independently reviewed; OS data is preliminary

Median PFS, mosMedian OS, mos Pemetrexed plus Cisplatin versus Gemcitabine plus Cisplatin Pem/CisGem/Cisp-valuePem/CisGem/Cisp-value Nonsquamous N= Squamous N= Pemetrexed vs Placebo * PemPlacebop-valuePemPlacebop-value Nonsquamous N= < Squamous N= Efficacy by Histology * PFS data independently reviewed (N=430 nonsquamous; N=151 squamous); OS data is preliminary

Conclusions  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