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C.P. Belani 1 , T. Brodowicz 2 , P. Peterson 3 , W. John 3 , G. Scagliotti 4

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.

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C.P. Belani 1 , T. Brodowicz 2 , P. Peterson 3 , W. John 3 , G. Scagliotti 4

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  1. 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

  2. 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 pemetrexed1 We report the results of THI analyses performed on two large randomized trials evaluating the effects of pemetrexed. Role of Histology as a Predictive Factor 1Peterson, et al. WCLC. 2007; P2-328, Seoul, Korea.

  3. Study Design – Pemetrexed/Cisplatin vs. Gemcitabine/Cisplatin Double-blind, Placebo-controlled, Multicenter, Phase III Trial Cisplatin 75 mg/m2 d1+ Pemetrexed 500 mg/m2 d1 (N=862) Randomization factors: • Stage • PS • Gender • Histo vs. cyto dx • Brain mets. hx 1:1 Randomization Each cycle repeated q3weeks up to 6 cycles Cisplatin 75 mg/m2 d 1 + Gem 1.25 mg/m2d 1 & 8 (N=863) 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 # Nonsquamous pts : CisPem 71.7%, CisGem 72.4% B12, folate, and dexamethasone given in both arms

  4. Study Design – Maintenance Pemetrexed vs. Placebo Double-blind, Placebo-controlled, Multicenter, Phase III Trial • 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) 2:1 Randomization Placebo (d1, q21d) + BSC (N=222) Median PFS Pemetrexed 4.04 mos Placebo 1.97 mos HR=0.599 (95% CI: 0.49–0.73) p <0.00001 # Nonsquamous pts : Pemetrexed 74%, Placebo 70.3% B12, folate, and dexamethasone given in both arms

  5. 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

  6. The Interaction Test 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.

  7. Treatment-by-Histology Interactions * PFS data independently reviewed; OS data is preliminary

  8. Efficacy by Histology * PFS data independently reviewed (N=430 nonsquamous; N=151 squamous); OS data is preliminary

  9. 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

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