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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. 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

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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.

study design pemetrexed cisplatin vs gemcitabine cisplatin
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

study design maintenance pemetrexed vs placebo
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

treatment by histology analysis
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
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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.

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Treatment-by-Histology Interactions

* PFS data independently reviewed; OS data is preliminary

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Efficacy by Histology

* PFS data independently reviewed (N=430 nonsquamous; N=151 squamous); OS data is preliminary

conclusions
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