ERLOTINIB AS A SINGLE AGENT IN PATIENTS p WITH ADVANCED OR METASTATIC NSCLC: A MULTIVARIATE ANALYSIS

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ERLOTINIB AS A SINGLE AGENT IN PATIENTS (p) WITH
ADVANCED OR METASTATIC NSCLC A MULTIVARIATE
ANALYSIS IN A PROSPECTIVE STUDY
C. Pallarès
C. Pallarès, L. Paz-Ares, J. López-Picazo, R.
Pérez-Carrión, A. Montes, G. López-Vivanco, J. de
Castro, M. Cobo, A. García Velasco, P. Regueiro,
B. Massutí, on behalf of the Spanish TargeT Trial
investigators Hospital de la Santa Creu i Sant
Pau, Barcelona, Spain H. Univ. 12 de Octubre,
Madrid, Spain Clínica Universitaria de Navarra,
Pamplona, Spain MD Anderson International
España, Madrid, Spain Institut Català
d'Oncologia. H. Duran i Reynals, L'Hospitalet de
Llobregat, Spain Hospital de Cruces, Barakaldo,
Spain H. Univ. La Paz, Madrid, Spain H. Univ.
Carlos Haya, Málaga, Spain Institut Català
d'Oncologia. H. Dr. Josep Trueta, Girona, Spain
Roche Farma, España, Madrid, Spain Hospital
Gral. Univ. de Alicante, Alicante, Spain.
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Introduction

• Lung cancer is the leading cause of cancer death
  and despite considerable medical advances, the
  five years survival is about 14. 1
• Erlotinib is a tyrosine kinase inhibitor of the
  human epidermal growth factor receptor
  (HER1/EGFR) that provides a targeted mechanism of
  action through the inhibition of receptor
  phosphorylation and subsequent intracellular
  signal transduction cascade, DNA synthesis and
  cell growth.2-5
• Erlotinib is approved for treatment of patients
  with locally advanced or metastatic non-small
  cell lung cancer after failure of at least one
  prior chemotherapy regimen on the basis of the
  results of a large double-blind,
  placebo-controlled trial (BR.21).6
• The TargeT trial was a Spanish non-randomized
  phase II trial evaluating the efficacy and safety
  of erlotinib in patients with either advanced or
  metastatic NSCLC.
• 1. Jemal, C. et al. CA Cancer J Clin. 2006
  Mar-Apr56(2) 106-30. 2. Arteaga, C. Semin
  Oncol. 200330 3-14.3. Voldborg, BR. et al. Ann
  Oncol. 19978 1197-1206.4. Scagliotti, GV. et
  al. Clin Cancer Res. 200410 4227-4232.5.
  Hirsch, FR, et al. J Clin Oncol. 200321
  3798-3807.6. Shepherd, FA. et al. N Engl J Med.
  2005 353 123-132.

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Study Design (I)

• Patients
• Patients with histologically confirmed stage IIIB
  or IV NSCLC who had received treatment with
  chemotherapy in first or second line were
  eligible for recruitment into the TargeT trial.
• Chemotherapy-naive patients non suitable for
  first line conventional chemotherapy were also
  eligible for the study.
• Eligibility criteria were gt18 years old, ECOG
  0-2, adequate bone marrow, hepatic, and renal
  function and written informed consent.
• Trial design
• Open-label, multicenter, non-randomized, phase II
  trial.
• Patients were treated with erlotinib 150 mg/day
  until disease progression or withdrawal.

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Study Design (II)

• Efficacy assessments
• Physical Examination.
• Radiological assessment of tumor response by CT
  Scan was performed every six weeks. Responses
  were evaluated according to RECIST criteria and
  confirmed 6 weeks later.
• Safety assessments
• Evaluation of the safety profile of erlotinib as
  determined by NCI CTCAE version 3.0.

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Objectives

• Primary Endpoint
• Evaluate time to progression (TTP) in the intent
  to treat (ITT) population with erlotinib
  administered as first, second and third or
  successive lines of treatment.
• Secondary Endpoints
• Determine the efficacy of erlotinib in terms of
  clinical benefit (CR, PR and SD) when
  administered to patients with advanced or
  metastatic NSCLC.
• Determine overall survival in this patient
  population.
• Define safety profile of erlotinib as determined
  by NCI-CTCAE v3.0.

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Results (I)

• From June 2004 to August 2005, a total of 975
  patients were enrolled in the study.
• 565 patients had measurable disease and were
  evaluable for response 4 CR, 85 PR, 239 SD and
  237 PD.

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Results (II) Baseline Characteristics
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Results (III) Univariate Analysis of Response
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Results (IV) TTP among All Evaluable Patients
Median TTP (95 CI) 3.5 (3.2-3.9) months
Kaplan-Meier Curve for Time To Progression among
All Evaluable Patients
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Results (V) TTP by Smoking History
Multivariate HR 1.8 (1.4-2.4) plt0.0001
Kaplan-Meier Curve for Time To Progression by
Smoking History
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Results (VI) TTP by Histology
Kaplan-Meier Curve for Time To Progression by
Histology
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Results (VII) TTP by Line of Treatment
Kaplan-Meier Curve for Time To Progression by
Line of Treatment
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Results (VIII) OS among All Patients
Median survival (95 CI) 5.7 (5.1-6.2) months
Kaplan-Meier Curve for Overall Survival among All
Patients
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Results (IX) OS by Smoking History
Multivariate HR 2.0 (1.6-2.6) plt0.0001
Kaplan-Meier Curve for Overall Survival by
Smoking History
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Results (X) OS by Histology
Kaplan-Meier Curve for Overall Survival by
Histology
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Results (XI) OS by Line of Treatment
Kaplan-Meier Curve for Overall Survival by Line
of Treatment
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Results (XII) Safety

• Most common adverse events related to erlotinib
  were rash and diarrhea. No unexpected toxicities
  were observed.
• Rash was the predominant toxicity, occurring in
  61.5 of patients. Most cases of rash were mild
  to moderate. There were only 10 cases of grade 4
  rash (1.2).
• Diarrhea was observed in 30.2 of patients (0.6
  grade 4).

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Conclusions

• This large experience confirms erlotinib as an
  active agent in patients with advanced NSCLC,
  achieving disease control rate gt50, median TTP
  3.5 months and median survival time of 5.7
  months.
• The effect in disease control rate seems not to
  be dependent on performance status.
• Use of erlotinib in first line of treatment in
  patients not suitable for cytotoxic chemotherapy
  achieves better results than in 2nd and 3rd or
  successive lines of treatment in terms of TTP.
• The results of erlotinib as treatment of 2nd and
  3rd line do not differ.
• No significant differences in TTP or survival
  were found between adenocarcinoma and SCC in the
  present study.
• In multivariate analysis, the absence of smoking
  history is the most significant predictive factor
  for a longer TTP.