Figure 7. KaplanMeier Curve for Overall Survival by Histology.

1
P3-130
A large Spanish experience with erlotinib in
advanced non-small-cell lung cancerL.G.
Paz-Ares1, J.L. González-Larriba2, N. Viñolas3,
A. Arizcum4, D. Gutiérrez Abad5, C. Madroñal6,
J.R. Delgado7, P. Martínez del Prado8, M.L.
Amador9, B. Massutí10, on behalf of the Spanish
TargeT Trial investigators 1Hospital Univ. 12 de
Octubre, Madrid, Spain, 2Hospital Clínico San
Carlos, Madrid, Spain, 3CSC-Hospital Clínic,
Barcelona, Spain, 4Hospital General Río Carrión,
Palencia, Spain, 5Hospital Ntra. Sra. de
Sonsoles, Ávila, Spain, 6Institut dOncologia
Corachán, Barcelona, Spain, 7Hospital Univ.
Virgen de las Nieves, Granada, Spain, 8Hospital
de Basurto, Bilbao, Spain, 9Roche Farma, S.A.,
Madrid, Spain, 10Hospital Gral. Univ. de
Alicante, Alicante, Spain

• Introduction
• Lung cancer is the leading cause of cancer death
  worlwide.1
• The BR.21 pivotal study comparing single-agent
  activity of erlotinib versus placebo was the
  first randomized trial to demonstrate that an
  EGFR TKI is able to prolong survival after
  chemotherapy for advanced NSCLC. The median
  overall survival was 6,7 months for erlotinib
  versus 4,7 months for placebo (HR 0,70, 95 CI
  0,580,85
• 0,001).2
• Erlotinib is now approved for the treatment of
  advanced NSCLC patients after failure of at least
  one prior chemotherapy regimen.
• The TargeT trial is an open label, non-
  randomized trial carried out in 203 Spanish
  institutions.

Safety Most common adverse events related to
erlotinib were rash and diarrhea. No unexpected
toxicities were observed. Rash was the
predominant toxicity, occurring in 61,4 of
patients. Most cases of rash were mild to
moderate. Grade 3-4 rash was observed in 10,7 of
patients. Diarrhea was observed in 31,7 of
patients (3,8 grade 3-4).

• Results
• Between June 2004 and March 2006, 1796 patients
  were enrolled into the TargeT trial. Baseline
  characteristics e described in Table 1.
• 1539 were included in the efficacy analyses.
  In patients with at least one target lesion, the
  response rate was evaluated according to RECIST
  879 patients, with 11 CR, 154 PR, 343 SD and 371
  PD (Table 2).

Abstract Background Erlotinib is an orally
active and selective inhibitor of HER1/EGFR
tyrosine kinase, which gained approval for the
treatment of previously treated patients with
advanced non-small cell lung cancer (NSCLC). The
randomized, phase III study BR.21 demonstrated a
significant survival benefit for patients with
advanced NSCLC who received erlotinib versus
placebo (HR 0,70 95 CI 0,58-0,85), after
failure to one or more previous treatments. The
TargeT trial is a large, Spanish, non-randomized,
phase II trial evaluating the efficacy and safety
of erlotinib in patients with advanced or
metastatic NSCLC. Methods Patients with
previously treated advanced or metastatic NSCLC
or patients that were not suitable for first line
conventional chemotherapy, stage IIIB/IV, PS 0-2
were enrolled to receive oral erlotinib 150
mg/day until disease progression or withdrawal.
The primary endpoint of the study was time to
progression (TTP) in the intent to treat (ITT)
population. Results 1.796 patients were
enrolled from June 04 to March 06 and 1.539
evaluated for this analysis. Demographics median
age 65 y range 26-95 male 72 stage IV 82
PS 0/1/2 21/54/25 adenocarcinoma histology
53, SCC 25,0, LCC 16, other 6
current/former smoker 78. Patients receiving
erlotinib as 1st/2nd/3rd line were 29/ 39/33,
respectively. 879 were analyzed for response 11
patients reached CR (1), 154 PR (18), for and
overall response rate of 19 . Control disease
rate was 58. In the exploratory subgroup
analysis, higher response rate (RR) was related
to female gender (35,9 vs. 11,1 plt0,0001), the
absence of smoking habits (42,2 vs. 11,7
plt0,0001) and adenocarcinoma histology (25,8 vs.
11,4 plt0,0001). Patients receiving erlotinib in
the first line setting reached significantly
higher RRs (31,5) than in further lines of
treatment (13,8 plt0,0001). All these factors
remained as predictive factors for response in
the multivariate analysis, with the exception of
gender. Similar results were found regarding
control disease rate. In the ITT population,
median time to progression was 3,9 months 95 CI
3,5-4,4 and median overall survival 6,1 months
95 CI 5,5-6,4 months. Statistically
significant differences were found in favor of
nonsmokers (TTP and OS plt0,0001), patients with
a good performance status (TTP p0,004 OS
plt0,0001) and adenocarcinoma (for the comparison
with other grouped histologies TTP p0,002 OS
plt0,0001), both in the univariate and
multivariate analysis (p refers to the latter
analysis). Interestingly, no differences between
adenocarcinoma and SCC specifically were
detected. Treatment in the first line setting was
also associated with longer TTP in the Cox model
(p0,002), but not with longer survival. Finally,
female gender did not significantly associate
with TTP or survival. As expected, rash and
diarrhea were the most frequent adverse events.
Conclusions This interim analysis in a very
large, unselected population with advanced NSCLC
in a real-practice clinical setting confirms that
erlotinib is active and well tolerated in
patients with advanced NSCLC untreated or that
have previously failed to conventional
chemotherapy. Our data indicate that good
performance status and non smoking history are
the most convincing predictive factors for a
longer TTP and survival in patients treated with
erlotinib.
Median Time To Progression (95 CI) 3,9
(3,5-4,4) months
Median overall survival (95 CI) 6,1 (5,5-6,4)
months

• Conclusions
• These results in a real-life setting confirm the
  effectiveness of single agent erlotinib in
  patients with advanced NSCLC.
• Treatment with single agent erlotinib achieved a
  response rate of 18,8 and a disease-control rate
  of 57,8. Response and control of disease was
  higher among women, patients with adenocarcinoma
  (including BAC), nonsmokers and those receiving
  erlotinib as first option of treatment for
  advanced disease.
• The median overall survival of 6,1 months is
  similar to the one achieved in the pivotal
  erlotinib trial BR.21.
• Exploratory multivariate analyses show that
  history of not smoking and good performance
  status are significant predictors factors of
  longer time to progression and survival.
• Treatment with erlotinib in the first line
  setting is also associated with longer time to
  progression and survival (data not shown).
• Rash and diarrhea are the main toxic effects of
  erlotinib.
• On the basis of these results, erlotinib is an
  effective and well tolerated option for patients
  with advanced NSCLC.

Figure 5. Kaplan-Meier Curve for Overall Survival
among All Patients.
Figure 1. Kaplan-Meier Curve for TTP among All
Evaluable Patients.

• Study design
• Patients
• Eligible patients had confirmed stage IIIB/IV
  NSCLC, and had failed or were unsuitable for
  chemotherapy. Chemotherapy-naïve patients
  harboring mutations in the TK domain of HER1/EGFR
  were also eligible for the study.
• Inclusion criteria were gt18 years of age, ECOG
  performance status 0-2, adequate hematologic and
  biochemical values and written informed consent.
• Trial design
• Open-label, multicenter, non-randomized, phase II
  trial.
• Erlotinib (150 mg/d p.o.) was administered until
  disease progression or unacceptable toxicity.
• Patients were monitored on a regular basis.
• Efficacy assessments
• Responses were assessed with the use of Response
  Evaluation Criteria in Solid Tumors (RECIST).

Multivariate HR 2,0 (1,6-2,5) plt0,0001
Multivariate HR 2,1 (1,7-2,5) plt0,0001
Figure 6. Kaplan-Meier Curve for Overall Survival
by Smoking Status.
Figure 2. Kaplan-Meier Curve for Time To
Progression by Smoking Status.

• References
• Jemal, C. et al. CA Cancer J Clin. 2006 56
  106-130.
• 2. Shepherd, FA. et al. N Engl J Med. 2005 353
  123-132.

Figure 7. Kaplan-Meier Curve for Overall Survival
by Histology.
Figure 3. Kaplan-Meier Curve for Time To
Progression by Histology.

• Objectives
• Primary endpoint
• Evaluate time to progression (TTP) in the intent
  to treat (ITT) population.
• Secondary endpoints
• Determine the efficacy of erlotinib in terms of
  disease control rate complete response (CR)
  partial response (PR) stable disease (SD).
• Determine overall survival (OS) in this patient
  population.
• Define safety profile of erlotinib as determined
  by NCI-CTCAE v3.0.

Multivariate HR 1,3 (1,1-1,6) p0,004
Multivariate HR 2,5 (2,2-2,9) plt0,0001
Figure 8. Kaplan-Meier Curve for OS by
Performance Status ECOG.
Figure 4. Kaplan-Meier Curve for TTP by
Performance Status ECOG.