This document discusses the treatment of metastatic disease in lung cancer. It emphasizes the importance of determining histology (squamous vs. non-squamous) and biomarkers to guide treatment decisions. For squamous cell carcinoma, EGFR/ALK testing is not recommended and treatment involves platinum-based doublets or cetuximab-containing regimens. For non-squamous, testing for EGFR/ALK is recommended, and if negative, initial treatment with carboplatin/pemetrexed is an option. The prognostic value of TTF-1 is also discussed, as its negativity highly predicts EGFR mutation negativity. Treatment decisions should incorporate histology, biomarker status, and other clinical factors.

1. Doença Metastática
Presente & Futuro

2. Doença Metastática
KPS &
Co-
morbidades

3. Doença Metastática
KPS & Histologia
Co-
morbidades

4. SWOG – Taxano/ Vinca & Histologia
 N = 741
 S9806, S0003, and CDDP/Vin arm of S9308
 No difference in any efficacy outcome by histology
Histology N (%) OS PFS
Median, Mos Adjusted HR* Median, Mos Adjusted HR*
(P Value) (P Value)
Adeno 424 (57) 8.5 1.00 (referent) 4.3 1.00 (referent)
SCCA 128 (17) 8.4 0.987 (.89)† 4.5 0.986 (.89)‡
Large cell 82 (11) 7.9 0.974 (.83) 4.2 1.03 (.81)
NSCLC, NOS 107 (14) 9.6 0.971 (.79) 5.0 0.87 (.20)
*HR from Cox proportional hazards model with adenocarcinoma as referent, adjusted for sex.
†HR for SCCA vs all others combined, OS: 0.995 (95% CI: 0.82-1.21; P = .96).
‡HR for SCCA vs all others combined, PFS: 1.01 (95% CI: 0.83-1.22; P = .94)
Chansky K, et al. IASLC WCLC 2009. Abstract B2.7

5. Histology Is Not a Predictor of OS From
Antimicrotubule or Gem-Based Therapy
1.0 All Patients (N = 607) 1.0 VC Patients (N = 201)
Proportion Surviving
Proportion Surviving
Adeno Large cell Adeno Large cell
0.8 Other Squamous 0.8 Other Squamous
0.6 0.6
0.4 0.4
0.2 0.2
0 0
0 6 12 18 24 30 36 0 6 12 18 24 30 36
OS (Mos) OS (Mos)
1.0 PC Patients (N = 201) 1.0 GC Patients (N = 205)
Proportion Surviving
Proportion Surviving
Adeno Large cell Adeno Large cell
0.8 Other Squamous 0.8 Other Squamous
0.6 0.6
0.4 0.4
0.2 0.2
0 0
0 6 12 18 24 30 36 0 6 12 18 24 30 36
OS (Mos) OS (Mos)
Scagliotti G, et al. J Thorac Oncol. 2009;4:1568-1571.

6. JMDB Trial: Cisplatin/Pemetrexed vs
Cisplatin/Gemcitabine in Advanced NSCLC
Survival Probability
1.0 Median (95% CI)
0.8 CP 10.3 (9.8-11.2)
No difference in OS or PFS 0.6
CG 10.3 (9.6-10.9)
CP vs CG Adjusted HR (95% CI)
0.4
between study arms 0.2
0.94 (0.84-1.05)
0
0 6 12 18 24 30
Survival Time (Mos) in All Patients
Survival Probability
1.0 Median (95% CI)
0.8 CP 11.8 (10.4-13.2)
Cis/pem improves OS over cis/gem 0.6
CG 10.4 (9.6-11.2)
CP vs CG Adjusted HR (95% CI)
0.4
in non-SCCA (HR: 0.81; P = .005) 0.2
0.81 (0.70-0.94)
0
0 6 12 18 24 30
Survival Time (Mos) in Patients With
Nonsquamous Histology
Survival Probability
1.0 Median (95% CI)
0.8 CP 9.4 (8.4-10.2)
Cis/gem improves OS over cis/pem 0.6
CG 10.8 (9.5-12.1)
CP vs CG Adjusted HR (95% CI)
in SCCA (HR: 1.23; P = .05) 0.4
0.2
1.23 (1.00-1.51)
0
0 6 12 18 24 30
Scagliotti GV, et al. J Clin Oncol. 2008;26:3543-3551. Survival Time (Mos) in Patients With
Squamous Histology

7. Doença Metastática
KPS & Histologia
Co-
morbidades
Biologia
Molecular

8. Tratamento da Doença Metastática
Primeiro, determine a Histologia
 Classifique entre escamoso ou não-
escamoso
 Todos pacientes sem diagnóstico óbvio de
escamoso devem ser considerados não-
escamosos
 Céls escamosas P63 positivo & TTF-1 negativo
 Adenocarcinomas TTF-1 positivo (70%) e P63
negativo

9. Tratamento da Doença Metastática
Se escamoso ….
– Mutaçao EGFR e testagem para ALK não estão
recomendadas
• Treatmento
– 1 linha: dupla de carboplatin/cisplatina e
outro(paclitaxel, docetaxel, gemcitabina,
vinorelbina), cetuximab/vinorelbine/cisplatin,
• Pemetrexed não recomendado
– 2 linnha: docetaxel, erlotinib
– 3 linha: erlotinib não recomendado

10. Tratamento da Doença Metastática
Se não-escamoso ….
• TTF-1 positivo?
• NÃO, QT está indicada enquanto aguarda
pesquisa de biomarcador
• Opções
– Carboplatin/pemetrexed
– Carboplatin/pemetrexed/bevacizumab (???)
– Carboplatin/paclitaxel/bevacizumab
– Erlotinib/Geftinib (se positivo para mutação
EGFR)

11. Tratamento da Doença Metastática
TTF-1 ….
• TTF-1–negative lung adenocarcinomas will
be negative for EGFR mutations[1]
• Expressed in 71% to 76% of
adenocarcinomas[2]
• No or very low staining in squamous and
large-cell carcinomas[3]
1. Somaiah N, et al. World Conference on Lung Cancer 2011. Abstract O38.02.
2. Di Loreto C, et al. J Clin Pathol. 1997;50:30-32.
3. Fabbro D, et al. Eur J Cancer. 1996;32A:512-517.

12. Tratamento da Doença Metastática
EGFR Mutation and TTF-1 Status: Negative
Predictive Value
• NPV is dependent on the prevalence of
EGFR mutations
• NPV for a TTF-1 negativity to predict for
EGFR mutation–negative status
– For an estimated 13% prevalence
• 99.5% (95% CI: 98.6% to 99.9%)
– For an estimated 15% prevalence
• 99.4% (95% CI: 98.4% to 99.9%)
Somaiah N, et al. ASCO 2011. Abstract 7530.