This document discusses therapeutic options for first line treatment of advanced non-small cell lung cancer (NSCLC). It provides details on chemotherapy regimens such as platinum doublets with paclitaxel, gemcitabine or docetaxel. It also discusses targeted therapies like bevacizumab, erlotinib and gefitinib. The document reviews clinical trials that established current standard first line treatments and highlights the need for personalized treatment based on tumor markers and mutations.

1. Therapeutic Options for
First Line
Advanced Non Small Cell Lung Cancer
นพ.จิรเจษฎ์ สุขสุเพิ่ม
อายุรแพทย์โรคมะเร็ง ศูนย์มะเร็ง รพ.จุฬารัตน์ 9

2. นพ.จิรเจษฎ์ สุขสุเพิ่ม
อายุรแพทย์โรคมะเร็ง ศูนย์มะเร็ง รพ.จุฬารัตน์ 9
ศูนย์มะเร็ง รักษามะเร็งปอด และ ให ้คาแนะนาเกี่ยวกับ
- Medical Pleurodesis for malignant Pleural effusion
- Conventional Intraveneous Chemotherapy ทุกชนิด : Carbo/Gemcitabine
- Choice of Oral chemo : Navelbine , Etoposide
- Intraveneous Anti Vascular Growth Factor (Avastin)
- Oral targeted TKIs : Gefitinib , Erlotinib
- Oral targeted Anti-ALK : Crizotinib
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3. นพ.จิรเจษฎ์ สุขสุเพิ่ม
อายุรแพทย์โรคมะเร็ง ศูนย์มะเร็ง รพ.จุฬารัตน์ 9
ศูนย์มะเร็ง รักษามะเร็งปอด และ ให ้คาแนะนาเกี่ยวกับ
Growth factors support :
- Filgastrim for Neutropenia (มี PEG filgastrim form ฉีดเข็มเดียว=แบบ ODx5)
- Oral Eltrombopax for Thrombocytopenia (Platelet drop from chemo)
- PAIN control Solution Non Opioid to all Opioid (MO syrup is in process)
- Zoledronic acid (Zometa/Local brand) for releive Bone PAIN
- RadioTherapy : Convention, IMRT 3มิติ (ศูนย์มะเร็งกรุงเทพ ซ.อารีย์)
- ให ้คาแนะนา BrachyTherapy (ฝังแร่) และ ประสานส่งตัว
- Contact of Bone scan (อุรุพงษ์) PET Scan (ศูนย์จุฬาภรณ์)
- Genetic test : EGFR mutation, ALK rearrange (N-health)

4. Lung Cancer: A Leading Cause of
Cancer-Related Deaths
 221,130 new
cases of lung
cancer
 156,940 deaths
due to lung
cancer
Men
Lung and bronchus 28%
Prostate 11%
Colon and rectum 8%
Pancreas 6%
Leukemia 4%
Women
Lung and bronchus 26%
Breast 15%
Colon and rectum 9%
Pancreas 7%
Ovary 6%
Leading Sites* by Sex, United States, 2010 Estimates
*Excludes basal and squamous cell skin cancer, and in situ carcinomas except urinary bladder.
American Cancer Society. Cancer Facts & Figures 2011.

5. Risk Factors for Lung Cancer
 Smoking
 Lung cancer deaths due to smoking
 ~ 91% males and 80% females[1]
 Environmental factors[2]
 Second-hand smoke 3% to 5%
 Radon 3% to 5%
 Industrial pollution 0% to 5%
 Radiation exposureRare
 Asbestos, radon, radiation, silicosis, and berylliosis
 Arsenic exposure, talc, obesity, genetic factors
1. CDC. Lung Cancer. 2011.
2. American Cancer Society. Lung Cancer. 2011.

7. Lung Cancer Subtypes
 The WHO classification for primary lung cancer recognizes 4 major
histology types[1]
Small-cell
carcinoma
13.0%
Large-cell
carcinoma
5.0%
Adenocarcinoma
38.3%
19.7%
Squamous cell
carcinoma
Other*
24.0%
Percent distribution by histology among histologically
confirmed lung cancer cases, 2001-2004[2]
1. Brambilla E, et al. Eur Respir J. 2001;18:1059-1068.2. SEER Database. Lung and Bronchus Cancer
(Invasive), 1975-2004.
*Including adenosquamous
carcinoma; carcinomas with
pleomorphic, sarcomatoid or
sarcomatous elements;
carcinoid tumor; carcinomas of
salivary gland type; and
unclassified carcinoma

8. 6th Edition Descriptor 7th Edition N0 N1 N2 N3
T1 (≤ 2 cm) T1a IA IIA IIIA IIIB
T1 (> 2-3 cm) T1b IA IIA IIIA IIIB
T2 (> 3 to ≤ 5 cm) T2a IB IIA IIIA IIIB
T2 (> 5-7) T2b IIA IIB IIIA IIIB
T2 (> 7 cm) T3 IIB IIIA IIIA IIIB
T3 invasion IIB IIIA IIIA IIIB
T4 (same lobe nodules) IIB IIIA IIIA IIIB
T4 (extension) T4 IIIA IIIA IIIB IIIB
M1 (ipsilateral lung) IIIA IIIA IIIB IIIB
T4 (pleural effusion) M1a IV IV IV IV
M1 (contralateral lung) IV IV IV IV
M1 (distant) M1b IV IV IV IV
7th Edition of TNM Staging
Goldstraw P, et al. J Thorac Oncol. 2007;2:706-714.

9. Chemotherapy vs Best Supportive
Care in Advanced NSCLC: Meta-
Analysis
 Meta-analysis of 8 trials (778 patients) using
cisplatin-based chemotherapy[1]
 Absolute improvement in survival of 10% at 1 yr[1]
 Median survival, BSC vs chemo: 4 vs 8+ mos,
respectively
 Median survival now 12+ mos in more recent
trials
 VEGF-targeted therapy plus platinum doublet[2]
 Quality-of-life benefit from chemotherapy[3]
1. NSCLC Collaborative Group, et al. BMJ. 1995;311:899-909. 2. Herbst R, et al. Clin Lung Cancer.
2009;10:20-27 3. Klastersky J, et al. Lung Cancer. 2001;34(suppl 4):S95-S101.

10. First-line Treatment: 2 Agents Are
More Effective Than 1
 Meta-analysis: 65 trials (N = 13,601) between
1980-2001
 Compared efficacy of
 Doublet vs single-agent regimens
 Triplet vs doublet regimens
Delbaldo C, et al. JAMA. 2004;292:470-484.
Survival Outcome Doublet vs Single-Agent
Regimens
Triplet vs Doublet
Regimens
1-yr OS
Doublet > single-agent
 OR: 0.80; 95% CI: 0.70-0.91;
P < .001
 5% absolute benefit
Triplet = doublet
 OR: 1.01; 95% CI: 0.85-1.21;
P = .88
Median OS
Doublet > single-agent
 MR: 0.83; 95% CI: 0.79-0.89;
P < .001
Triplet = doublet
 MR: 1.00; 95% CI: 0.94-1.06;
P = .97

11. Agents With Activity in Advanced
NSCLC
*Not all drugs listed have FDA approval.
Older Agents* Newer Agents*
 Carboplatin
 Cisplatin
 Etoposide
 Ifosfamide
 Mitomycin C
 Vinblastine
 Vindesine
 Docetaxel
 Gemcitabine
 Irinotecan
 Paclitaxel
 Topotecan
 Vinorelbine
 Pemetrexed
 Gefitinib
 Erlotinib
 Bevacizumab
 Cetuximab
 Crizotinib

12. History of Therapy in Advanced
NSCLC: FDA Approval Dates
First line
Second line
Third line
Maintenance
Not approved
1970 1980 1990 2000
Median
OS (mos)
12+
~ 6
~ 2-4
BSC Single-agent platinum Doublets
Bevacizumab + PC
Carboplatin*
1989
Erlotinib
Pemetrexed
2004
Docetaxel
1999
Paclitaxel
Gemcitabine
1998
Vinorelbine
1994
Docetaxel
2002
Bevacizumab
2006
Gefitinib
2003
Standard therapies
*Label does not include
NSCLC-specific indication
Pemetrexed
2008/2009
Histology-directed therapy
~ 8-10
Cisplatin*
1978
1. FDA Web site. 2. NCCN. Clinical practice guidelines in oncology. v.3.2011. 3. Schrump, et al. Non-small
cell lung cancer. In: Cancer: Principles and Practice of Oncology. 7th ed. Philadelphia, PA: Lippincott
Williams & Wilkins; 2005.

13. Paclitaxel 225 mg/m2 over 3 hrs on Day 1
Carboplatin AUC 6.0 mg/mL/min on Day 1
3-wk cycle
Docetaxel 75 mg/m2 on Day 1
Cisplatin 75 mg/m2 on Day 1
3-wk cycle
Gemcitabine 1000 mg/m2 on Days 1, 8, 15
Cisplatin 100 mg/m2 on Day 1
4-wk cycle
Reference Arm
Paclitaxel 135 mg/m2 over 24 hrs on Day 1
Cisplatin 75 mg/m2 on Day 2
3-wk cycle
ECOG 1594: Comparison of 4
First-line Doublet Regimens in
Advanced NSCLC
Stratified by:
 ECOG PS (0/1 vs 2)
 Weight loss in previous 6 mos
(< 5% vs ≥ 5%)
 Disease stage (IIIB vs IV or recurrent)
 Brain metastases (yes vs no)
Advanced-stage, previously
untreated NSCLC patients
(N = 1207)
Schiller JH, et al. N Engl J Med. 2002;346:92-98.

14. ECOG 1594: OS
Schiller JH, et al. N Engl J Med. 2002;346:92-98.
1.0
0.8
0.6
0.4
0.2
0
Proportionofpatients
Mos
0 5 10 15 20 25 30
Survival by Treatment Group
All Randomized Cases
Cisplatin/paclitaxel
Cisplatin/gemcitabine
Cisplatin/docetaxel
Carboplatin/paclitaxel

15. Advanced-stage, previously
untreated NSCLC patients
(N = 1725)
Cisplatin 75 mg/m2 on Day 1
Gemcitabine 1250 mg/m2 on Days 1 and 8
Six 3-wk cycles
Cisplatin 75 mg/m2 on Day 1
Pemetrexed 500 mg/m2 on Day 1
Six 3-wk cycles
Scagliotti GV, et al. J Clin Oncol. 2008;26:3543-3551.
CONSORT: Phase III Gemcitabine or
Pemetrexed + Cisplatin as First-line Therapy
Stratified by:
 ECOG PS (0 vs 1)
 Disease stage (IIIB vs IV)
 Brain metastases (yes vs no)
 Sex (male vs female)
 Pathologic diagnosis (histologic vs cytologic)
 Treatment center

16. Scagliotti GV, et al. J Clin Oncol. 2008;26:3543-3551.
Survival Pemetrexed
+ Cisplatin
(n = 862)
Gemcitabine
+ Cisplatin
(n = 863)
HR
(95% CI)
P Value
Median OS, mos
10.3 10.3
0.94
(0.84-1.05)
Noninferior
Adenocarcinoma
(N = 847)
12.6 10.9
0.84
(0.71-0.99)
.03
Large-cell carcinoma
(N = 153)
10.4 6.7
0.67
(0.48-0.96)
.03
Squamous cell
carcinoma
(N = 473)
9.4 10.8
1.23
(1.00-1.51)
.05
CONSORT: Efficacy

17. Chemotherapy Today and the
Need for Targeted Therapies
 Doublet chemotherapy for 4-6 cycles is standard
 Can now select chemotherapy based on histology
 Future selection by other markers (ie, ERCC1)
 There is a need for “targeted” chemotherapy and
other agents
 Antiangiogenesis: VEGF targeted (bevacizumab, etc)
 EGFR-targeted antibody (cetuximab), TKI (erlotinib,
etc)
 Newer targets (ALK and others)
 Recent identification of “driver mutations” in 50% of
NSCLC adenocarcinomas

18. The Angiogenic Switch
Small tumor
 Nonvascular
 “Dormant”
Larger tumor
 Vascular
 Metastatic potential
1-2 mm
Angiogenic
Switch
VEGF

19. Bevacizumab

21. E4599: Efficacy
RR: 15% for Paclitaxel/Carboplatin vs
35% for Paclitaxel/Carboplatin + Bevacizumab
PFS(%)
0
20
40
60
80
100
OS(%)
0 6 12 18 24 30 42
Mos
PCB group
(305 events in 417 patients)
PC group
(344 events in 433 patients)
.Sandler A, et al. N Engl J Med. 2006;355:2542-2550.
0
20
40
60
80
100
0 6 12 18 24 30
Mos
36
HR: 0.79 (P = .003)
HR: 0.66 (P < .001)
PCB group
(374 events in 417 patients)
PC group
(405 events in 433 patients)

22. Bevacizumab in Special
Populations: Summary
 Caution with elderly patients; ongoing trials
 Hemoptysis remains an issue, but
anticoagulation can be considered cautiously
 Safe in patients with treated brain metastases
 Squamous histology still a major bleeding risk

23. EGFR and NSCLC
 EGF binds to the EGFR
to regulate cell growth, proliferation, and differentiation
 Erlotinib and gefitinib are inhibitors of the TK enzyme in the
EGFR
 Cetuximab is a monoclonal human-murine chimeric antibody
against EGFR with some NSCLC activity
Baselga J. Oncologist. 2002;7(suppl 4):2-8. Lynch TJ, et al. N Engl J Med. 2004;350:2129-2139. Shepherd
FA, et al. N Engl J Med. 2005;353:123-132. Rosell R, et al. N Engl J Med. 2009;361:958-967.

30. Gefitinib,Erlotinib,Afatinib
Crizotinib

31. Previously
untreated patients
with stage IIIB/IV
NSCLC; never or
light ex-smokers;
PS 0-2
(N = 1217)
Up to six
3-wk cycles
Gefitinib 250 mg/day PO
(n = 609)
Paclitaxel 200 mg/m2 IV on Day 1 +
Carboplatin AUC 5-6 mg/mL/min IV on Day 1
(n = 608)
Mok TS, et al. N Engl J Med. 2009;361:247-257.
IPASS: Gefitinib vs
Carboplatin/Paclitaxel in Select
Patients With Advanced NSCLC
 Primary endpoint: PFS (noninferiority)
 Secondary endpoints: ORR, OS, QoL, safety, disease-related symptoms
 Exploratory endpoints: EGFR mutation, EGFR gene copy number, EGFR protein
expression
Randomized from
March 2006 to October 2007

32. IPASS: PFS in EGFR Mutation–
Positive vs –Negative Patients
EGFR Mutation Positive EGFR Mutation Negative
Treatment by subgroup interaction test, P < .001
HR: 0.48 (95% CI: 0.36-0.64)
P < .001
No. events gefitinib,: 97 (73.5%)
No. events C/P,: 111 (86.0%)
Gefitinib (n = 132)
Carboplatin/paclitaxel (n = 129)
HR: 2.85 (95% CI: 2.05-3.98)
P < .001
No. events gefitinib: 88 (96.7%)
No. events C/P: 70 (82.4%)
132 71 31 11 3 0
129 37 7 2 1 0
108
103
0 4 8 12 16 20 24
Gefitinib
C/P
0
0.2
0.4
0.6
0.8
1.0
ProbabilityofPFS
At risk:
91 4 2 1 0 0
85 14 1 0 0 0
21
58
Gefitinib (n = 91)
Carboplatin/paclitaxel (n = 85)
Mos
Incidence of EGFR mutation on IPASS participants: 261/437 (59.7%)
Mok TS, et al. N Engl J Med. 2009;361:947-957.
0 4 8 12 16 20 24
0
0.2
0.4
0.6
0.8
1.0
ProbabilityofPFS
Mos

33. EURTAC: First-line Erlotinib vs
Chemo in European Patients With
EGFR Mutations
 174 patients
 Trial run in Europe (lead by Spanish group)
Outcome CT Erlotinib HR P Value
Response rate, % 15 58 - NR
Median PFS, mos 5.2 9.7 0.37 < .0001
Median OS, mos NR NR 0.80 .42
Most common
toxicities, %
ALT elevation: 72
Anemia: 46
Neutropenia: 36
ALT elevation: 80
Rash: 80
Diarrhea: 57
Rosell R, et al. ASCO 2011. Abstract 7503.

34. EURTAC: PFS in ITT
Population
Erlotinib (n = 86)
Chemotherapy (n = 87)
HR: 0.37 (95% CI: 0.25-
0.54; log-rank P < .0001)
PFSProbability
1.0
0.8
0.6
0.4
0.2
0
0 3 6 9 12 15 18 21 24 27 30 33
Mos
5.2 9.7
Patients at Risk, n
Erlotinib
Chemo
86
87
63
49
54
20
32
8
21
5
17
4
9
3
7
1
4
0
2
0
2
0
0
0
Rosell R, et al. ASCO 2011. Abstract 7503.

35. EURTAC vs Asian Trials in EGFR
Mutated NSCLC: RR and PFS
 None of the EGFR-TKI vs chemo as first-line
therapy trials in EGFR mut NSCLC have shown
a significant OS benefit
Study Response Rate, % PFS, Mos (HR)
EURTAC 58.0 vs 14.9 9.7 vs 5.2 (0.37)
OPTIMAL 83 vs 36 13.1 vs 4.6 (0.16)
NEJ 002 74 vs 31 10.8 vs 5.4 (0.30)
WJTOG 3405 62 vs 31 9.2 vs 6.3 (0.49)
Rosell R, et al. J Clin Oncol. 2011;29(suppl). Abstract 7503.

37. Summary: First-line NSCLC
Therapy
 Doublet chemotherapy still standard backbone
regimen
 Some selection possible; histology
 Targeted drugs can add to doublet chemotherapy
 Bevacizumab and cetuximab with survival benefit
 MANY with NO benefit in unselected patients in this
setting
 EGFR-TKIs, VEGFR-TKIs, MMPs, immunomodulators
 Targeted agents where target is known can
replace first-line chemotherapy (EGFR-TKI in
EGFR mutants)
 Better biomarkers will lead to better targeting