Therapeutic Options for

First Line Advanced Non Small Cell Lung

Cancer

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นพ.จิ�รเจิษฎ์ สุ�ขสุ�เพ��ม อายุ�รแพทยุโรคมะเร�ง ศู�นยุมะเร�ง รพ.จิ�ฬาร�ตน 9

ศู�นยุมะเร�ง ร�กษามะเร�งปอด และ ให้%ค&าแนะน&าเก'�ยุวก�บ

- Medical Pleurodesis for malignant Pleural effusion

- Conventional Intraveneous Chemotherapy ท�กชน�ด : Carbo/Gemcitabine

- Choice of Oral chemo : Navelbine , Etoposide

- Intraveneous Anti Vascular Growth Factor (Avastin)

- Oral targeted TKIs : Gefitinib , Erlotinib

- Oral targeted Anti-ALK : Crizotinib•

นพ.จิ�รเจิษฎ์ สุ�ขสุ�เพ��ม อายุ�รแพทยุโรคมะเร�ง ศู�นยุมะเร�ง รพ.จิ�ฬาร�ตน 9

ศู�นยุมะเร�ง ร�กษามะเร�งปอด และ ให้%ค&าแนะน&าเก'�ยุวก�บ Growth factors support :

- Filgastrim for Neutropenia (ม' PEG filgastrim form ฉี'ดเข�มเด'ยุว=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 3ม�ต� (ศู�นยุมะเร�งกร�งเทพ ซ.อาร'ยุ)- ให้%ค&าแนะน&า BrachyTherapy (ฝั.งแร/) และ ประสุานสุ/งต�ว

- Contact of Bone scan (อ�ร�พงษ) PET Scan (ศู�นยุจิ�ฬาภรณ์)- Genetic test : EGFR mutation, ALK rearrange (N-health)

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%

WomenLung 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.

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 exposure Rare Asbestos, radon, radiation, silicosis, and berylliosis Arsenic exposure, talc, obesity, genetic factors

1. CDC. Lung Cancer. 2011.2. American Cancer Society. Lung Cancer. 2011.

Lung Cancer Subtypes

The WHO classification for primary lung cancer recognizes 4 major histology types[1]

Small-cellcarcinoma

13.0%

Large-cell carcinoma

5.0%

Adenocarcinoma38.3%

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

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.

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.

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 DoubletRegimens

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 OSDoublet > 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

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

History of Therapy in Advanced NSCLC: FDA Approval Dates

First lineSecond lineThird lineMaintenanceNot approved

1970 1980 1990 2000

MedianOS (mos)

12+

~ 6~ 2-4

BSC Single-agent platinum Doublets

Bevacizumab + PC

Carboplatin*1989

ErlotinibPemetrexed

2004

Docetaxel1999

PaclitaxelGemcitabine

1998

Vinorelbine1994

Docetaxel2002

Bevacizumab2006

Gefitinib2003

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.

Paclitaxel 225 mg/m2 over 3 hrs on Day 1Carboplatin AUC 6.0 mg/mL/min on Day 1

3-wk cycle

Docetaxel 75 mg/m2 on Day 1Cisplatin 75 mg/m2 on Day 1

3-wk cycle

Gemcitabine 1000 mg/m2 on Days 1, 8, 15Cisplatin 100 mg/m2 on Day 1

4-wk cycle

Reference ArmPaclitaxel 135 mg/m2 over 24 hrs on Day 1

Cisplatin 75 mg/m2 on Day 23-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.

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

Pro

po

rtio

n o

f p

atie

nts

Mos0 5 10 15 20 25 30

Survival by Treatment GroupAll Randomized Cases

Cisplatin/paclitaxelCisplatin/gemcitabineCisplatin/docetaxelCarboplatin/paclitaxel

Advanced-stage, previously untreated NSCLC patients

(N = 1725)

Cisplatin 75 mg/m2 on Day 1Gemcitabine 1250 mg/m2 on Days 1 and 8

Six 3-wk cycles

Cisplatin 75 mg/m2 on Day 1Pemetrexed 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

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, mos10.3 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 6.70.67

(0.48-0.96)

.03

Squamous cell carcinoma(N = 473)

9.4 10.81.23

(1.00-1.51)

.05

CONSORT: Efficacy

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

The Angiogenic Switch

Small tumor Nonvascular “Dormant”

Larger tumor Vascular Metastatic potential

1-2 mm

Angiogenic

SwitchVEGF

Bevacizumab

E4599: Efficacy

RR: 15% for Paclitaxel/Carboplatin vs35% for Paclitaxel/Carboplatin + Bevacizumab

PF

S (

%)

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)

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

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.

http://www.jthoracdis.com/article/viewFile/257/html/1901

Gefitinib,Erlotinib,Afatinib

Crizotinib

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

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

Pro

bab

ilit

y o

f P

FS

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 20 240

0.2

0.4

0.6

0.8

1.0

Pro

bab

ilit

y o

f P

FS

Mos

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: 72Anemia: 46

Neutropenia: 36

ALT elevation: 80Rash: 80

Diarrhea: 57

Rosell R, et al. ASCO 2011. Abstract 7503.

EURTAC: PFS in ITT Population

Erlotinib (n = 86)Chemotherapy (n = 87)

HR: 0.37 (95% CI: 0.25-0.54; log-rank P < .0001)

PF

S P

rob

abili

ty

1.0

0.8

0.6

0.4

0.2

00 3 6 9 12 15 18 21 24 27 30 33

Mos

5.2 9.7

Patients at Risk, nErlotinibChemo

8687

6349

5420

328

215

174

93

71

40

20

20

00

Rosell R, et al. ASCO 2011. Abstract 7503.

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.

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