มะเร็งปอด ประชุมองค์กรแพทย์ 2003 ppt
TRANSCRIPT
Therapeutic Options for
First Line Advanced Non Small Cell Lung
Cancer
นพ.จิ�รเจิษฎ์ สุ�ขสุ�เพ��ม อายุ�รแพทยุโรคมะเร�ง ศู�นยุมะเร�ง รพ.จิ�ฬาร�ตน 9
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.
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