Emerging Treatment Paradigms in NSCLC
Edward S. Kim, MD
MD Anderson Cancer Center
Tobacco Use in the USA
1900-1999
4500
4000
100
90
Per capita cigarette
consumption
80
3500
70
3000
60
2500
50
Male lung cancer death rate
2000
40
1500
30
1000
20
Female lung cancer death
rate
500
0
10
Age-Adjusted Lung Cancer Death
Rates*
Per Capita Cigarette Consumption
5000
0
00 9 05 9 10 9 15 9 20 9 25 9 30 9 35 9 40 9 45 9 50 9 55 9 60 9 65 9 70 9 75 9 80 9 85 9 90 9 95
9
1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1
Year
*Age-adjusted to 2000 US standard population.
Source: Death rates: US Mortality Public Use Tapes, 1960-1999, US Mortality Volumes, 1930-1959, National
Center for Health Statistics, Centers for Disease Control and Prevention, 2001. Cigarette consumption: Us
Department of Agriculture, 1900-1999.
Cancer Deaths in the US
Male
8
0
6
0
†Uterine
1990
1980
Year
1970
1990
1980
1970
0
1960
0
1950
2
0
1940
2
0
1960
4
0
1940
4
0
Pancreas
Liver
Prostate
Stomach
Lung & bronchus
Colon & rectum
1930
6
0
Rate per 100,000
Uterus†
Breast
Pancreas
Ovary
Stomach
Lung & bronchus
Colon & rectum
1930
Rate per 100,000
8
0
1950
Female
cancer death rates are for uterine cervic and uterine corpus combined.
Source: US Mortality Public Use Data Tapes 1960-1996. US Mortality Volumes 1930-1959,
National Center for Health Statistics, Centers for Disease Control and Prevention, 1999.
History of Therapy in Advanced NSCLC:
FDA Approval Dates
Docetaxel
2002
First-line
Second-line
Paclitaxel
Gemcitabine
1998
Not approved
Cisplatin*
1978
Carboplatin*
1989
Best supportive care
Bevacizumab
2006
Vinorelbine
1994
12+
~8–10
~6
~2–4
1970
Erlotinib
Pemetrexed
2004
Docetaxel
1999
Third-line
1980
1990
Single-agent platinum
*Label does not include NSCLC-specific indication
Gefitinib
2003
Median
overall
survival,
months
2000
Doublets
Bevacizumab + PC
Standard Therapies
Food and Drug Administration. At http://www.fda.gov/cder/cancer/druglistframe.htm. Accessed August 28, 2006.; National Comprehensive
Cancer Network (NCCN). Practice Guidelines in Oncology. Non-small cell lung cancer v2.2006. Accessed August 28, 2006. Schrump et al.
Non-small cell lung cancer. In: Cancer: Principles and Practice of Oncology. 7th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2005.
FDA Approved Chemotherapy Regimens for
Advanced NSCLC
• First-Line
–
–
–
–
–
Cisplatin + paclitaxel (24 hour infusion)
Cisplatin + vinorelbine (4 week)
Cisplatin + gemcitabine (3 or 4 week)
Cisplatin + docetaxel (3 week)
Bevacizumab + carboplatin + paclitaxel
• Second-Line
– Docetaxel
– Pemetrexed
– Erlotinib
ECOG 1594: Treatment Schema
Stage IIIB or IV
NSCLC
Stratified by:
•
•
•
•
Extent of disease
PS
Weight loss
Brain metastases
*Control arm.
R
A
N
D
O
M
I
Z
E
Arm A*
q 3 wk
Paclitaxel: 135 mg/m2, day 1
Cisplatin: 75 mg/m2, day 2
Arm B
q 4 wk
Cisplatin: 100 mg/m2, day 1
Gemcitabine: 1000 mg/m2, days 1,8,15
Arm C
q 3 wk
Docetaxel: 75 mg/m2, day 1
Cisplatin: 75 mg/m2, day 1
Arm D
q 3 wk
Paclitaxel: 225 mg/m2, day 1
Carboplatin: AUC=6, day 1
Schiller JH et al. N Engl J Med. 2002;346:92-98
ECOG 1594
Survival by Treatment Group
1.0
0.8
Cisplatin + Paclitaxel
Cisplatin + Gemcitabine
Cisplatin + Docetaxel
Carboplatin + Paclitaxel
0.6
0.4
0.2
0.0
0
5
10
15
20
25
30
Months
Schiller JH et al. N Engl J Med. 2002;346:92-98
TAX 326: Schema
R
A
N
Stratification by:
D
• Stage IIIB or IV
O
• Geographic region M
I
Z
E
q3 wk
Docetaxel: 75 mg/m2 IV +
Cisplatin: 75 mg/m2 IV
q3 wk
Docetaxel: 75 mg/m2 IV +
Carboplatin: AUC 6 IV
q4 wk
Vinorelbine: 25 mg/m2 IV d 1, 8, 15, 22 +
Cisplatin: 100 mg/m2 IV d 1
Premed: Dexamethasone 8 mg PO bid  6 doses (first dose on evening prior to docetaxel
infusion) for the docetaxel groups.
Fossella FV et al: JCO 2003
TAX 326: Survival
Docetaxel/Cisplatin vs. Vinorelbine/Cisplatin
1.0
Cumulative Probability
0.9
0.8
P = .044, Adjusted Log-Rank
1-yr Survival 46 vs 41%
2-yr Survival 21 vs 14%
0.7
0.6
0.5
0.4
0.3
0.2
Docetaxel/Cisplatin
0.1
Vinorelbine/Cisplatin
0.0
0
3
6
9
12
15
18
21
24
27
Survival Time (months)
30
33
Fossella FV et al: JCO 2003
The Bottom Line: Metastatic NSCLC
Study
N
ORR(%)
MST (mos)
SWOG 9509
Carbo-Pac
Cis-Vino
208
202
25
28
8.0
8.0
EGOG 1594
Cis-Pac
Cis-Gem
Cis-Doce
Carbo-Pac
292
288
293
290
21.3
21
17.3
15.3
8.1
8.1
7.4
8.3
Italian Study
Cis-Gem
Carbo-Pac
Cis-Vino
205
201
201
30
32
30
9.8
9.9
9.5
EORTC 08975
Cis-Pac
Cis-Gem
Gem-Pac
159
160
161
31
36
27
8.1
8.8
6.9
TAX 326
Doce-Cis
Doce-Carbo
Cis-Vino
408
406
404
NA
NA
NA
10.9
9.1
10.0
Chemotherapy and Targeted Therapy
Trial Phase
Target
Population
III
All NSCLC
Negative for
survival
All NSCLC
Negative for
survival
All NSCLC
Negative for
survival
All NSCLC
Negative for
survival
All NSCLC
Negative for
survival
All NSCLC
Negative for
survival
All NSCLC
Negative for
survival
Non-squamous,
no brain mets
Positive for
survival
Biological
Agent
Class
Gefitinib
EGFR-TKI
Gefitinib
EGFR-TKI
III
Erlotinib
EGFR-TKI
III
Erlotinib
EGFR-TKI
III
Bexarotene
Rexinoid
III
Bexarotene
Rexinoid
III
Lonafarnib
Farnesyl
Transferase
III
Bevacizumab
VEGF
III
Outcome
Case 1: NSCLC
• HPI: 76 year old female with choking episode. Heimlich maneuver
x 3 successful. Hospital w/u revealed 2 cm RLL nodule.
• PMH: Asthma, HTN, DM Type II, R RCCA – 1997
• Meds: HCTZ, Inderal, Nabumetone
• Allergies: None
• SH: Widow, cigarettes: 20 pack-years
• ETOH: 3 beers/day
• FH: Negative
• ROS: Rib pain, unsteady gait, no weight loss
• PE: No supraclavicular nodes, C/V: RRR, Resp: clear to A&P,
Abd: no masses Ext: no C/C/E Neuro: no focal deficits
Case 1: NSCLC
•
What is the desired work-up for the nodule?
1.
2.
3.
4.
Biopsy
Biopsy, CT chest, abdomen
Biopsy, CT chest, abdomen, bone scan, MRI brain
Referral to medical oncology
Case 1: NSCLC
•
•
•
•
•
FNA: NSCLC
Bone Scan: Multiple increased rib lesions
MRI Brain: No metastases
CT Chest: 2 cm lesion RLL, no adenopathy
CT-PET: FDG avid lesion RLL, no other abns
Case 1: NSCLC
•
What is the optimal treatment for this patient at this time?
1.
2.
3.
4.
Lobectomy
Lobectomy and nodal sampling
Lobectomy and nodal dissection
Surgery followed by radiation
VATS Lobectomy
Technique
Courtesy S. Swisher
Case 1: NSCLC
Pathology: T2N0M0
Case 1: NSCLC
•
What is the appropriate next therapy for this patient?
1.
2.
3.
4.
Adjuvant chemotherapy
Adjuvant chemotherapy followed by radiation
Observation
Radiation alone
Randomized International Adjuvant Lung
Cancer Trial (IALT): Design
N=1867
Select eligibility criteria:
• Stage I-III
• Complete surgical
resection within 60 days
• Age ≤ 75
R
A
N
D
O
M
I
Z
E*
Cisplatin 80 mg/m2 q 3 wk  4 OR
Cisplatin 100 mg/m2 q 4 wk  3-4 OR
Cisplatin 120 mg/m2 q 4 wk  3
PLUS
Etoposide 100 mg/m2  3 days/cycle OR
Vinorelbine 30 mg/m2 weekly OR
Vinblastine 4 mg/m2 weekly OR
Vindesine 3 mg/m2 weekly
No chemotherapy
± Thoracic Radiotherapy  60 Gy†
*Each center selected chemotherapy regimen
†Optional,
but predefined by N stage at each center
International Adjuvant Lung Cancer Trial Collaborative Group. N Engl J Med. 2004;350 (4):351-360
IALT: Overall Survival
Overall Survival (%)
100%
Chemotherapy
Control
80%
Median
OS (mos)
50.8
44.4
5-yr
OS (%)
44.5
40.4
Chemotherapy
60%
Control
40%
HR = 0.86 [0.76-0.98]
P < 0.03
20%
0%
0
1
2
3
4
5
450
432
308
286
181
164
Years
At risk:
932
935
775
774
624
602
International Adjuvant Lung Cancer Trial Collaborative Group. N Engl J Med. 2004;350 (4):351-360
Phase III Trial of Adjuvant Chemotherapy in
Completely Resected Stage IB/II NSCLC
Intergroup JBR.10 Trial
Median Survival, months
5-Year Survival, %
Observation
(n = 238)
CisplatinVinorelbine
(n = 243)
HR
P value
73
94
0.7
0.012
54%
69%
0.0022
Winton et al. Proc Am Soc Clin Oncol. 2004;22(No 14S):621s. Abstract 7018
CALGB 9633: Overall Survival
1.0
1.0
Then and Now
Observation
Chemo
0.8
0.6
Probability
0.2
0.4
0.8
0.6
0.4
0.2
HR = 0.80; 90% CI: 0.60-1.07
P = 0.10
0.0
HR = 0.62; 90% CI: 0.44-0.89
P = 0.01
0.0
Probability
Observation
Chemo
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
Survival Time (Years)
Survival Time (Years)
ASCO: 2004
ASCO: 2006
7
8
9
ANITA: Phase III Adjuvant Vinorelbine (N) and Cisplatin (P) vs.
Observation (OBS) in Completely Resected (Stage I-III)
Non-Small Cell Lung Cancer (NSCLC) Patients (pts)
•
•
•
•
•
840 patients
Median age: 59 (range 18-75)
35% stage I, 30% II, 35% IIIA
Median survival 65.8 vs. 43.7 months
5-year survival by stage I-II-IIIA
– NP: 62% - 52% - 42%
– OBS: 63% - 39% - 26%
• No benefit was observed in stage I
RADIANT
Erlotinib NSCLC Adjuvant Trial
Placebo
Eligible pts:
• Stage IB /
IIIA NSCLC
1st Line platinum–based
chemo x 4 cycles
Erlotinib
Stratify by
smoking HX
Collect tissue
Treatment for 2-years
Primary Endpoint: Progression-free survival
• Overall population
• Never smokers
E1505: Phase III Adjuvant
Chemotherapy  Bevacizumab
Eligibility
• Resected IB–IIIA
• ≥ lobectomy
• No previous
chemotherapy
• No planned XRT
• No CVA/TIA
• No ATE in 12 months
N = 1,500
R
A
N
D
O
M
I
Z
E
• Primary end point: overall survival
• Secondary end points: disease-free survival,
safety [bleeding and arterial thromboembolic
events (ATEs)]
Chemotherapy* x 4 cycles
Chemotherapy* x 4 cycles +
Bevacizumab x 1 year
*Specified regimens
•
•
•
•
Carboplatin and paclitaxel
Cisplatin and docetaxel
Cisplatin and vinorelbine
Cisplatin and gemcitabine
Approved: ECOG Executive Committee and CTEP
Principal investigator: Heather Wakelee
Case 2: NSCLC
• HPI: 69 year old female with h/o T1N1 breast CA x 22 yrs.
F/U CXR reveals 3 cm RUL mass.
• PMH: HTN, PVD, R Breast CA – 1983
• Meds: Lipitor, Atenolol, Naproxen
• Allergies: None
• SH: Widow, cigarettes: 50 pack-years
• ETOH: none x 1 year
• FH: Negative
• ROS: Rib pain, unsteady gait, no weight loss
• PE: No supraclavicular nodes, C/V: RRR, Resp: clear to A&P,
Chest: well healed mastectomy scar, Abd: no masses, Ext: no
C/C/E, Neuro: no focal deficits
Case 2: NSCLC
•
What is the optimal work-up for this patient?
1.
2.
3.
4.
Biopsy
Biopsy, CT chest, abdomen
Biopsy, CT chest, abdomen, bone scan, MRI brain
Referral to medical oncology
Case 2: NSCLC
• FNA: NSCLC
• CT Chest: 3.7 cm lesion RUL, no adenopathy
• CT-PET: FDG avid lesion RUL, R paratrach node avid, no other
nodes or metastases
• EBUS: R4 LN: positive, all other negative
Case 2: NSCLC
•
What is the preferred treatment at this time for this
patient?
1.
2.
3.
4.
Surgery followed by radiation
Induction chemotherapy followed by surgery
Induction chemoradiotherapy followed by surgery
Concurrent chemotherapy and radiation
Case 2: NSCLC
• Induction Chemotherapy: Docetaxel, cisplatin, no RT
• Surgery: FOB/MED, RUL, MLND
Case 2: NSCLC
Pathology: T1N2M0
Case 2: NSCLC
•
What is the appropriate next therapy for this patient?
1.
2.
3.
4.
Adjuvant chemotherapy
Adjuvant chemotherapy followed by radiation
Observation
Radiation alone
Approach to Resectable Stage IIIA, N2
NSCLC
Survival Comparison of
Preoperative Chemotherapy
S9900
Endpoint
DePierre
BLOT
Preop
Surgery
Preop
Surgery
OS, median
43 mo
47 mo
40 mo
37 mo
26 mo
1-yr survival
84%
82%
79%
77%
73%
2-yr survival
68%
69%
63%
59%
52%
Adapted from Pisters et al. J Clin Oncol. 2005;23(No16s):624s. Oral Presentation.
Current Issues for Stage IIIA N2 LN+
Resectable NSCLC
• The role of surgery?
• Addition of RT to induction chemo increases pathologic
CR rates, but also toxicity
• Does RT add survival benefit to justify the increased
toxicity of bimodality induction therapy for this group of
patients?
• An ongoing dilemma reflected by variability in treatment
approaches across the country
• Published clinical trials limited by heterogeneity of patient
population(s) studied
INT 0139: Definitive CT/RT vs Induction
CT/RT  Surgery for Stage IIIA NSCLC
Median F/U 81 months
Stage IIIA
(T1-3, pN2,
M0)
NSCLC
N = 429
(396
eligible)
Considered
Resectable
R
A
N
D
O
M
I
Z
E
Cis/VP16
x 2 cycles
w/concurrent
XRT 45Gy
Cis/VP16
x 2 cycles
w/concurrent
XRT 45Gy
Re-evaluate 2 to 4 weeks
post RT; if no PD
Surgery
Continue
RT to
61GY
Cis/VP16
x 2 cycles
Cis/VP16
x 2 cycles
Re-evaluate 7 days prior to
RT completion; if no PD
Albain et al. J Clin Oncol. 2005;23(No16s):624s. Abstract 7014.
INT 0139: Exploratory Analyses
Pneumonectomy “Matched”
CT/RT/S
CT/RT
OS, median
19 mo
29 mo
3-yr survival
36%
45%
5-yr survival
22%
24%
38
42
CT/RT/S
CT/RT
OS, median
34 mo
22 mo
5-yr survival
36%
18%
57
74
# Dead (Total matched n=51of 54)
Lobectomy “Matched”
# Dead (Total matched n=90 of 98)
Albain et al. J Clin Oncol. 2005;23(No16s):624s. Abstract 7014.
MDACC Neoadjuvant Trial Schema
Patients with stage I-III NSCLC
No prior chemotherapy or radiotherapy
Cisplatin 80 mg/m2 +
Docetaxel 75 mg/m2
For 3 cycles
Surgical resection ± XRT
Erlotinib 150 mg po for 1 year
Who’s Appropriate for Multimodality Surgical
Resection?
• Microscopic single station N2
• T4 N0-1
• Perhaps responding larger N2
Stage IIIA “Bulky” N2 and Stage IIIB
NSCLC
• Multimodality approach with chemotherapy and radiation
therapy
– Randomized evidence of survival benefit of chemo-RT over RT
alone
– Concurrent: generally accepted as standard definitive treatment of
patients with good PF
– Sequential: less toxic; defendable treatment option
• Unclear impact of surgery on local control in combined
modality approach
– Downstaging
Case 3: NSCLC
•
HPI: 62 year old male with DJD. C/o 8-10 months of progressive SOB.
Spirometry normal.
– Continued SOB for few months, saw pulmonologist. Repeat spirometry, Advair
started. CXR revealed 4 cm RML lesion and moderate pleural effusion.
•
PMH: DJD
•
Meds: Celebrex prn
•
Allergies: None
•
SH: Married, never smoker
•
ETOH: Rare
•
FH: Negative
•
ROS: Rib pain, SOB, no weight loss
•
PE: No supraclavicular nodes, C/V: RRR, Resp: clear to A&P, Chest: well
healed mastectomy scar, Abd: no masses, Ext: no C/C/E, Neuro: no focal
deficits
Case 3: NSCLC
• What is the optimal work-up at this time?
1. Biopsy, CT chest, abdomen
2. Thoracentesis, CT chest, abdomen, bone scan
3. Thoracentesis, CT chest, abdomen, bone scan, brain scan
4. Hospice care
Case 3: NSCLC
• CT Chest: 4.2 cm lesion extending
across mediastinum, no adenopathy
• Thoracentesis: 600 cc drained
• Bone scan: Lytic bone lesion right 5th rib
• Brain scan: Clean
• Pathology: Metastatic adenocarcinoma
Case 3: NSCLC
•
What is the optimal treatment for this patient?
1.
2.
3.
4.
5.
6.
Cisplatin doublet
Carboplatin + docetaxel
Carboplatin + paclitaxel
Carboplatin + gemcitabine
Carboplatin + taxane + bevacizumab
Bevacizumab + erlotinib
Case 3: NSCLC
• Standard
– Doublet chemotherapy
• Standard “plus”
– Doublet chemotherapy + bevacizumab
• Non-standard
– Erlotinib
Case 3: NSCLC
• Started: carboplatin + docetaxel + bevacizumab
9-12-05
11-30-05
Case 3: NSCLC
11-15-06
Progression on maintenance
bevacizumab
1-10-07
Erlotinib added to bevacizumab
EGFR Inhibitors in Lung Cancer
Agent (Manufacturer)
Gefitinib
(AstraZeneca)
Erlotinib
(Genentech)
Lapatinib
(GlaxoSmithKline)
Cetuximab
(Imclone/BMS)
Panitumumab
(Amgen)
Matuzumab
(EMD Pharmaceuticals)
Mechanism
Phase in
Development
Clinical Toxicities
HER1/EGFR TK inhibitor
Limited access
Interstitial lung disease,
diarrhea, skin rash
HER1/EGFR TK inhibitor
Approved
Interstitial lung disease,
diarrhea, skin rash
Dual HER1/EGFR & 2
inhibitor
II
Diarrhea, skin rash, N/V,
fatigue
HER1/EGFR MoAb
Approved CRC,
SCCHN
Skin rash, hypersensitivity
reactions
HER1/EGFR MoAb
II
Skin rash, asthenia
HER1/EGFR MoAb
II
Skin rash, flushing
Angiogenesis Inhibitors in Lung Cancer
Agent
Mechanism
Phase in
Development
Manufacturer
Bevacizumab
MoAb-Inhibits VEGF binding
III
Genentech
AE-941
Inhibits VEGF binding & MMPs
III
AEterna Laboratories
VEGF trap
Blocks VEGF-1 and VEGF-2
I → II
Regeneron/
sanofi-aventis
Multi-targeted TKIs that includes VEGF inhibition:
ZD6474
VEGFR-2, EGFR
II → III
AstraZeneca
ZD2171
VEGFR-1, VEGFR-2, VEGFR-3
I/II
AstraZeneca
Sunitinib
pan-VEGFR, PDGF, RET, others
II
Pfizer
Sorafenib
VEGFR-2, PDGF, RAF, others
II → III
Bayer/Onyx
AMG 706
VEGFR, PDGF, Kit, RET
II
Amgen
AEE788
VEGFR, EGFR, HER2
I/II
Novartis
Vatalanib
pan-VEGF inhibitor
II
Schering/Novartis
Phase III Trial of Paclitaxel/Carboplatin Plus
Bevacizumab (E4599)
CP  6*
First-line
Stage IIIB/IV NSCLC
(N = 842)
Non-squamous cell
CP  6 +
Bevacizumab
(15 mg/kg q3wk),
then
Bevacizumab
until PD
PD
PD
• Primary end point: Survival
• Exclusion criteria: Squamous cell histology, CNS metastases, active cardiovascular disease
• Accrual complete April 2004
C: carboplatin; P: paclitaxel
*No crossover allowed in this trial
Bevacizumab with Chemotherapy in NSCLC
Survival
Patients surviving, %
100
Hazard ratio = 0.77, P = 0.007
Median survival: 12.5 vs. 10.2 months
Survival at 1-year: 52% vs. 44%
Survival at 2-years: 22% vs. 17%
80
60
40
20
Carboplatin and paclitaxel
Carboplatin and paclitaxel +
bevacizumab
0
0
6
12
18
24
30
36
Months
Sandler et al. NEJM 2006
Carboplatin + Docetaxel + Bevacizumab
in NSCLC
•
•
•
•
•
•
Phase II single institution
Similar eligibility as E4599
20 patients enrolled
PR 74%
SD 26%
Disease control rate (PR+SD) was 100% after 4 cycles of
therapy
• SAE: neutropenic fever, hemoptysis
• Overall well tolerated
W. William et al. PASCO 2007 abstract
SWOG 0536: Phase II Study
•
•
•
•
Chemo-naïve
Non-Squamous
No Hemoptysis
No Brain Mets
Paclitaxel
Carboplatin
Cetuximab
Bevacizumab
Cetuximab
Bevacizumab
until progression
N = 90
Goal to assess hemorrhage frequency
PI: Kim
Erlotinib in NSCLC
BR.21: Overall Survival
Survival Distribution Function
1.00
42.5% improvement in median survival
0.75
Erlotinib
(n = 488)
Placebo
(n = 243)
Median survival (months)
6.7
4.7
1-year survival (%)
31
21
HR = 0.73, P < 0.001
0.50
31%
0.25
Erlotinib
21%
Placebo
0
0
5
10
15
20
25
30
*HR and P-value adjusted for stratification factors at randomization plus HER1/EGFR status.
Overall Survival Probability
Erlotinib + Bevacizumab in Refractory
Advanced NSCLC
Median OS = 12.6 mos
73.2% alive at 6 mos (95% CI 59.6-89.9%)
51.8% alive at 12 mos (95% CI 36.5-73.6%)
1.0
0.8
0.6
0.4
0.2
0
0
5
10
Time (Months)
15
Bevacizumab Plus Chemotherapy or Erlotinib
Preliminary Results
Treatment Group
Chemo +
Placebo
(n = 41)
Chemo +
Bevacizumab
(n = 40)
Bevacizumab +
Erlotinib
(n = 39)
12%
13%
18%
3 mos
4.8 mos
HR = 0.66
(95% CI 0.38- 1.16)
4.4 mos
HR = 0.72
(95% CI 0.42- 1.23)
OS (6-month rate)
62%
72%
78%
Toxicity
SAEs
Drug DC’d b/c AE
Pulm hem (gr 3-5)
54%
24%
0
40%
25%
5%
33%
10%
3%
ORR
PFS, median
Fehrenbacher et al. J Clin Oncol. 2006;24(No 18S):379s. Abstract 7062
Individualized Therapy
• Chemotherapy
– Taxanes in breast cancer
• Targeted therapy
– Trastuzumab in breast
– Imitinab in GIST
– ? Lung
Lung Metagene Model to Refine the Assessment
of Risk and Guide the Use of Adjuvant
Chemotherapy in Stage IA NSCLC
Genes
Alive 5 years Dead of cancer by 2.5 years
Tumor Sample (Patients)
Potti et al. NEJM 2006
ERCC1 and Lung Cancer
• Patients with completely resected non-small-cell lung cancer and excision
repair cross-complementation group 1 (ERCC1)-negative tumors appear to
benefit from adjuvant cisplatin-based chemotherapy, whereas patients with
ERCC1-positive tumors do not.
Olaussen et al. NEJM 2006
BATTLE
Biomarker-based Approaches of Targeted
Therapy for Lung Cancer Elimination
PI:
Co-PI:
Waun Ki Hong, MD
Edward S. Kim, MD
Roy Herbst, MD, PhD
Li Mao, MD
BATTLE Workflow Timeline
Registration
BIOPSY
Response
Assign Trial
Adaptive
Randomization
Patient
Registration
Consent
Evaluate
Eligibility
Baseline
Visit
Collect
Tissue
Biomarker
Profile
Trial Specific
Consent Signed
Drug Starts
Measure
Response
8-weeks
2-weeks
5 Biomarker Groups
EGFR (+)
K-RAS(+) or B-RAF(+)
VEGF(+) or VEGFR(+)
RXRs(+) or Cyclin D1(+)
All(-)
Biomarkers used to
randomize based on
pre-study hypothesis
Randomize
Treatment
EGFR mutation
EGFR gene amplify
pEGFR (Y1068)
ErbB3 expression
K-RAS mutation
B-RAF mutation
VEGF expression
VEGFR-2 expression
RXR expression
RXR expression
RXR expression
Cyclin D1 expression
Cyclin D1 amplification
1. Enrollment
2. Biopsy
3. Biomarker
assessment
4. Place into
trials
SCHEMA: BATTLE
After Cycle 1
At Progression
Biopsy and
Biomarker
assessment and
profiling
(optional)
CT scan
Biopsy and
Biomarker
assessment and
profiling
(optional)
Proposed
Phase II Trials
(optional)
Proposed
Phase II Trials
Erlotinib
ZD6474
Bexarotene +
Erlotinib
BAY43-9006
CT scans after
cycles 2, 4, 6
until progression
Erlotinib
ZD6474
Bexarotene +
Erlotinib
BAY43-9006
Treatment Options
Metastatic Breast Cancer
• Single Chemotherapy
–
–
–
–
–
Taxanes
Capecitabine
Gemcitabine
Navelbine
Trastuzumab
• Combos
–
–
–
–
–
• ER-PR+
– Aromatase inhibitors
• Exemestane, anastrozole,
letrozole
– Tamoxifen
– Fulvestrant
– Megace
Taxanes + trastuzumab
Navelbine + trastuzumab
Carboplatin + paclitaxel + trastuzumab
Gemcitabine + paclitaxel
Docetaxel + capecitabine
Treatment Options
Metastatic Lung Cancer
• Chemotherapy
– Platinums
– Taxanes
• Docetaxel, paclitaxel
–
–
–
–
Pemetrexed
Gemcitabine
Navelbine
CPT-11
• Combinations
–
–
–
–
Taxanes + EGFR
EGFR + VEGF
Mitomycin + vinblastine
Bevacizumab
• Targeted Agents
– EGFR inhibitors
• Cetuximab, erlotinib, gefitinib
– Angiogenesis inhibitors
• Sorafenib
– Proteosome inhibitors
• Bortezomib
– Other TKIs
– mTOR
• CCI-779
• RAD001
– RAS/RAF
Future Objectives
• Define a high-risk population
– Prior to diagnosis
– After curative treatment
• Screening strategy
• Better patient-defined treatments
– Chemotherapy
– Targeted therapy
Principles of Lung Cancer Therapy
• Chemotherapy and targeted therapy with similar efficacy
• Paradigm is in evolution
• Targeted ± chemotherapy/targeted combinations
investigated
• Performance status and quality of life very important to
patients
• Tissue-based personalized therapy is the future
• Looking forward to the next few years