emerging treatment paradigms in nsclc
DESCRIPTION
Emerging Treatment Paradigms in NSCLC. Edward S. Kim, MD MD Anderson Cancer Center. Per capita cigarette consumption. Male lung cancer death rate. Female lung cancer death rate. Tobacco Use in the USA 1900-1999. *Age-adjusted to 2000 US standard population. - PowerPoint PPT PresentationTRANSCRIPT
Emerging Treatment Paradigms in NSCLC
Edward S. Kim, MDMD Anderson Cancer Center
Tobacco Use in the USA1900-1999
0
500
1000
1500
2000
2500
3000
3500
4000
4500
5000
Year
Per
Cap
ita C
igare
tte C
on
su
mp
tio
n
0
10
20
30
40
50
60
70
80
90
100
Ag
e-A
dju
ste
d L
un
g C
an
cer
Death
R
ate
s*
Per capita cigarette
consumption
Male lung cancer death rate
Female lung cancer death rate
*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.
†Uterine 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.
Year
Female
Uterus†
BreastPancreasOvaryStomachLung & bronchusColon & rectum
1930
Rat
e p
er 1
00,0
00
1940
1950
1960
1970
1980
1990
80
60
40
20
0
1990
Rat
e p
er 1
00,0
00
Male
1930
1940
1950
1960
1970
1980
80
60
40
20
0
PancreasLiverProstateStomachLung & bronchusColon & rectum
Cancer Deaths in the US
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.
History of Therapy in Advanced NSCLC: FDA Approval Dates
*Label does not include NSCLC-specific indication
First-line
Second-line
Third-line
Not approved
First-line
Second-line
Third-line
Not approved
19701970 19801980 19901990 20002000
Medianoverallsurvival,months
12+
~8–10~6
~2–4
Best supportive careBest supportive care Single-agent platinumSingle-agent platinum DoubletsDoublets Bevacizumab + PCBevacizumab + PC
Cisplatin*Cisplatin*19781978
Carboplatin*Carboplatin*19891989
ErlotinibErlotinibPemetrexedPemetrexed
20042004
DocetaxelDocetaxel19991999
PaclitaxelPaclitaxelGemcitabineGemcitabine
19981998
VinorelbineVinorelbine19941994
DocetaxelDocetaxel20022002
BevacizumabBevacizumab20062006
GefitinibGefitinib20032003
Standard Therapies
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
Schiller JH et al. N Engl J Med. 2002;346:92-98
*Control arm.
Arm A* q 3 wkStage IIIB or IV
NSCLC Stratified by:• Extent of disease • PS• Weight loss• Brain metastases
Cisplatin: 100 mg/m2, day 1Gemcitabine: 1000 mg/m2, days 1,8,15
Docetaxel: 75 mg/m2, day 1Cisplatin: 75 mg/m2, day 1
Arm C q 3 wk
Paclitaxel: 225 mg/m2, day 1Carboplatin: AUC=6, day 1
Arm D q 3 wk
Arm B q 4 wk
Paclitaxel: 135 mg/m2, day 1Cisplatin: 75 mg/m2, day 2R
ANDOM
I
ZE
ECOG 1594 Survival by Treatment Group
0 5 10 15 2520 30
0.0
1.0
0.8
0.2
0.4
0.6
Months
Cisplatin + PaclitaxelCisplatin + GemcitabineCisplatin + DocetaxelCarboplatin + Paclitaxel
Schiller JH et al. N Engl J Med. 2002;346:92-98
TAX 326: Schema
Fossella FV et al: JCO 2003
Docetaxel: 75 mg/m2 IV + Cisplatin: 75 mg/m2 IV
Docetaxel: 75 mg/m2 IV + Carboplatin: AUC 6 IV
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.
Stratification by: • Stage IIIB or IV• Geographic region
q3 wk
q4 wk
RANDOM
I
ZE
q3 wk
TAX 326: SurvivalDocetaxel/Cisplatin vs. Vinorelbine/Cisplatin
Fossella FV et al: JCO 2003
Docetaxel/Cisplatin
Vinorelbine/Cisplatin
Cum
ulat
ive
Pro
babi
lity
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0 3 6 9 12 15 18 21 24 27 30 33
Survival Time (months)
P = .044, Adjusted Log-Rank
1-yr Survival 46 vs 41%
2-yr Survival 21 vs 14%
The Bottom Line: Metastatic NSCLC Study N ORR(%) MST (mos) SWOG 9509 Carbo-Pac 208 25 8.0 Cis-Vino 202 28 8.0
EGOG 1594 Cis-Pac 292 21.3 8.1 Cis-Gem 288 21 8.1 Cis-Doce 293 17.3 7.4 Carbo-Pac 290 15.3 8.3
Italian Study Cis-Gem 205 30 9.8 Carbo-Pac 201 32 9.9 Cis-Vino 201 30 9.5
EORTC 08975 Cis-Pac 159 31 8.1 Cis-Gem 160 36 8.8 Gem-Pac 161 27 6.9
TAX 326 Doce-Cis 408 NA 10.9 Doce-Carbo 406 NA 9.1 Cis-Vino 404 NA 10.0
Chemotherapy and Targeted Therapy
Biological Agent
Class Trial PhaseTarget
Population Outcome
Gefitinib EGFR-TKIIII All NSCLC Negative for
survival
Gefitinib EGFR-TKI IIIAll NSCLC Negative for
survival
Erlotinib EGFR-TKI IIIAll NSCLC Negative for
survival
Erlotinib EGFR-TKI IIIAll NSCLC Negative for
survival
Bexarotene Rexinoid IIIAll NSCLC Negative for
survival
Bexarotene Rexinoid IIIAll NSCLC Negative for
survival
LonafarnibFarnesyl
TransferaseIII
All NSCLC Negative for survival
Bevacizumab VEGF IIINon-squamous, no brain mets
Positive for survival
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. Biopsy
2. Biopsy, CT chest, abdomen
3. Biopsy, CT chest, abdomen, bone scan, MRI brain
4. Referral to medical oncology
• What is the desired work-up for the nodule?1. Biopsy
2. Biopsy, CT chest, abdomen
3. Biopsy, CT chest, abdomen, bone scan, MRI brain
4. Referral to medical oncology
34% 36%
43%
22%
13%
8%
17% 28%
Outside U.S.
U.S.
1 2 3 4
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. Lobectomy
2. Lobectomy and nodal sampling
3. Lobectomy and nodal dissection
4. Surgery followed by radiation
• What is the optimal treatment for this patient at this time?1. Lobectomy
2. Lobectomy and nodal sampling
3. Lobectomy and nodal dissection
4. Surgery followed by radiation
32% 29%
37%
32%
22%
7%
15% 26%
Outside U.S.
U.S.
1 2 3 4
VATS LobectomyTechnique
Courtesy S. Swisher
Case 1: NSCLC
Pathology: T2N0M0
Case 1: NSCLC
• What is the appropriate next therapy for this patient?1. Adjuvant chemotherapy
2. Adjuvant chemotherapy followed by radiation
3. Observation
4. Radiation alone
• What is the appropriate next therapy for this patient?1. Adjuvant chemotherapy
2. Adjuvant chemotherapy followed by radiation
3. Observation
4. Radiation alone
30% 20%
20%
7%
3%
43%
44% 33%
Outside U.S.
U.S.
1 2 3 4
International Adjuvant Lung Cancer Trial Collaborative Group. N Engl J Med. 2004;350 (4):351-360
*Each center selected chemotherapy regimen†Optional, but predefined by N stage at each center
N=1867Select eligibility criteria:
• Stage I-III
• Complete surgical resection within 60 days
• Age ≤ 75
RANDOMIZE*
Cisplatin 80 mg/m2 q 3 wk 4 ORCisplatin 100 mg/m2 q 4 wk 3-4 ORCisplatin 120 mg/m2 q 4 wk 3
PLUS
Etoposide 100 mg/m2 3 days/cycle ORVinorelbine 30 mg/m2 weekly ORVinblastine 4 mg/m2 weekly OR Vindesine 3 mg/m2 weekly
No chemotherapy
± Thoracic Radiotherapy 60 Gy†
Randomized International Adjuvant Lung Cancer Trial (IALT): Design
IALT: Overall Survival
Control
Chemotherapy
Years
164286432602774935181308450624775932
At risk:
0%
20%
40%
60%
80%
100%
0 1 2 3 4 5
HR = 0.86 [0.76-0.98]P < 0.03O
vera
ll S
urvi
val (
%)
Median 5-yr OS (mos) OS (%)
Chemotherapy 50.8 44.5Control 44.4 40.4
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
Observation(n = 238)
Cisplatin-Vinorelbine
(n = 243)HR P value
Median Survival, months 73 94 0.7 0.012
5-Year Survival, % 54% 69% 0.0022
Winton et al. Proc Am Soc Clin Oncol. 2004;22(No 14S):621s. Abstract 7018
ASCO: 2006
0 2 4 6 8
Survival Time (Years)
0.0
0.2
0.4
0.6
0.8
1.0
Pro
babi
lity
ObservationChemo
0 1 2 3 4 5 6 7 8 9
HR = 0.80; 90% CI: 0.60-1.07 P = 0.10
ASCO: 2004
0 2 4 6 8
Survival Time (Years)
0.0
0.2
0.4
0.6
0.8
1.0
Pro
babi
lity
0 1 2 3 4 5 6 7 8 9
HR = 0.62; 90% CI: 0.44-0.89 P = 0.01
ObservationChemo
CALGB 9633: Overall Survival Then and Now
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
RADIANTErlotinib NSCLC Adjuvant Trial
Primary Endpoint: Progression-free survival • Overall population• Never smokers
Eligible pts:• Stage IB /
IIIA NSCLC
Placebo
Erlotinib
Collect tissue
Treatment for 2-years
Stratify by smoking HX
1st Line platinum–based chemo x 4 cycles
Approved: ECOG Executive Committee and CTEP
Principal investigator: Heather Wakelee
*Specified regimens• Carboplatin and paclitaxel• Cisplatin and docetaxel• Cisplatin and vinorelbine• Cisplatin and gemcitabine
• Primary end point: overall survival
• Secondary end points: disease-free survival, safety [bleeding and arterial thromboembolic events (ATEs)]
E1505: Phase III Adjuvant Chemotherapy Bevacizumab
RANDOMI ZE
Chemotherapy* x 4 cycles
Chemotherapy* x 4 cycles +Bevacizumab x 1 year
Eligibility• Resected IB–IIIA• ≥ lobectomy• No previous
chemotherapy• No planned XRT• No CVA/TIA• No ATE in 12 months
N = 1,500
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. Biopsy
2. Biopsy, CT chest, abdomen
3. Biopsy, CT chest, abdomen, bone scan, MRI brain
4. Referral to medical oncology
• What is the optimal work-up for this patient?1. Biopsy
2. Biopsy, CT chest, abdomen
3. Biopsy, CT chest, abdomen, bone scan, MRI brain
4. Referral to medical oncology
21% 68%
70%
4%
8%
7%
0% 22%
Outside U.S.
U.S.
1 2 3 4
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. Surgery followed by radiation
2. Induction chemotherapy followed by surgery
3. Induction chemoradiotherapy followed by surgery
4. Concurrent chemotherapy and radiation
• What is the preferred treatment at this time for this patient?1. Surgery followed by radiation
2. Induction chemotherapy followed by surgery
3. Induction chemoradiotherapy followed by surgery
4. Concurrent chemotherapy and radiation
32% 32%
18%
28%
33%
8%
16% 33%
Outside U.S.
U.S.
1 2 3 4
Case 2: NSCLC
• Induction Chemotherapy: Docetaxel, cisplatin, no RT• Surgery: FOB/MED, RUL, MLND
Case 2: NSCLC
• What is the appropriate next therapy for this patient?1. Adjuvant chemotherapy
2. Adjuvant chemotherapy followed by radiation
3. Observation
4. Radiation alone
• What is the appropriate next therapy for this patient?1. Adjuvant chemotherapy
2. Adjuvant chemotherapy followed by radiation
3. Observation
4. Radiation alone
49% 12%
10%
10%
6%
29%
51% 33%
Outside U.S.
U.S.
1 2 3 4
Approach to Resectable Stage IIIA, N2 NSCLC
Survival Comparison of Preoperative Chemotherapy
Endpoint BLOTS9900 DePierre
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
Stage IIIA (T1-3, pN2,
M0)NSCLCN = 429
(396 eligible)
Considered Resectable
RANDOMIZE
Cis/VP16 x 2 cycles
w/concurrent XRT 45Gy
Cis/VP16 x 2 cycles
w/concurrent XRT 45Gy
Surgery
Cis/VP16 x 2 cycles
Cis/VP16 x 2 cycles
Re-evaluate 2 to 4 weeks post RT; if no PD
Re-evaluate 7 days prior to RT completion; if no PD
Albain et al. J Clin Oncol. 2005;23(No16s):624s. Abstract 7014.
Continue RT to 61GY
Median F/U 81 months
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%
# Dead (Total matched n=51of 54) 38 42
Lobectomy “Matched” CT/RT/S CT/RT
OS, median 34 mo 22 mo
5-yr survival 36% 18%
# Dead (Total matched n=90 of 98) 57 74
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
• 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
32% 46%
53%
6%
5%
16%
16% 26%
Outside U.S.
U.S.
1 2 3 4
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. Cisplatin doublet
2. Carboplatin + docetaxel
3. Carboplatin + paclitaxel
4. Carboplatin + gemcitabine
5. Carboplatin + taxane + bevacizumab
6. Bevacizumab + erlotinib
• What is the optimal treatment for this patient?1. Cisplatin doublet
2. Carboplatin + docetaxel
3. Carboplatin + paclitaxel
4. Carboplatin + gemcitabine
5. Carboplatin + taxane + bevacizumab
6. Bevacizumab + erlotinib
15% 10%
8%
12%
3%
43%
6%
18%
5% 78%
2%Outside U.S.
U.S.
1 2 3 4 5 6
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) MechanismPhase in
DevelopmentClinical Toxicities
Gefitinib(AstraZeneca)
HER1/EGFR TK inhibitor Limited accessInterstitial lung disease,
diarrhea, skin rash
Erlotinib(Genentech)
HER1/EGFR TK inhibitor ApprovedInterstitial lung disease,
diarrhea, skin rash
Lapatinib(GlaxoSmithKline)
Dual HER1/EGFR & 2 inhibitor II
Diarrhea, skin rash, N/V, fatigue
Cetuximab(Imclone/BMS)
HER1/EGFR MoAbApproved CRC,
SCCHNSkin rash,
hypersensitivity reactions
Panitumumab(Amgen)
HER1/EGFR MoAb II Skin rash, asthenia
Matuzumab(EMD Pharmaceuticals)
HER1/EGFR MoAb II Skin rash, flushing
Agent MechanismPhase in
DevelopmentManufacturer
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 → IIRegeneron/
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
Angiogenesis Inhibitors in Lung Cancer
Phase III Trial of Paclitaxel/Carboplatin Plus Bevacizumab (E4599)
First-line Stage IIIB/IV NSCLC
(N = 842)Non-squamous cell
CP 6*
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
0 6 12 18 24 30 36
0
20
40
60
80
100
Months
Carboplatin and paclitaxel
Carboplatin and paclitaxel + bevacizumab
Hazard ratio = 0.77, P = 0.007Median survival: 12.5 vs. 10.2 monthsSurvival at 1-year: 52% vs. 44%Survival at 2-years: 22% vs. 17%
Pat
ient
s su
rviv
ing,
%
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
PaclitaxelCarboplatinCetuximab
Bevacizumab
CetuximabBevacizumab
until progression
N = 90
Goal to assess hemorrhage frequency
PI: Kim
Erlotinib in NSCLC BR.21: Overall Survival
1.00
0.75
0.50
0.25
0
*HR and P-value adjusted for stratification factors at randomization plus HER1/EGFR status.
42.5% improvement in median survival
Sur
viva
l Dis
trib
utio
n F
unct
ion
Erlotinib
Placebo
0 5 10 15 20 25 30
31%
21%
HR = 0.73, P < 0.001
Erlotinib(n = 488)
Placebo(n = 243)
Median survival (months) 6.7 4.7
1-year survival (%) 31 21
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
Ove
rall
Sur
viva
l Pro
babi
lity
Time (Months)0 5 10 15
Treatment Group
Chemo + Placebo (n = 41)
Chemo + Bevacizumab
(n = 40)
Bevacizumab + Erlotinib (n = 39)
ORR 12% 13% 18%
PFS, median 3 mos4.8 mos
HR = 0.66 (95% CI 0.38- 1.16)
4.4 mosHR = 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%
Bevacizumab Plus Chemotherapy or Erlotinib Preliminary Results
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
Potti et al. NEJM 2006
Alive 5 years Dead of cancer by 2.5 years
Tumor Sample (Patients)
Gen
esLung Metagene Model to Refine the Assessment
of Risk and Guide the Use of Adjuvant Chemotherapy in Stage IA NSCLC
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: Waun Ki Hong, MDCo-PI: Edward S. Kim, MD
Roy Herbst, MD, PhDLi Mao, MD
BATTLE Workflow Timeline
PatientRegistration
Consent
EvaluateEligibility
BaselineVisit
CollectTissue
BiomarkerProfile
2-weeks
AdaptiveRandomization
Trial SpecificConsent Signed
Drug Starts
8-weeks
Measure Response
Registration BIOPSY Assign Trial Response
RandomizeBiomarkers used to randomize based on pre-study hypothesis
Treatment
5 Biomarker Groups EGFR (+)
K-RAS(+) or B-RAF(+) VEGF(+) or VEGFR(+)
RXRs(+) or Cyclin D1(+) All(-)
EGFR mutationEGFR gene amplify
pEGFR (Y1068)ErbB3 expressionK-RAS mutationB-RAF mutation
VEGF expressionVEGFR-2 expression
RXR expressionRXR expressionRXR expression
Cyclin D1 expression Cyclin D1 amplification
At Progression
Biopsy and Biomarker
assessment and profiling
(optional)
After Cycle 1
Biopsy and Biomarker
assessment and profiling
(optional)CT scan
Proposed Phase II Trials
ErlotinibZD6474
Bexarotene + Erlotinib
BAY43-9006
Proposed Phase II Trials
(optional)
ErlotinibZD6474
Bexarotene + Erlotinib
BAY43-9006
1. Enrollment2. Biopsy3. Biomarker
assessment4. Place into
trials
CT scans after cycles 2, 4, 6
until progression
SCHEMA: BATTLE
Treatment OptionsMetastatic Breast Cancer
• Single Chemotherapy– Taxanes– Capecitabine– Gemcitabine– Navelbine– Trastuzumab
• Combos– Taxanes + trastuzumab– Navelbine + trastuzumab– Carboplatin + paclitaxel + trastuzumab– Gemcitabine + paclitaxel– Docetaxel + capecitabine
• ER-PR+– Aromatase inhibitors
• Exemestane, anastrozole, letrozole
– Tamoxifen– Fulvestrant– Megace
Treatment OptionsMetastatic 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