current modalities in the treatment of lung cancer
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Hackensack University Medical CenterJohn Theurer Cancer Center
New Frontiers in the Management of Solid and Liquid Tumors
Lung Cancer Update2011
Harry Harper, M.D.Christopher Azzoli, M.D.
November 4, 2011
Lung Cancer Update, 2011OVERVIEW
• Lung cancer facts and figures• Screening smokers for lung cancer• NSCLC:
– Surgery– Chemotherapy + XRT– Chemotherapy
• SCLC:– Chemotherapy– Chemotherapy + XRT– Prophylactic cranial irradiation
Cancer in the United States, 2011
New Cases Deaths
Prostate 240,890 Lung 156,940
Breast 230,480 Colorectal 49,380
Lung 221,130 Breast 39,520
Colorectal 141,210 Prostate 33,720
Jemal, Cancer Facts & Figures 2011, CA, 2011
1522
55
1522
55
1222
59
0102030405060708090
100
Localized Regional Distant
Stage at Diagnosis: Females
60
33
5
61
32
4
51
39
8
0102030405060708090
100
Localized Regional Distant
All RacesWhiteAfrican American
Breast Cancer Lung Cancer
Perc
ent (
%)
Jemal A et al. CA Cancer J Clin. 2010;60:227-300.
Current, orformer heavy
cigarette smoker(>1ppd x 30 years)
Age 55-74Randomized
Low-dose fast spiral CT
CXR
Years0 1 2
September, 2002 – February, 200450,000 participants randomized
Monitor through 2009
Primary endpoint:Mortality due to lung cancer
0 1 2
National Lung Screening Trial
Lung cancers detectedScan 1
Lung cancers detected Scan 2
Lung cancers detected Scan 3
Lung cancer deaths
Total deaths
Lung Cancer Deaths Avoided
CT 270 168 211Total: 649
427 1877 1 for every 320 screened
Mammogram:1 for every
570 from age 50
CXR 136 65 78Total:279
503
HR 0.80
1998
HR 0.93
24% CT scans “abnormal” (>4mm solid nodule or enlarged nodes)7% of CXR were “abnormal”
NLST, NEJM 2011
Criteria Total Smokers Current Former
55-74, ≥30 pack years 7,425,000 4,027,000 3,398,000
50-79, ≥20 pack years 13,500,000 9,114,000 4,386,000
55-74, any smoking history 26,627,000 7,738,000 18,889,000
≥50, any smoking history 46,481,000 14,729,000 31,752,000
≥21, ≥10 years of smoking any amount
77,005,000 39,883,000 37,122,000
CDC sponsored National Health and Nutrition Examination Survey (NHANES)9,762 Americans polled in 2007-08
Data Courtesy of Peter Bach
Estimated American Smokers at Risk
“We’re gonna need a bigger boat.”
“Don’t smoke cigarettes.”
IIIALYMPHNODES
NSCLCStaging
I
II
IIIB
Major change:7th-Edition TNM StagingJuly, 2009
IIA
Node-negative tumors>5cm are now stage II
Best Treatment for NSCLC: SURGERYO
vera
ll Su
rviv
al
Goldstraw, et al. J Thorac Oncol. 2007;2:706-714
51 3 7 9
8988 / 15952 : TOTAL
Surgically resected patients, 1990 – 2000Overall Survival with Surgery
Benefit of Adjuvant Cisplatin+Vinorelbine
HR 0.925Y risk 36%
HR 0.835Y risk 61%
HR 0.835Y risk 74%
LACE, N=4584Pignon , JCO 2008;26
N=1371
N=1616
N=1247
HR 0.925Y risk 36%
HR 0.835Y risk 61%
HR 0.835Y risk 74%
LACE, N=4584Pignon , JCO 2008;26
Stage IB
Stage II
Stage III
Number Needed to Treatto Save 1 Life
1 / absolute risk reduction
1 / 3% = 33 patients
1 / 10% = 10 patients
1 / 13% = 8 patients
Benefit of Adjuvant Cisplatin+Vinorelbine
N=1371
N=1616
N=1247
Best Treatment for Unresectable/Inoperable NSCLC:RADIATION THERAPY
REFERENCES:1. Dillman, NEJM 19902. RTOG 94-10, Curran, JNCI, 20113. Chemo before chemo+RT (induction) is toxic, does not improve overall survival (CALGB 39801)4. Docetaxel after chemo+RT (consolidation) is toxic, does not improve overall survival (HOG 01-24)
Unresectable Stage III (N2-N3) NSCLC:MST(mos)
3YS(%)
FebrileIllness
G3-4Esophagitis
XRT only (>6000 rads) 11 m < 10% 3% 3%
Cisplatin-based chemo, then XRT“SEQUENTIAL”
15 m 10-20 8% 5%
Cisplatin-based chemo plus XRT“CONCURRENT”
17 m 20-30 15% 30%
Important clinical trials in unresectable stage IIIB NSCLC
RANDOM I ZE
Cisplatin + Pemetrexed x 3Concurrent XRT to 6600cGy
Cisplatin + Etoposide x 3Concurrent XRT to 6600cGy
N=600
US NIH, 2011.
Pemetrexed x 4
Dealer’s choice x 4:EtoposideVinorelbinePaclitaxel
Best treatment for stage IV NSCLC:DRUG THERAPY
Survival NoChemo
Cytotoxic chemo
Chemo + anti-angio
genesis
TargetEGFR
mutation
MST (mo) 4 8 12 301-year (%) 10 20 50 90
2-year (%) 0 3 10 30
• Improving length of life• Improving quality of life
R
Results Pem/Cis Gem/Cis HRNo. patients 862 863Median survival (mos) 10.3 10.3 0.94Adenocarcinoma (847) 12.6 10.9Large cell (153) 10.4 6.7SqCC (473) 9.4 10.8 1.23
Scagliotti et al, 2008.
n=1725Stage IV NSCLCRecord histology
One cycle = 3 weeks, stop at 6 cycles
Cisplatin 75 mg/m2 Day 1 plus Pemetrexed 500 mg/m2 Day 1
Cisplatin 75 mg/m2 Day 1 plus Gemcitabine 1,250 mg/m2 Days 1, 8
“Cytotoxic” Chemotherapyfor Stage IV NSCLC
Four cycles of pemetrexed (500 mg/m2, Day 1) + cisplatin (75 mg/m2, Day 1)* n=900
Pemetrexed 500 mg/m2
+ BSC* (D1, q21d) until disease progressionN=372 pts
Placebo + BSC* (D1, q21d)
until disease progressionN=186 pts
CR, PR, or SD and ECOG PS of 0 or 1
2:1 randomization
“Continuation Maintenance” Chemotherapy
Paz-Ares et al, 2011.
Paz-Ares et al, 2011PFS HR=.62, OS results pending
Biologic/Molecular Targets for New Drugs
IGFR
P P
Gene Transcription
Angiogenesis Proliferation Metastasis Adhesion
Gene Transcription
Angiogenesis Survival
P P P PP P
PDGFVEGF
VEGFRPDGFR
VEGF
EGFR
Tumor cell Endothelial cell
EML4-ALK
bevacizumab
Gefitinib Erlotinib
Vandetanib
figitumumabcetuximab
Crizotinib
Raf
mTOR
Akt
Pi3K
MEK
ERK
P
MET
P
CC CC
PP
Sorafenib Sunitinib Axitinib
Pazopanib Motesanib
Raf
mTOR
Akt
Pi3K
MEK
ERK
Sorafenib Sunitinib Axitinib
Pazopanib MotesanibVandetanib
XL-184
ARQ197 XL-184
Crizotinib
MetMab
Sandler et al, NEJM 2006.
Target Angiogenesis: BevacizumabSQUAMOUS HISTOLOGY EXCLUDED
(for squamous histology, rate of hemoptysis 30% in phase 2 testing
0 6 12 18 24 30 36
0
20
40
60
80
100
Time (mos)
p = .003; HR = 0.79 Median OS: 12.3 mos vs.
10.3 mos1-Yr OS: 51% vs. 44%2-Yr OS: 23% vs. 15%
Patie
nts
Surv
ivin
g (%
)
OS
0
20
40
60
80
100
Patie
nts
With
PFS
(%)
0 6 12 18 24 30 36Time (mos)
p < .001; HR = 0.66 Median PFS: 6.2 mos vs.
4.5 mos6-Mos PFS: 55% vs. 33%1-Yr PFS: 15% vs. 6%
PFSCbPCbP + Bevacizumab
CbPCbP + Bevacizumab
RR: 15% for CbP Vs. 35% for CbP + Bevacizumab
Bevacizumab with other Drugs
End Point CG + Placebo CG + Bev (7.5 mg/kg) CG + Bev (15 mg/kg)
PFS, HR (95% CI) NA 0.75 (0.62–0.91); p = .0026
0.82 (0.68–0.98); p = .0301
Median PFS (mos) 6.1 6.7 6.5RR (%) 20 34 (p < .0001) 30 (p < .017)Median Survival (mos)HR, p value 13.1 13.6
(0.92, p = .3664)13.4
(1.02, p = .8420)
1.0
0.8
0.6
0.4
0.2
Time (mos)0 6 12 183 9 15
PFS
0.0
CG + Bevacizumab 15 mg/kg
CG + Placebo
Time (mos)
1.0
0.8
0.6
0.4
0.2
0.0
1.0
0.8
0.6
0.4
0.2
0.00 6 12 183 9 15
1.0
0.8
0.6
0.4
0.2
0.0
1.0
0.8
0.6
0.4
0.2
0.00 6 12 183 9 15
1.0
0.8
0.6
0.4
0.2
0.0
1.0
0.8
0.4
0.2
0.00 12 183 9 15
CG + Bevacizumab 7.5 mg/kg
CG + Placebo
PFS
Poss
ibili
ty o
f PFS
(%)
Reck et al, 2010, 2009.
SQUAMOUS HISTOLOGY EXCLUDED
Pemetrexed500 mg/m2 iv q21d
CarboplatinAUC 6 iv q21d
Bevacizumab15 mg/kg iv q21d
Arm A - 450 Patients Arm B - 450 Patients
Paclitaxel200 mg/m2 iv q21d
CarboplatinAUC 6 iv q21d
Bevacizumab15 mg/kg iv q21d
Pemetrexed500 mg/m2 iv q21d
Bevacizumab15 mg/kg iv q21d
Bevacizumab15 mg/kg iv q21d
Post discontinuation follow up
Induction Therapy:up to four 21-day cycles
Maintenance Therapy:until PD or treatment discontinuation
Patients with PD:follow up q90d until death
Patients without PD:follow up q6w until PD;
thereafter, follow up q90d until death
Patients with CR, PR, or SDAfter induction therapy
Continue on to maintenance therapy
Determination of Eligibility
Ongoing BevacizumabTrials
Primary Endpoint: OS
Patel et al, 2009.
Testing Bevacizumab forEarly-stage NSCLC: ECOG 1505
• Cisplatin and vinorelbine• Cisplatin and docetaxel• Cisplatin and gemcitabine• Cisplatin and pemetrexed
Primary endpoint: overall survival
Secondary endpoints: disease-free survival, safety[bleeding and arterial thromboembolic events]
Eligibility• Resected IB (>4cm) – IIIA• ≥ lobectomy• Adequate MLND sampling
• All pts: level 7• Left: level 5 or 6 • Right: level 4
• No previous chemotherapy• No planned XRT• No CVA / TIA / ATEN = 1500
RANDOM I ZE
Chemotherapy* x 4 cycles
Chemotherapy* x 4 cycles +bevacizumab x 1 year
No molecular markers being studied prospectivelyAccrual has been slow. Results anticipated in 2016.
Agent Description Reference
Sorafenib Multi-kinase inhibitor including VEGFR Spigel et al, 2010
Sunitinib Multi-kinase inhibitor including VEGFR Govindan et al, 2010
Axitinib Multi-kinase inhibitor including VEGFR Kelly et al, 2010
BIBF 1120 (intedanib)
Multi-kinase inhibitor including VEGFR, PDGFR, FGFR Reck, 2010
Cediranib Multi-kinase inhibitor including VEGFR Mitchell et al, 2010
Vandetanib Multi-kinase inhibitor including EGFR and VEGFR Morabito et al, 2010
HuMV833 Antibody to VEGF-A Jayson et al, 2002
IMCL 1121b (ramucirumab)
Antibody to VEGFR2 Spratlin et al, 2010
IMC-18F1 Antibody to VEGFR1 Schwartz et al, 2010
VEGF Trap (aflibercept)
Antibody to VEGF-A Leighl et al, 2010
Angiogenesis: Targeted Agents on the Horizon
VEGFR = vascular endothelial growth factor receptor; PDGFR = platelet-derived growth factor receptor; FGFR = fibroblast growth factor receptor.
Ove
rall
surv
ival
(%)
Months
Pirker et al, 2009, and 2011
Target EGFR: Cetuximab
RETROSPECTIVE SUBGROUP ANALYSIS:
• HR = 0.80 in the 354 patients with the highest EGFR IHC score
• HR = 1.05 in patients with lower EGFR IHC score
CT
cetuximabuntil PD
Stage IV NSCLC
EGFR expression by IHC
N=1,688
CT + cetuximab
RANDOMIZE ITT (n=1125) Median
OS1-year
survival
▬ CT + cetuximab(n=557)
11.3 mo 47%
▬ CT(n=568)
10.1 mo 42%
HR=0.871, p=0.044
The Biggest Discovery:EGFR Activating Mutations
Pao, Nature Reviews Cancer 10, 760-774
5 days on gefitinib
Stage IV 1st-line EGFR TKI for EGFR mutationStudy Drugs ORR PFS OS
IPASSYang, ESMO 2010
gefitinibvs.carbo + paclitaxel
71%
47%
N=261HR 0.48P<.0001
HR 1.00P=0.990
First-SIGNALLee, IASLC 2009
gefitinibvs.cis + gemcitabine
85%
37%
N=42HR 0.62P=.084
HR 0.82 P=.648
WJTOG 3405 TsurutaniESMO 2009
gefitinibvs.cis + docetaxel
62%
32%
N=172HR 0.49 P<.001
Not reported
NEJ 002MaemondoNEJM 2010
gefitinibvs. carbo + paclitaxel
74%
31%
N=228HR 0.30P<.001
HR NSP=0.31
OPTIMALZhou, ESMO 2010
erlotinibvs.carbo + gemcitabine
83%
36%
N=154HR 0.16 P<.0001
Not reported
0.0
0.2
0.4
0.6
0.8
1.0
Prob
abili
ty o
f OS
No EGFR mutationEGFR mutation
0 1 2 3 4 5 6 7 8Years After Surgery
No. At RiskNo EGFR mutation896 778 517 293 160 104 65 26 10EGFR mutation222 204 133 91 55 33 18 7 4
No EGFR mutation: Median OS = 6.3yr (95%CI: 5.6 - 7.8)EGFR mutation: Median OS = 6.9yr (95%CI: 6.3 - NA)p (adj for stage) < 0.001
EGFR mutation is Prognostic of Survival in Early-stage NSCLC
DatacourtesySandraD’AngeloMSKCC
Testing erlotinib for early-stage NSCLC with EGFR mutation
NCI Personalized Adjuvant Trial “PAT”
Resected NSCLCTested positive forEGFR activating/sensitizing mutationN=400
RANDOM I ZE
Erlotinib for 2 years
Placebo for 2 years
US NIH, 2011.
ALK gene translocation drives 3% of NSCLC
Vysis LSI ALK dual color break apart probe
Kwak et al, 2010.
Break-apart FISH assay of tumor cells from a patient with
rearrangement of the gene encoding ALK
• Study A (N = 136 patients), ORR 50%, median duration 10 months
• Study B (N = 119 patients), ORR 61%, median duration 12 months
• 94% had received prior systemic treatment for NSCLC
• No differences in ORR by performance status, the number of prior chemotherapeutic regimens, or the percentage of cells found to have the ALK gene rearrangement were noted.
Phase II studies of crizotinib for patients with stage IV NSCLC and ALK translocation
FDA Approval Announcement, 8/26/2011
First-line crizotinib for patients with ALK Translocation
Crizotinib 250 mg PO BID
Pemetrexed 500 mg/m2 + cisplatin 75 mg/m2 or carboplatin AUC 5, q 21 days
1º endpoint: To demonstrate that crizotinib is superiorto first-line chemotherapy
2º endpoint: ORR, OS, Duration of Response Safety
US NIH, 2011.
Randomized Study of Crizotinib vs Pem/Cis or Pem/Carbo in Untreated Patients with Non-squamous Carcinoma of the Lung With EML4-ALK Mutation
Novel Agents Under Phase III Investigation: Currently Recruiting Trials
Agent Mechanism of Action Study ID Primary Completion Date
Tivantinib (ARQ 197)
c-Met inhibitor NCT01244191 May 2013
Tivantinib (ARQ 197)
c-Met inhibitor NCT01395758 June 2012
Iniparib PARP inhibitor NCT01082549 (ECLIPSE) March 2013
PF-02341066 ALK inhibitor NCT00932893 June 2012
Afatinib EGFR/HER2 inhibitor NCT01121393 (LUX-Lung 6) May 2012
Afatinib EGFR/HER2 inhibitor NCT01085136 (LUX-Lung 5) March 2012
Talactoferrin Immunostimulant NCT00706862 (FORTIS-C) March 2013
Ipilimumab Anti-CTLA4 Antibody NCT01285609 August 2014
Ramucirumab VEGFR-2 inhibitor NCT01168973 June 2014
Necitumumab EGFR inhibitor NCT00981058 (SQUIRE) May 2013
Vargatef Multikinase inhibitor NCT00806819 (LUME-Lung 2) May 2013
MetMab Met inhibitor Recruitment will begin later this year (2011)
US NIH, 2011.
Problem: With so many new drugs, and targets, how do we know we are giving the right drug to the right patient?
Solution: Test! Don’t guess!
Lung Cancer Mutation ConsortiumIncidence of Single Driver Mutations
At least 1 mutation was found in 54% (280/516) of tumors completely tested (CI 50%–59%)
Kris et al, ASCO 2011.97% of Mutations Mutually Exclusive
Lung Cancer Mutation Consortium Targeted Clinical Trials
Target Agent(s)EGFR Erlotinib + OSI 906
Erlotinib + MM 121KRAS Tivantinib + Erlotinib
GSK1120212MET Amplification MetMAB
EML4-ALK CrizotinibNRAS GSK1120212
Kris et al, ASCO 2011.
MEK1 GSK1120212BRAF (V600E) GSK2118434
BRAF (not V600E) GSK1120212HER2 Afatinib
PIK3CA BKM120
Real progress for patients with stage IV NSCLC
Survival NoChemo
Cytotoxic chemo
Chemo+bev
EGFRTKI for EGFR
mutant
MST (mo) 4 8 12 301-year (%) 10 20 50 90
2-year (%) 0 3 10 30
• Improving length of life• Improving quality of life
SMALL CELLLUNG CANCER
LimitedStage
ExtensiveStage
Surgery rarely an option.No molecular markers discovered yet.No new drugs for 20 years!
Twice Daily Thoracic Radiotherapy for Limited Stage SCLC
Turrisi et al, NEJM, 1999
• 417 patients with limited stage SCLC• 4 cycles etoposide + cisplatin with concurrent once vs.
twice daily RT to 45 Gy starting with first cycle
2-year survival41 vs. 47%
5-year survival16 vs. 26%p = 0.04
Prophylactic Cranial IrradiationAuperin et al, NEJM, 1999
• 7 randomized trials, 987 pts with CR
• 5% increase in survival at 3 yrs• Higher dose improved local
recurrence but no effect on survival
Death Brain Mets
54% ↓ risk16% ↓ risk
PCI in Extensive SCLC286 patients with extensive SCLC and response after 4-6 cycles of chemotherapy were randomized to PCI or no PCI
Median survival: 6.7 vs 5.4 mo1 yr survival: 27% vs 13%
Slotman et al, NEJM 2007
IP: median 9.3 mo (0.1-32.6) 1yr 35.4%, 2yr 8.0%EP: median 10.2 mo (0.3-44.6) 1yr 36.7%, 2yr 7.9%
Etoposide + cis (n = 110)Irinotecan + cis (n = 221)
P = 0.6226
Months
Prob
abili
ty
1.00.9
0.8
0.70.6
0.50.4
0.30.2
0.10
0 10 20 30 40
Hanna, J Clin Oncol 24:2038, 2006
For Extensive Stage: Cisplatin + Etoposide
Greater proportion had improved dyspnea, anorexia, hoarseness and fatigue with topotecan
von Pawel, JCO, 17:658, 1999
Topotecan CAV
Response Rate 24% 18%
Med Survival 6 mo 6 mo
Grade 4 (% pts)NeutropeniaAnemiaPlatelets
70%3%
29%
72%2%5%
TransfusionsRBCsPlts
52%20%
27%2%
“2nd-line” Chemo for Extensive SCLC
• Rechallenge with 1st regimen if time to relapse > 6 months
• Topotecan• CAV • Irinotecan• Paclitaxel• Docetaxel• Gemcitabine• Vinorelbine• Amrubicin: active, but failed to
significantly improve survival vs. topotecan in phase 3 study
“2nd-line” Chemo for Extensive SCLC:
n=637amrubicin 40 mg/m2 IV on days 1-3
vs.topotecan 1.5 mg/m2 IV on days 1-5
HR 0.82, p=NSprimary refractory subgroup, HR 0.77, p=.047
Jotte R, J Clin Oncol 29: 2011;29(15s):(abstract 7000),453s
Lung Cancer Update, 2011REVIEW
• Lung cancer facts and figures• Screening smokers for lung cancer• NSCLC:
– Surgery– Chemotherapy + XRT– Chemotherapy
• SCLC:– Chemotherapy– Chemotherapy + XRT– Prophylactic cranial irradiation
The era of personalized medicine has arrived !
EGFR, ALK …
Screening saves lives !
Newest stories:
OLDEST STORY:“Don’t smoke cigarettes.”
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