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Lung Cancer HighlightsASCO 2004
Heather Wakelee, MDStanford University
Adjuvant Therapy Abstracts: 7018, 7019
EGFR inhibitors
Abstracts: 7010, 7011, 7022
Adjuvant Therapy
Abstracts: 7018, 7019
Early Stage NSCLC Survival
Stage
II
IIII
IIIAIIIA
% Alive at 5 years
50-7050-70
30-5030-50
10-3010-30
National Cancer Institute: SEER Cancer Statistics Review; 1990-1999..Gloeckler Ries LA, The Oncologist 8:541-552, 2003
NSCLC Adjuvant Chemotherapy1995 Meta-Analysis
• Cisplatin-based regimens:• HR 0.87 (.74-1.02 95% CI) • 5% 5 year survival (p.08)
• Consensus: • Adjuvant Chemotherapy
Experimental
BMJ 31: 899-908, 1995
Post 1995 Meta-Analysis:NSCLC Randomized Adjuvant Trials
JNCI 03; NEJM 04; Lung Cancer 03; ASCO 04; ASCO 04
Trial Stage n Chemo Survival
ALPI I-III 1209 MVdP No
BLT I-III 381 Platin-based No
IALT I-III 1867 Vinca or EP Yes
NCIC IB-II 482 VbP YES
CALGB IB 344 PacCb YES
Adjuvant Lung Project: Italy (ALPI) ASCO 2002
• 1078 patients • Resected stage I-IIIA disease• Randomized to obs vs. post-op
chemo*• Radiation therapy optional (~45%)• HR=0.96 (0.81 - 1.13), p=0.585
Tonato Proc ASCO 2002, abstr 1157Scagliotti, JNCI 95:1453; 2003
*mitomycin / vindesine / cisplatin x 3
ALPI - Overall SurvivalScagliotti, JNCI 2003
ALPI - Overall SurvivalScagliotti, JNCI 2003
Events/Total
MVdP 278/548
Control 288/540
PROBABILITY
YEARS
HR 0.96 [0.81 - 1.13]p=0.589
International Adjuvant Lung Cancer Trial (IALT) ASCO
2003• 1867 patients• Resected stage IB - IIIA NSCLC• Randomized to obs vs. post-op chemo*• Radiation therapy optional (~30%)• 4.1% absolute benefit at 5 years,
p<0.03
LeChevalier Proc ASCO 2003, abstr 6NEJM 350:351, 2004
*cisplatin + etoposide or vinca alkaloid
0%
20%
40%
60%
80%
100%
0 1 2 3 4 5
HR= 0.86 [0.76-0.98] p<0.03
IALT - Overall Survival
___ Control
___ Chemotherapy
Years
164286432602774935
181308450624775932At risk
JBR.10 - Study Design
RANDOM I
ZE
STRATIFIED Nodal * N0 * N1ras * Neg * Pos * UNK
No ChemotherapyELIGIBLE (N=482)
* T2N0, T1-2N1
* Lobectomy
* N2 samplingChemotherapyVbP* x 4 cycles
Winton, ASCO 23:7018, 2004
*Cisplatin 50 mg/m2 day 1,8 q 4 wVinorelbine 25 mg/m2 weekly x 16
JBR.10 - Overall Survival
SUMMARY STATISTICS:Log-Rank test for equality of groups: p=0.0164Wilcoxon test for equality of groups: p=0.0100Survival rate at 5 years for Observation: 54% - % C.I. ( 48%, 61%)Survival rate at 5 years for Vinorelbine: 69% - % C.I. ( 62%, 75%)
Observation Vinorelbine
Percentage
0
20
40
60
80
100
Time (years) # At Risk(Observation) # At Risk(Vinorelbine)
0.0239243
2.0182193
4.094
121
6.04751
8.01310
10.000
____ Vin/Cis, ____ Observation
*HR 0.7, p=0.012
Years
Winton, ASCO 23:7018, 2004
HR 0.696 [.524-.923]p=0.012 5 year survival
69%69% vs. 54%
%
A
L
I
V
E
QOL Results: After Completion of Treatment
• No differences in global or any of the QoL performance scales
• Clinically and statistically significant differences after completion of treatment in :– Parasthesias, numbness, hearing
Winton, ASCO 23:7018, 2004
JBR.10 - ConclusionsAdjuvant VbP in Stage IB/II NSCLC
• Adjuvant VbP safe (59% 3+ cycles)
• Limited impact on QoL - neurotoxicity
• Absolute benefit 15% at 5 years, p=0.0022
• 30% reduction risk of death, p=0.012
Winton, ASCO 23:7018, 2004
CALGB 9633 - Study Design
RANDOM I
ZE
STRATIFIED:
HistologyDifferentiationMediastinoscopy
No ChemotherapyELIGIBLE:(N=344)
T2N0
Lobectomy
N1/N2 sampling ChemotherapyPacCb* x 4 cycles
Strauss, ASCO 23:7019, 2004
*Paclitaxel 200 mg/m2 q 3 wCarboplatin AUC 6 q 3 w
CALGB 9633 - Overall Survival
----- Chemotherapy ----- Observation
HR 0.62 [0.41-0.95]p=0.028
0 20 40 60 80
Survival Time (Months)
0.0
0.2
0.4
0.6
0.8
1.0
Probability
5 year survival71% vs. 59%
4 yr
Strauss, ASCO 23:7019, 2004
CALGB 9633 - ConclusionsAdjuvant carboplatin/paclitaxel in
Stage IB NSCLC• Safe (85% 4 cycles)
• Overall Survival– Absolute benefit 12% at 4 years, p =.028– 38% reduction risk of death, p=0.028
• Lung Cancer Specific Mortality– Absolute reduction 11% at 4 years– 49% reduction risk of death, p=0.018
Strauss, ASCO 23:7019, 2004
NCIC & CALGB Adjuvant Chemotherapy
Why are the NCIC/CALGB results better? Patient Selection
Earlier stage disease No stage III vs. 39% IALT, 28% ALPI
Therapy 2 drug regimen Inclusion of 3rd generation agent Better compliance
CALGB 85% vs. 74% IALT, 60%ALPI Lack of radiation
No PORT vs. 27% IALT, 43% ALPI
Conclusions-NSCLC Adjuvant Chemotherapy• Adjuvant chemotherapy is the new standard of
care for completely resected stage IB-IIIA NSCLC– Cisplatin versus Carboplatin remains a ?– Which “new” agent to use also debatable
• Role of neoadjuvant therapy, especially for stage IIIA, needs further exploration– SWOG 9900 closed– Open NATCH, CHEST, MRC-Lu-22– Opening cis/docetaxel x 3 pre or post-op
• PORT remains of unclear benefit• How to customize therapy?
New directions in adjuvant therapy
• NCIC BR-19– Ongoing North American Intergroup trial
•Resected NSCLC post adjuvant chemotherapy•Randomized to Gefitinib vs. placebo
• New adjuvant trials of targeted agents should incorporate chemotherapy– Cooperative group trials in development
•bevacizumab plus chemotherapy - ECOG
EGFR Inhibition
Abstracts: 7010, 7011, 7022
R
K
R
K
ligand
Cell surface
Survival Proliferation Angiogenesis MetastasisCellular Responses
PI3K
Shc
Grb2 Ras Sos
Raf
MEK1/2
Akt
MAPK
PTEN
GSK-3mTOR FKHR BadIntra-CellularSignaling
NF-
[PI4P,PI4,5 P2][PI3,4P2 PI3,4,5 P3]
p27
Gene Transcription/Cell Cycle Progression
ProliferationAnti-Apoptosis
HER2EGFR
Rationale for Study of EGFR Inhibitors Concurrent with
Combination Chemotherapy
• Synergistic or additive in preclinical models
• Safety demonstrated phase II trials
• Encouraging phase II efficacy data
0.00.10.20.30.40.50.60.70.80.91.0
Survival time (months)0 4 8 12 16 20 24
500 mg/day 250 mg/dayPlacebo
MST (months)1-year
500 mg8.7
37%
250 mg9.8
41%
Placebo9.9
42%
0.00.10.20.30.40.50.60.70.80.91.0
Survival time (months)0 4 8 12 16 20 24
500 mg/day 250 mg/dayPlacebo
MST (months)1-year
500 mg9.9
43%
250 mg9.9
41%
Placebo11.145%
INTACT 1INTACT 1Gemcitabine-
Cisplatin
INTACT 2INTACT 2Paclitaxel-
Carboplatin
INTACT Trials Show No Advantage to Gefitinib + Chemotherapy
JCO March 04
TALENT and TRIBUTE: Study Designs
Screening
Randomization
Daily oral erlotinib + chemotherapy
Placebo + chemotherapy
150mg/day p.o. after dose-selection phase TALENT: gemcitabine + cisplatinTRIBUTE: carboplatin: + paclitaxel
Daily oral erlotinib alone Placebo
Until disease progression Until disease progression
ASCO 2004 TRIBUTE (n=1,059) and TALENT (n=1,172) Phase III Trials
Endpoint Benefit to Chemo + Erlotinib?
Response rates No
Response duration No
Time to progression/death No
Time to symptom progression No
QOL parameters No
Overall survival No
TALENTGatzemeier, ASCO 23:7010, 2004 TRIBUTEHerbst, ASCO 23:7011, 2004
INTACT-1, INTACT-2, TALENT, TRIBUTE
• Lack of true predictive factor
• Chemotherapy and TKIs may kill same population of cells
• Despite their pro-cell death effects, the additional antiproliferative mechanism of TKIs may reduce chemotherapy benefit
“Negative” Results in >4300 PatientsRandomized…Why?
TRIBUTE: Overall Survival after 6 monthsS
urv
ival
rat
e
1.0
0.8
0.6
0.4
0.2
0
Months of study
0 5 10 15 20 25
ErlotinibPlacebo
Herbst, ASCO 23:7011, 2004
NCI Canada BR.21 Advanced NSCLC
RANDOM I ZE
Erlotinib* 150 mg
daily
Placebo “150 mg”daily
*2:1 Randomization
Stratified by:CenterPS, 0/1 vs 2/3Response to prior Rx (CR/PR:SD:PD)Prior regimens, (1 vs 2)Prior platinum, (Yes vs no)
Shepherd, ASCO 23:7022, 2004
NCI Canada BR.21 ResultsEndpoint Erlotinib Placebo (n=427) (n=211)
CR+PR 9% <1%
Stable 35% 27%
PFS* (months) 2.2 1.8
OS* (months) 6.7 4.7
1 year survival 31% 22%
* p<0.001**p=0.04, 0.01, 0.02 for cough, dyspnea, pain respectively
Shepherd, ASCO 23:7022, 2004
NCI Canada BR.21 Overall Survival
*Adjusted for stratification factors
Erlotinib
Placebo
*HR 0.72,
p=0.001
Months
31%
22%
0
20
40
60
80
100
0.0 10.0 20.0
Per
cen
tag
e
Shepherd, ASCO 23:7022, 2004
BR.21 Factors Correlated w/ Response
Erlotinib
(N = 427)
P
Gender Male 6% 0.0065
Female 14%
Histology Adeno 14% <0.0001
Other 4%
Ever smoked Yes 4% <0.0001
No 25%
UNK 13%
Shepherd, ASCO 23:7022, 2004
BR.21 Factors NOT Correlated w/ Response
• EGFR status (3% RR if Neg)• Number of Prior Regimens (1 vs
2+)• Prior Platinum• Prior Response• ECOG Performance Status
Shepherd, ASCO 23:7022, 2004
BR.21 Survival by Smoking History
Months
SUMMARY STATISTICS:Log-Rank test for equality of groups: p=0.0000
Smoked/OSI-774 Smoked/PlaceboNever Smoked/OSI-774 Never Smoked/Placebo
Percentage
0
20
40
60
80
100
Time (months) # At Risk(Smoked/OSI-774) # At Risk(Smoked/Placebo)
# At Risk(Never Smoked/OSI-774) # At Risk(Never Smoked/Placebo)
0.035818710442
10.011646639
20.07340
30.00000
_____ Erlotinib Non-Smoker
_____ Erlotinib Smoker
_____ Placebo Non-Smoker
_____ Placebo Smoker
p=0.03*
* significant difference across the levels of the factor.
Shepherd, ASCO 23:7022, 2004
%
A
L
I
V
E
BR.21 Summary• First placebo controlled randomized trial
– oral EGFR-TKI can prolong survival
• Erlotinib Rx - Significant associations: – longer overall survival– longer progression free survival– improved lung cancer-related symptoms– improved QoL
Shepherd, ASCO 23:7022, 2004
Response and Sensitivity to EGFR Inhibition by Gefitinib Predicted by
Activating Mutations Clustered in Tyrosine Kinase Domain*
• Lynch TJ, Bell DW, Sordella R et al. NEJM 350:2124, 2004
• Paez JG, Janne PA, Lee JC et al. Science, 5/2004
*Reviewed/Discussed ASCO Special Session 6/07/2004
EGFR Mutations Cluster Within the ATP Binding Pocket of the Active Form of EGFR Kinase Domain
The EGFR Activating Mutations in NSCLC and Benefit from TKIs
Known So Far• Somatic mutation, gain-of-function• <10% unselected
patients• Majority selected responders, few non-responders• Adeno, female, Japanese (non-
smokers)• Lower dose needed than wild type
Not Yet Known• Frequency entire denominator and in all responders• Presence in stable disease• Will not fully explain OS benefit from TKIs• Mechanism for resistance if mutation but no response• Can subset be identified that benefits from chemo+TKI• When/who to test for mutation• Other mutations• Are all TKIs the same?
EGFR TKI Future Directions
• EGFR TKI proven benefit as single agent third (or second) line for advanced NSCLC
• New directions with TK inhibition:- Sequential approaches- Pulsed therapy- Inhibit cross-talk among signaling pathways- Populations enriched for mutation - early use
• Combine with other targeted agents– (gefitinib/bexarotene trial at Stanford)
• Tumor/blood specimens phase III trials
Conclusions
• Adjuvant Chemotherapy is new STANDARD of CARE for NSCLC– Stage IB-IIB– Which regimen is still open to debate
• EGFR-TKI can prolong survival– Should not be combined with
chemotherapy– Many predictive factors
•Mutation analysis, gender, smoking history…