HIGHLIGTHS IN LUNG CANCER

1
HIGHLIGTHS IN LUNG CANCER

• G. Giaccone, MD PhD
• National Cancer Institute
• Bethesda, USA

2
NSCLC

• Treatment of early disease
• Treatment of advanced disease
• Patient selection for EGFR TKIs
• Angiogenesis inhibition

3
Early NSCLC

• Adjuvant chemotherapy becoming standard for
  radically resected NSCLC
• Cisplatin-based (cisplatin and a vinca alkaloid)

4
Pre-operative chemotherapy in patients with
resectable non-small cell lung cancer First
results of the MRC LU22 / NVALT 2 / EORTC 08012
multi-centre randomized trialPresented by
Marianne Nicolsonon behalf ofDavid Gilligan,
Ian Smith, Harry Groen, Christian Manegold, Jan
van Meerbeeck, Penelope Hopwood, Matthew
Nankivell, Cheryl Pugh, Richard Stephens and all
the collaborators
5
Trial design

• Untreated NSCLC
• Any sex, agegt18
• No distant metastases
• Fit for chemotherapy and surgery
• WHO PS 0-2

6
Sample Size

• To detect an absolute survival improvement of 15
  (from 40 with surgery alone, to 55 with
  neo-adjuvant chemotherapy) (5 significance
  level, 90 power)
• Requires 233 events
• Target 450 patients over 3 years
• First patient entered July 1997

7
Progression Free Survival
S CT-S Events 152 147 2-year PFS 52 53

HR 0.96 95 CI 0.77, 1.21 p 0.74
8
Overall Survival
S CT-S Events 122 122 5-year OS 45 44

HR 1.02 95 CI 0.80, 1.31 p 0.86
9
Summary
In this trial, neo-adjuvant chemotherapy

• Was feasible and acceptable (75 received 3
  cycles)
• Gave good response rates (45 CR/PR)
• Caused down-staging in 20

• And did not adversely affect
• Quality of life
• Type of surgery
• Post-op complications
• Complete resection rates
• Planned timing of surgery (data not shown)
• Post-op nights in hospital (data not shown)

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Summary

• However in this trial
• There was no evidence that neo-adjuvant
  chemotherapy had an effect on
• Progression-free survival
• Overall survival

How does this trial add to the available evidence?
11
Updated systematic review
Number of patients


Trial
HR (95 CI)
CT S
S
Hazard Ratio
Dautzenberg 1990
13 13
1.03 0.37, 2.93
Roth 1994
28 32
0.89 0.42, 1.88
Rosell 1994
30 30
0.63 0.32, 1.24
Depierre 2002
179 176
0.83 0.64, 1.07
JCOG9209 2003
31 31
0.75 0.43, 1.30
Sorensen 2005
44 46
0.89 0.49, 1.63
SWOG9900 2005
168 167
0.84 0.60, 1.18
Current trial
258 261
1.02 0.80, 1.31
Total
751 756
0.88 0.76, 1.01
0.1
0.2
0.5
1
2
5
10
Favours CTS
Favours S
Test for heterogeneity Chi² 3.04, df 7 (P
0.88), I² 0
Test for overall effect Z 1.78 (P 0.07)
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Locally advanced NSCLC

• Concomitant chemo-radiotherapy becoming standard
  also in Europe
• Role of consolidation docetaxel (SWOG)?
• Timing and choice of drugs still not settled

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Phase III trial of cisplatin plus etoposide plus
concurrent chest radiation with or without
consolidation docetaxel in patients with
inoperable stage III non-small cell lung cancer
HOG LUN 01-24/USO 02-033

• Nasser Hanna, Marcus Neubauer, Rafat Ansari,
  Ramaswamy Govindan, Daniel Bruetman, William
  Fisher, Naveed Chowhan, Sreenivasa Nattam,
  Constantin Yiannoutsos, Lawrence Einhorn

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SWOG 9504Gandara et al JCO 2003212004-10
Concurrent Chemoradiation PE Cisplatin 50 mg/m2
IV d 1, 8, 29, 36 Etoposide 50 mg/m2 IV d 1-5,
29-33 RT 45 Gy (1.8 Gy/fraction) 16 Gy boost (2
Gy/fraction)
Consolidation Docetaxel X 3 cycles
Median Survival Time 26 months
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HOG LUN 01-24/USO 02-033

• ChemoRT
• Cisplatin 50 mg/m2 IV d 1,8,29,36Etoposide 50
  mg/m2 IV d 1-5 29-33Concurrent RT 59.4 Gy (1.8
  Gy/fr)

Stratification Variables PS 0-1 vs 2 IIIA vs
IIIB CR vs. non-CR
Randomize
Observation
Docetaxel 75 mg/m2 q 3 wk ? 3
16
Grade 3/4 Hematological Toxicities
17
Grade 3/4 Non-Hematological Toxicities
p-value corresponds to comparison of Docetaxel
vs. Observation groups Includes 1 patient death
18
Hospitalizations and Transfusions
p-value corresponds to comparison of Docetaxel
vs. Observation groups
19
Progression-Free Survival (ITT) Randomized
Patients (n147)

20
Overall Survival (ITT)Randomized Patients (n147)
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Advanced disease

• Platinum-based chemotherapy for PS 0-1
• Single agent for worse PS
• Chemotherapy has reached a plateau
• Several doublets shown to have similar efficacy
  in first-line treatment
• Brain metastases respond to chemotherapy
• Duration of therapy
• 4 cycles, may be longer if continuous response
  and therapy well tolerated (max 6 cycles)
• Introduction of targeted agents
• Bevacizumab with carboplatin-paclitaxel approved
  by FDA

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Phase III Trial of Bevacizumab in Non-Squamous
NSCLC ECOG 4599N855 (eligible)
(PC) Paclitaxel 200 mg/m2 Carboplatin AUC 6 (q
3 weeks) x 6 cycles
No crossover to Bevacizumab permitted

• Eligibility
• Non-squamous NSCLC
• No Hx of hemoptysis
• No CNS metastases

(PCB) PC x 6 cycles Bevacizumab (15mg/kg q 3
wks) to PD

• Stratification Variables
• RT vs no RT
• Stage IIIB or IV vs recurrent
• Wt loss lt5 vs gt5
• Measurable vs non-measurable

Sandler, et al. NEJM, Dec 2006
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Response Rate
N 769 patients (Measurable Disease) PC PCB
P value 15 35 lt0.001
24
E4599 Overall Survival
1.0
12 mo 24 mo
PC 44.4 15.4
0.8
BV/PC 51.0 22.0
HR 0.80, P 0.003
Proportion surviving
0.6
Medians 10.3, 12.3
0.4
0.2
0.0
0
6
42
48
18
30
12
24
36
Patients at risk
444
318
1
0
104
9
190
36
5
PC
BV/PC
434
340
3
0
127
25
216
54
8
Survival (months)
25
Progression-Free Survival
Medians 4.5, 6.2 months
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Grade 3 5 Non-Hematologic Toxicity
27
Treatment Related Deaths

• PC PCB 427 420
• Hemorrhage
• Hemoptysis 0 5
• GI bleed 1 2
• Neutropenic fever 1 5
• Cerebrovascular 0 2
• Pulmonary Embolus 0 1
• Total 2 15

Two deaths due to cardiac ischemia not felt to
be treatment related
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AVAiL first-line phase III trial ofAvastin plus
chemotherapy in NSCLC
No Avastin after progression
PD
CG ? 6 placebo
Previously untreated, stage IIIB, IV or recurrent
non-squamous NSCLC (n1,050)
CG ? 6 Avastin 7.5mg/kg every 3 weeks
PD
CG ? 6 Avastin 15mg/kg every 3 weeks
PD

• Cisplatin 80mg/m2 i.v. every 3 weeks gemcitabine
  i.v. 1,250mg/m2 on days 1 and 8 of each 3-week
  cycle
• Primary endpoint progression-free survival
• Secondary endpoints overall survival, time to
  treatment failure, response rate
• Stratification factors disease stage, ECOG PS,
  region, gender

CG cisplatin/gemcitabine
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Progression-free survival primary analysis
(intent-to-treat) of bevacizumab 7.5mg/kg versus
pooled placebo
1.0
1.0
0.8
0.8
Possibility of PFS
Possibility of PFS
0.6
0.6
0.4
0.4
Placebo CG
Bev 7.5mg/kg CG
0.2
0.2
0.0
0.0
0
6
12
18
3
9
15
Time (months)
30
Progression-free survival primary analysis
(intent-to-treat) of bevacizumab 15mg/kg versus
pooled placebo
1.0
1.0
0.8
0.8
Possibility of PFS
Possibility of PFS
0.6
0.6
0.4
0.4
Placebo CG
Bev 15mg/kg CG
0.2
0.2
0.0
0.0
0
6
12
18
3
9
15
Time (months)
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Safety Severe (Gr ?3) adverse events of special
interest
32
Safety Pulmonary haemorrhage events

• Of note
• 38 of patients had central lesions
• 4/10 patients with severe pulmonary haemorrhage
  had central lesions
• 9 of patients had therapeutic anticoagulation
• but none of them had a severe pulmonary
  haemorrhage

33
Treatment of advanced NSCLC after first-line
chemotherapy

• Docetaxel registered in second-line, based on an
  increase of survival of 2 m over BSC
• Pemetrexed registered based on an equivalence
  study with docetaxel, less toxic
• Erlotinib registered in second- and third-line
  based on increase in survival of 2 m over BSC

34
BR.21 erlotinib phase III study in advanced,
relapsed NSCLC
stage IIIB/IV, relapsed NSCLC PS 03failed one
or two prior regimens
21 randomization
Daily oral erlotinib150mg/day
Daily oral placebo

• n731 patients
• Primary objective overall survival
• Secondary objectives response rate,
  stable-disease rate, duration of response, time
  to disease progression, and QoL

Shepherd et al. NEJM 2005
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Tumor Response in Selected Subsets
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Patient selection for EGFR TKIs

• Positive selection
• Patient characteristics
• never-smoking, female, adenocarcinoma, East Asian
• EGFR mutations
• EGFR FISH
• EGFR overexpression
• Negative selection
• K-ras mutations
• Resistant EGFR mutations (e.g. T790M)
• C-Met amplification

38
Predictivity of response to EGFR TKIs
prospective studies

• Mutations 75 -100
• FISH 50 - 70
• IHC ?
• FISH / IHC ?
• Never smokers 40 50

39
EGFR mutations and response to EGFR-TKI in
advanced NSCLC

• Mutation frequency approximately 12 in
  Caucasians
• More frequent in never-smokers, women,
  adenocarcinoma, BAC and Asians
• Rare or absent in other tumor types
• Presence of a mutation predicts response to small
  molecules EGFR inhibitors
• Presence of EGFR mutations confers distint
  survival advantage (20 m vs 8 m) upon treatment
  with EGFR TKIs
• Early event in lung carcinogenesis

40
Phase II study of Iressa monotherapy for NSCLC
patients with EGFR gene mutation
N28
Primary endpoint Response (gt50?)

• NSCLC N120
• Stage IIIB/IV
• PS 0-2
• 20-75 yr Less than 1 prior chemo

IRESSA 250 mg/day until PD

EGFR mutation Exon 18, 19, 21
RR75
-
Study off Standard chemotherapy
Okamoto I et al. Poster discussion, Monday June
5, 2-6 PM
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WJTOG3405

• Stratification by
• Adjuvant CTx Yes or No
• Institution
• DFSlt1y or gt1y

Randomize
Gefitinib
Yes
250mg/day
NSCLC Postop rec
EGFR mutation Exon 19 deletion L858R (exon 21)
CDDPDOC
80mg/sqm60mg/sqm, q3w X 3-6 courses
No
Resected specimen
Off study
Primary endpoint Progression free
survival Sample size Mutation ve 200
cases Activated on March 20, 2006
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SLCG Phase III Trial in EGFR-mutated NSCLC
R A N D O M I Z E

• Eligibility
• No prior Rx
• Stage IIIB or IV
• Mutated EGFR
• ECOG PS 0-2

Erlotinib 150 mg/day PO
Cross-over at PD
Platinum-based Chemo
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CALGB 30406 Randomized Phase IIStudy Trial
Design
Chemotherapy naive patients with stage III/IV
adenocarcinoma or BAC who are never or light
former smokersECOG PS 0-1
Daily oral erlotinib
Daily oral erlotinib 6 cycles
carboplatin/paclitaxel
Daily oral erlotinib
Daily oral erlotinib

• Patients can continue therapy until evidence of
  disease progression or toxicity present accrual
  20

never smoker ? 100 cigarettes/lifetime light
former smoker quit ? 1 year ago and ? 10 pack
years
44
Comparison of MALDI-TOF MS test with clinical
predictors of EGFR TKI sensitivity
Cox regression analysis for overall survival
using the covariates sex, smoking status,
histology, and MALDI-ToF MS test result ( n 206
NSCLC patients treated with gefitinib).
Taguchi F et al, JNCI 99, 838, 2007
45
2. Independent Blinded Validation (n 67 Italian
patients treated with gefitinib) Survival
P-diff 0.15
P-diff 0.10
p 0.007
p 0.0097
Survival (days)
Survival (days)
HR 0.49 0.22-0.79 MS 73 vs. 192 days (bad v.
good)
HR 0.52 0.25-0.83 MS 92 vs. 207 days (bad v.
good)
(8 undefined)
(1 undefined)
46
Concordance of Results between Colorado and
Vanderbilt (n 206 spectra)
Colorado
P-diff 0.15
Vanderbilt
89 concordance
Colorado
P-diff 0.10
Vanderbilt
97 concordance
47
Effect of MALDI-ToF MS test in smokers ( n 159)
Hazard Ratio 0.40 0.18-0.44 Logrank p lt 0.0001
Survival (days)
48
Effect of MALDI-ToF MS test in patients with
squamous histology (n37)
Hazard Ratio 0.23 0.06-0.35 Logrank p lt 0.0001
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Proposed Trial Schema
Erlotinib
IIIB/IV NSCLC No Prior Tx PS 0/1
Favor
Serum MALDI analysis
Chemo
Unfav
Standard of care
PrImary Endpoint PFS (lt 4 m with erlotinib
would be considered inferior) Estimated sample
size 665 pts Projected with favorable profile
466 Non-inferiority design Bevacizumab in
Bev eligible patients
Designed with 95 power at the one-sided
significance level of 0.05 to reject the null
hypothesis of inferiority of erlotinib
(estimating a hazard ratio (chemo/erlotinib) lt
0.80) if the true hazard ratio (chemo/erlotinib)
is 1.1 or more.
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Acquired EGFR mutations confer resistance to
gefitinib, but not all EGFR inhibitors
Kobayashi et al. NEJM, 352, 786-792, 2005
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EGFR InhibitorsActive in EGFR Resistance
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Activity of irreversible EGFR inhibitors in H1975
cells (L858R/T790M)
Cellular proliferation assay
Autophosphorylation assay
Carter et al. PNAS 102, 11011-11016, 2005
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EKB-569 irreversible EGFR inhibitor

• Phase I in Japan
• 2 minor responses seen in gefitinib resistant
  patients (del19 L858R)

Yoshimura et al. Lung Cancer 51, 363-368, 2006
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HKI-272 Phase I TrialPreliminary Efficacy
Wong ASCO 2006
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HKI-272 in Advanced NSCLC A Phase 2 study
A EGFR mutation (n46)
Yes
Yes
EGFR mutation?
Prior EGFR TKI?
B EGFR wt (n46)
No
No
C Adenocarcinoma lt10 pack-years (mutant EGFR
30) (n46)
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cMET is amplified in gefitinib resistant cells
Engelman et al. Science 2007
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MET siRNA inhibits pEGFR and ErbB3 signaling in
gefitinib resistant cells
Engelman et al. Science 2007
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Non-inferiority for survival study design
Gefitinib250 mg/day
Randomization
Post-study treatment

Overall survival
Docetaxel 60 mg/m2 every 3 weeks

• Stratification factors
• Sex, PS (0-1 vs 2), tumor type (adenocarcinoma vs
  others)
• Study sites

Change to opposite treatment only at patient
request

• Main inclusion criteria
• Advanced/metastatic (Stage IIIB/IV) or recurrent
  NSCLC
• One or two chemotherapy regimens (at least one
  containing platinum)
• Aged ? 20 years
• PS 0-2

Niho et al. ASCO 2007
PS, performance status NSCLC, non-small-cell
lung cancer
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Overall survival (ITT)
Gefitinib
Docetaxel
Probability of survival
N Events Median (months) 1-year survival
() Supportive Cox analysis with covariates
245 156 11.5 48
244 150 14.0 54
1.00
HR (95.24 CI) 1.12 (0.89, 1.40) p0.330
0.75
0.50
HR (95 CI) 1.01 (0.80, 1.27) p0.914
0.25
0.00
Months
0
2
4
6
8
10
12
14
16
18
20
22
24
26
28
30
32
34
36
At Risk
Gefitinib
245
226
197
169
148
127
98
77
63
47
35
29
25
18
9
5
4
1
0
Docetaxel
244
233
214
189
173
140
105
87
69
44
35
25
18
14
10
7
6
3
0
60
Progression-free survival (evaluable for
response)
Consistent results were observed in a sensitivity
analysis for the ITT populationPFS,
Progression-free survival
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Objective tumor response (RECIST)
50
Patients()
p0.735
40
30
p0.009
20
34.0
33.2
22.5
10
12.8
0
Objective response rate(CRPR)
Disease control rate(CRPRSD gt 12 weeks)
The vertical bars on the plot represent the 95
CIs p-values are derived from logistic
regression analysis
62
Quality of life andsymptom improvement
Patients()
50
Gefitinib
Docetaxel
40
p0.023
p0.562
p0.002
30
20
23.4
22.7
20.4
20.5
10
13.9
8.7
0
n
185
173
185
173
225
211
FACT-L
TOI
Symptom by LCS

• p-values are derived from logistic regression
  analysis
• FACT-L, Functional Assessment of Cancer Therapy
  Lung TOI, Trial Outcome Index LCS, Lung
  Cancer Subscale
• FACT-L Japanese version 4-A including 2 extra
  Japan-specific questions in subscale of
  social/family well-being

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Conclusions

• Non-inferiority in overall survival between
  gefitinib and docetaxel was not achieved (HR
  1.12 95.24 CI 0.89, 1.40) according to the
  predefined criteria (upper CI for HR lt1.25)
• No statistical evidence of a difference in
  overall survival (p0.330) between gefitinib and
  docetaxel

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SCLC

• State of the art
• Highlights
• PCI in extensive disease
• Role of topoisomerase I inhibitors in first-line
  treatment of extensive disease

65
SCLC state of the art

• Limited Disease
• Concomitant early radiotherapy for limited
  disease SCLC
• Cisplatin-etoposide best tested
• PCI for complete responders
• Surgery rarely used
• Extensive Disease
• Platinum-based chemotherapy
• Second-line therapy with topotecan

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Noda et al. NEJM 2000
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Hanna et al. 2006
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ASCO 2007, Chicago, IL
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ASCO 2007, Chicago, IL