Clinical Update and Advances in the Treatment of NSCLC

1
Clinical Update and Advances in the Treatment of
NSCLC
2
Program Overview

• Incidence and epidemiology
• Subtypes
• Staging
• Adjuvant therapy for resectable disease
• Management of treatment-related toxicities
• Neoadjuvant therapy
• Treatment of metastatic disease
• Treatment of the elderly and poor PS patients
• Targeted therapy
• Anti-EGFR targeted agents
• Antiangiogenic agents
• Summary and future directions

3
Lung CancerIncidence and Epidemiology
4
Leading Causes of Cancer-related Deaths
Leading Sites by Sex, United States, 2006
Estimates
MEN Lung and bronchus 31 Colon and
rectum 10 Prostate 9 Pancreas
6 Leukemia 4 WOMEN Lung and
bronchus 26 Breast 15 Colon and
rectum 10 Pancreas 6 Ovary 6
174,470 new cases of lung cancer
564,830 cancer deaths 162,460 (29) due to lung
cancer
Excludes basal and squamous cell skin cancer and
carcinoma in situ, except urinary bladder.
Includes both non-small cell lung cancer
(NSCLC) and small cell lung cancer. American
Cancer Society. Cancer Facts and Figures, 2006.
5
Lung Cancer High Incidence, High Mortality
American Cancer Society. Cancer Facts and
Figures, 2006.
6
Risk Factors for Lung Cancer

• Environmental factors
• Smoking/second-hand smoke
• Air pollution
• Lung disease (tuberculosis)
• Asbestos
• Radon
• Genetic predisposition
• Chronic obstructive pulmonary disease (COPD)
• Prevention

NCCN Guidelines. Version 2.2006 April 2006.
7
Lung Cancer Subtypes
Small Cell Lung Cancer 15
Squamous Cell Carcinoma 25-30
Adenocarcinoma 35-40
Non-small Cell Lung Cancer 85
Large Cell Carcinoma 10-15
http//www.ncbi.nlm.nih.gov.
8
Squamous Cell Carcinoma

• Occurs most frequently in men and older people of
  both sexes
• Strongly associated with smoking
• Prominent EGFR over-expression and increased gene
  copy number per cell

McDoniels-Silvers A. Clinical Cancer Research.
200281127-1138 Movsas B, et al. Non-small cell
lung cancer. Cancer Management A
Multidisciplinary Approach. CMP Media LLC,
Lawrence KS, 2005, 111-154.
9
Adenocarcinoma

• Most common type of lung cancer
• Includes bronchioaveolar carcinoma (BAC) as a
  subtype

McDoniels-Silvers A. Clinical Cancer Research.
200281127-1138 Movsas B, et al. Non-small cell
lung cancer. Cancer Management A
Multidisciplinary Approach. CMP Media LLC,
Lawrence KS, 2005, 111-154.
10
Prognostic Factors in NSCLC

• Stage at presentation
• Performance status
• Weight loss
• Sex
• Age
• Molecular markers associated with poor prognosis
• ras mutations
• Overexpression of EGFR

Ciardiello F. Curr Opinion Oncology.
200416130-135.
11
Non-small Cell Lung Cancer Stages TNM Staging
System
Stage IVM1
T, primary tumor N, regional lymph nodes M,
distant metastasis.
12
NSCLC Stages at Presentation
7 Stage II
24 Stage I
31 Stage III
38 Stage IV
Mountain CF. Semin Surg Oncol. 200018106-115.
13
NSCLC Survival
Mountain CF. Semin Surg Oncol. 200018106-115
Fry WA, et al. Cancer. 1996771949-1995.
14
NSCLC Stage IA/B
Stage IA
Stage IB
?2 cm

• Any of the following
• T gt3 cm
• Main bronchus involvement 2 cm distal to carina
• Tumor invades visceral pleura
• Tumor with distal atelectasis

T T lt3 cm no lobar bronchus involvement
N0 No lymph node involvement M0 No distant
metastasis
15
NSCLC Stage IIA/B
Stage IIB
Stage IIA
?2 cm

• Any of the following
• Tumor with main bronchus involvement lt2 cm distal
  to carina
• Tumor that invades chest wall, diaphragm,
  mediastinal pleura, parietal pericardium
• Tumor with distal atelectasis

T T lt3 cm no lobar bronchus involvement
N1 Ipsilateral peribronchial and/or
hilar nodes involved M0 No distant metastasis
16
NSCLC Stage IIIA
T3N1-2M0 Tumor that invades chest wall,
diaphragm, mediastinal pleura, parietal
pericardium
T1-2N2M0 T gt3 cm Tumor invades visceral
pleura Tumor with distal atelectasis T ?3 cm
no lobar-bronchus involvement
lt2 cm ?2 cm
N1 Ipsilateral peribronchial and/or hilar
nodes involved N2 Ipsilateral mediastinal
and/or subcarinal nodes involved M0 No
distant metastasis
17
Current Treatment Approaches
Strauss GM, et al. ASCO 2006. Abstract
7007. Single-agent chemotherapy recommended for
the elderly and individuals with poor performance
status (PS 2).
18
Adjuvant Therapy for Resectable Non-small Cell
Lung Cancer
19
Adjuvant Chemotherapy Rationale

• Adjuvant treatment decisions are based on
  determining the relative benefit of a treatment
• Reducing the risks for relapse and mortality vs
  potential side effects and complications

20
Adjuvant Therapy for Resectable NSCLC
Recommendations
Strauss GM, et al. ASCO 2006. Abstract 7007.
21
Common Adjuvant Therapy Combinations

• Drug combinations most frequently used in
  first-line chemotherapy for NSCLC
• Vinorelbine and cisplatin
• Gemcitabine and cisplatin
• Paclitaxel and cisplatin
• Docetaxel and cisplatin

22
Meta-analysis of Prior Adjuvant Chemotherapy
Studies
Efficacy of Adjuvant Chemotherapy vs Observation
Alone
Non-small Cell Lung Cancer Collaborative Group.
BMJ. 1995311899-909.
23
Meta-analysis of Prior Adjuvant Chemotherapy
Studies (cont.)
Surgery plus
chemotherapy
Surgery
HR0.86 0.74-1.02 P0.08
No. at riskSurgery plus chemotherapy 706 649 5
90 526 462 419 371 330 295 255 206Surgery 688 633
648 482 433 382 353 307 258 215 177
Non-small Cell Lung Cancer Collaborative Group.
BMJ. 1995311899-909.
24
Randomized Adjuvant Chemotherapy Trials

• IALT
• Cisplatin-based chemotherapy vs observation
• BR.10
• Cisplatin/vinorelbine vs observation
• CALGB 9633
• Carboplatin/paclitaxel vs observation
• ANITA
• Cisplatin/vinorelbine vs observation

25
IALT Schema Cisplatin-based Adjuvant Chemotherapy
RANDOMIZE
Cisplatin-based chemotherapy etoposide or
vinorelbine (as prespecified by treating
center) (n935)
Follow-up analysis

• N1867
• Completely resected stage I-III NSCLC
• Age gt18
• PS 0-1

Observation (n932)
Le Chevalier T, et al. N Engl J Med.
2004350351-360.
26
IALT Patient Characteristics
Le Chevalier T, et al. N Engl J Med.
2004350351-360.
27
IALT Effects of Cisplatin on Overall Survival
100
Chemotherapy
Control
80
60
40
HR0.86 0.76-0.98 Plt0.03
20
0
0
1
2
3
4
5
At riskChemotherapy 932 775 624 450 308 181Cont
rol 935 774 602 432 286 164
Years

• Absolute benefit at 5 years 4.1
• 7,000 lives saved per year worldwide

Arriagada R, et al. N Engl J Med.
2004350351-360.
28
IALT Survival Rates and Toxicities

• Survival
• OS at 5 years 44.5 vs 40.4 (Plt0.03)
• 4.1 absolute benefit
• DFS at 5 years 39.4 to 34.3 (Plt0.003)
• 5.1 absolute benefit
• ERCC1 may predict benefit of cisplatin-based
  adjuvant chemotherapy
• Toxicities
• 0.8 risk of treatment-related death with
  chemotherapy (7 patients)
• 23 risk of grade 4 toxicity, primarily
  neutropenia

Arriagada R, et al. N Engl J Med.
2004350351-360 Soria J, et al. ASCO. 2006.
Abstract 7010.
29
JBR.10 Schema Phase III Trial of Adjuvant
Chemotherapy
Vinorelbine 25 mg/m2 every week for 16 weeks
cisplatin 50 mg/m2 on days 1 and 8 every 4
weeks for 4 cycles (n242)
RANDOMIZE

• N482
• Completely resected stage IB/II NSCLC
• Age 18
• PS 0-1
• /- K-ras mutations

Follow-up analysis
Observation (n240)
Winton T, et al. N Engl J Med. 20053522589-2597.
30
JBR.10 Effects of Vinorelbine and Cisplatin
Adjuvant Chemotherapy
Efficacy of Adjuvant Chemotherapy vs Observation
Alone
Winton T, et al. N Engl J Med. 20053522589-2597.
31
JBR.10 Effects of Vinorelbine and Cisplatin
Adjuvant Chemotherapy
Overall Survival, All Patients
100
Vinorelbine plus cisplatin
Observation
80
69
60
Probability ()
54
40
20
P0.006
0
0
2
4
6
8
10
Years
Hazard ratio for death 0.69 (P0.04)
Winton T, et al. N Engl J Med. 20053522589-2597.
32
JBR.10 Survival for Stage IB and Stage II Subsets
Overall Survival, Patients with Stage IB
Non-small Cell Lung Cancer
Overall Survival, Patients with Stage II
Non-small Cell Lung Cancer
100
100
Observation
Observation
Vinorelbine plus cisplatin
Vinorelbine plus cisplatin
80
80
60
60
Probability ()
Probability ()
40
40
20
20
P0.79
P0.004
0
0
0
2
4
6
8
10
0
2
4
6
8
10
Years
Years
No. at risk Observation 108 91 57 29 8 0 Vinorel
bine 111 91 65 27 6 0 plus cisplatin
No. at risk Observation 112 91 57 18 5 0 Vinorel
bine 111 100 54 24 6 0 plus cisplatin
Winton T, et al. N Engl J Med. 20053522589-2597.
33
JBR.10 Adjuvant Chemotherapy in the Elderly
All randomized patients N482
18 patients who received vinorelbine 30
mg/m2/week excluded
Observation N240
Chemotherapy N224
Elderly (gt65) N67
Young (lt65) N157
Prognostic factors Dose intensity (N150 vs
63 Chemotherapy toxicities (N150 vs 63)
Pepe C, et al. ASCO 2006. Abstract 7009.
34
JBR.10 Adjuvant Chemotherapy in the Elderly
Overall Survival by Treatment Arm, Age gt65
Disease Specific Survival by Treatment Arm, Age
gt65
1.0 0.8 0.6 0.4 0.2 0.0
1.0 0.8 0.6 0.4 0.2 0.0
H-R0.61 Log-rank, P0.04
H-R0.66 Log-rank, P0.13
73
66
Probability
Probability
46
46
Observation N78 Chemotherapy N77
Observation N78 Chemotherapy N77
0 2 4 6 8 10 12
0 2 4 6 8 10 12
Time in years
Time in years
Pepe C, et al. ASCO 2006. Abstract 7009.
35
JBR.10 Survival Rates and Toxicities

• Survival
• OS at 5 years was 69 vs 54 (P0.012)
• RFS at 5 years was 61 vs 48 (P0.012)
• Toxicities
• Febrile neutropenia occurred in 7 of patients
• Neurotoxicity (paresthesias, numbness, and
  hearing problems) was also observed

RFS, relapse-free survival.
36
CALGB 9633 Schema Randomized Trial of Adjuvant
Chemotherapy
Paclitaxel 200 mg/m2 over 3 hours carboplatin
AUC 6 both on day 1 every 3 weeks for 4
cycles (n173)
RANDOMIZE
Follow-up analysis

• N384
• Completely resected stage IB NSCLC
• Age gt18

Observation (n171)
CALGB, cancer and leukemia group B. Strauss GM,
et al. J Clin Oncol. 2004227019 Strauss GM, et
al. ASCO 2006. Abstract 7007.
37
CALGB 9633 Overall Survival - ASCO 2004 vs ASCO
2006
ASCO 2004
ASCO 2006
1.0
1.0
Observation
Observation Chemo
Observation
Observation Chemo
Chemo
Chemo
0.8
0.8
0.6
0.6
Probability
Probability
0.4
0.4
HR0.80 90 CI 0.60-1.07 P0.10
0.2
0.2
HR0.62 90 CI 0.44-0.89 P0.01
0.0
0.0
0
2
4
6
8
0
1
2
3
4
5
6
7
8
9
0
2
4
6
8
0
1
2
3
4
5
6
7
8
9
Survival Time (Years)
Survival time (years)
Survival Time (Years)
Survival time (years)
Strauss GM, et al. J Clin Oncol. 2004227019
Strauss GM, et al. ASCO 2006. Abstract 7007.
38
CALGB 9633 Disease-free Survival ASCO 2004 vs
ASCO 2006
ASCO 2004
ASCO 2006
1.0
1.0
Observation
Observation
Chemo
Chemo
0.8
0.8
0.6
0.6
Probability
Probability
0.4
0.4
HR0.74 90 CI 0.57-0.96 P0.03
0.2
HR0.69 90 CI 0.51-0.92 P0.02
0.2
0.0
0.0
0
2
4
6
8
0
1
2
3
4
5
6
7
8
9
0
2
4
6
8
0
1
2
3
4
5
6
7
8
9
Survival time (years)
Survival time (years)
Strauss GM, et al. J Clin Oncol.
2004227019Strauss GM, et al. ASCO 2006.
Abstract 7007.
39
CALGB 9633 Survival Rates and Toxicities

• Study was closed early after an interim analysis
  showed a P-value for OS less than pre-specified
  stopping boundary
• DFS improved in intent to treat analysis with
  adjuvant chemotherapy
• Trend toward improvement in OS but not
  significant (P0.10)
• 3-year survival (79 vs 70, P0.45) compared
  with 5-year survival (60 vs 57, P0.32)
• Toxicities
• No treatment-related deaths were observed
• Myelosuppression was the most common grade 3 or 4
  toxicity
• Grade 3 neuropathy occurred in 5 of patients

Strauss GM, et al. J Clin Oncol. 20042270192
Strauss GM, et al. J Clin Oncol. 2004Suppl.
22621a Strauss GM, et al. ASCO 2006. Abstract
7007.
40
ANITA Schema Randomized Phase III Trial of
Adjuvant Chemotherapy
Vinorelbine 30 mg/m2/week for 16 weeks
cisplatin 100 mg/m2 on day 1 every 4 weeks for 4
cycles (n407)
RANDOMIZE

• N840
• Completely
• resected stage
• IB, II, or IIIA NSCLC
• PS 0,1, or 2
• Age 18-75

Follow-up analysis
Observation (n433)
Douillard J, et al. ASCO 2005. Abstract 7013.
41
ANITA Effects of Vinorelbine and Cisplatin
Adjuvant Chemotherapy
Efficacy of Adjuvant Chemotherapy vs Observation
Alone
Douillard J, et al. ASCO 2005. Abstract 7013.
42
ANITA Effects of Vinorelbine and Cisplatin in
Stage I (p T2N0) Disease
Stage I (p T2N0)
Overall Survival
1.00
OBS
NVB CDDP
0.75
Survival distribution function
0.50
0.25
0.00
0
20
40
60
80
100
120
Months
Douillard J, et al. ASCO 2005. Abstract 7013.
43
ANITA Effects of Vinorelbine and Cisplatin in
Stage II Disease
Stage II
1.00
OBS
NVB CDDP
0.75
Survival distribution function
0.50
0.25
0.00
0
20
40
60
80
100
120
Months
Douillard J, et al. ASCO 2005. Abstract 7013.
44
ANITA Effects of Vinorelbine and Cisplatin in
Stage IIIA Disease
Stage IIIA
1.00
OBS
NVB CDDP
0.75
Survival distribution function
0.50
0.25
0.00
0
20
40
60
80
100
120
Months
Douillard J, et al. ASCO 2005. Abstract 7013.
45
ANITA Survival Rates and Toxicities

• Survival
• Median survival was 65.8 months vs 43.7 months
  (P0.0131)
• OS at 2 years was 68 vs 63
• OS at 5 years was 51 vs 43
• OS at 7 years was 45 vs 37
• Toxicities
• Grade 3/4 toxicities
• Neutropenia 86
• Febrile neutropenia 8.5
• Peripheral neuropathy 3
• 5 patients (1) died of drug-related toxicity

46
Summary Randomized Adjuvant Chemotherapy Trials

• IALT
• Supported platinum-based chemotherapy, results
  were moderately significant
• BR.10
• Statistical advantage in prolonging overall
  survival demonstrated
• CALGB 9633
• Risk of death found to be significantly lower
• ANITA
• Overall survival and relapse rate significantly
  improved

47
LACE Adjuvant Cisplatin-based Chemotherapy
Improves Survival

• Meta-analysis of individual patient data
  collected and pooled from the 5 largest trials
  (ALPI, ANITA, BLT, IALT and JBR10) of
  cisplatin-based therapy in completely resected
  patients
• Compared cisplatin-based CT vs no CT, or
  cisplatin-based CT radiotherapy vs
  postoperative radiotherapy
• Primary endpoint
• Overall survival

Pignon JP, et al. ASCO 2006. Abstract 7008.
48
LACE Overall Survival By Trial
OS by Trail
0.0 0.5 1.0 1.5 2.0
Chemotherapy better Control better
Tests for heterogeneity P0.34 Chemotherapy
effect P0.004
Trials (associated drug(s)) ALPI, MTCVDS
ANITA, NVB BLT, NVB/VDS/MTCVDS/MTCIFM JBR10,
NVB IALT, NVB/VDS/VLB/VP16. Pignon JP, et al.
ASCO 2006. Abstract 7008.
49
LACE Benefit Appears to Be Stage Dependent
CT Effect and Stage
0.5 1.0 1.5 2.0 2.5
Chemotherapy better Control better
Tests for trend P0.051 CT may be detrimental
for stage IA, but stage IA patients were
generally not given the potentially best
combination cisplatinvinorelbine (13 of stage
IA patients vs 43 for other stages)
Pignon JP, et al. ASCO 2006. Abstract 7008.
50
LACE Summary

• Cisplatin-based chemotherapy improves overall and
  disease-free survival in patients with NSCLC
• Multi-variant analyses were not able to study the
  role of the associated drug and cisplatin dose,
  despite the large number of patients
• Cisplatin-based chemotherapy is effective in
  stage II and III NSCLC

Pignon JP, et al. ASCO 2006. Abstract 7008.
51
CISCA Cisplatin vs Carboplatin Meta-analysis

• Randomized trials comparing cisplatin- and
  carboplatin-based chemotherapy
• Primary endpoint
• Overall survival
• Secondary endpoints
• Response rate and toxicity
• 2,968 patients were randomized to receive CT with
  cisplatin (1,489) or with carboplatin (1,479),
  respectively
• RR was 30 (cisplatin) vs 24 (carboplatin)
• Carboplatin was associated with a relative risk
  of death 7 higher compared with cisplatin,
  P0.101)

Ardizzoni A. ASCO 2006. Abstract 7011.
52
Adjuvant Chemotherapy Summary

• Adjuvant chemotherapy in the setting of
  completely resected NSCLC is a subject of
  controversy
• Statistically significant survival benefit to
  such chemotherapy
• Toxicities related to treatment call into
  question whether this apparent clinical benefit
  warrants the risk

53
Management of Treatment-related Toxicities
54
Common Symptoms/Side Effects in NSCLC

• Symptoms related to disease
• Dyspnea
• Pain
• Fatigue
• Symptoms related to treatment
• Myelosuppression
• Pain
• Fatigue

55
Management of Dyspnea

• Assessment challenging, subjective based on
  patients responses
• Activity planning to avoid symptoms and allow
  relief
• Medications
• Corticosteroids
• Opioids
• Oxygen therapy
• Nontraditional/investigational therapies
• Acupuncture
• Massage
• Exercise

Bruera E, et al. Principles and Practice of
Supportive Oncology. Philadelphia, PA
Lippincott-Raven Publishers 1998295-308.
56
Management of Pain

• Assessment
• Must identify etiology for effective treatment
• Medications
• Opioids
• NSAIDs
• Corticosteroids
• Nonpharmacologic interventions
• Heat/cold
• Topical agents
• Massage
• Behavioral therapy

National Cancer Institute. Pain (PDQ) Health
Professional Version. Available at
http//www.cancer.gov/cancertopics/pdq/supportivec
are/pain/Patient/page4. Accessed January 30, 2006.
57
Myelosuppression

• Most common side effect of chemotherapy
• Neutropenia
• Anemia
• Neutropenia is the primary dose-limiting toxicity
  of chemotherapy
• Often results in dose reductions or delays in
  treatment

Rivera E. Breast Cancer Res. 2003 5(5)
R114-R120 Crawford J. J Support Oncol.
20042(suppl 2)36-39.
58
Neutropenia

• Chemotherapy-induced neutropenia can lead to
  febrile neutropenia
• Febrile neutropenia (FN)
• ANC gt1.0109/L with a temperature gt100.6F
• 30 of patients receiving CT for NSCLC
• Regimens with an intermediate risk of FN
  (10-20)
• Cisplatin, paclitaxel
• Regimens with a high risk of FN (gt20)
• Docetaxel, carboplatin
• Gemcitabine, ifosfamide, vinorelbine

ANC, absolute neutrophil count CT,
chemotherapy. Rivera E. Breast Cancer Res. 2003
5(5) R114R120 Kuderer NM, et al. Proc Am Soc
Clin Oncol. 200221250a Bonadonna G, et al.
BMJ. 2005330217.
59
Neutropenic Complications and Considerations

• Febrile neutropenia, severe neutropenia, or dose
  delay or reduction due to neutropenia
• Prophylactic use of colony-stimulating factors
  can reduce the risk, severity, and duration of
  severe and FN
• Maintaining chemotherapy dose intensity in the
  initial cycles may be associated with improved
  outcomes

Caggiano V, et al. Cancer. 20051031916-1924
Kuderer NM, et al. Proc Am Soc Clin Oncol.
200221250a Bonadonna G, et al. BMJ.
2005330217.
60
Assessment of Febrile Neutropenia

• Assessment
• Risk factors predictive for febrile neutropenia

Ozer H, et al. J Clin Oncol. 2000183558-3585.
National Comprehensive Cancer Network. Clinical
Practice Guidelines in Oncology Myeloid Growth
Factors in Cancer Treatment. v2.2005. 2005.
61
2005 NCCN Guidelines Decision Tree for Primary
Prophylaxis
1. Evaluate
3. Intervene
2. Assess Risk
High gt20 Risk
Disease
Chemotherapy Regimen
Intermediate10-20 Risk
Patient Risk Factors
Lowlt10 Risk
Treatment Intent
Risk of FN or neutropenic event compromising
treatment.
62
Clinical Benefit of Pegfilgrastim in First and
Subsequent Cycles
Placebo n 465
Docetaxel Pegfilgrastim OR Docetaxel Alone
S CR E E NING
C H EMO T H E RA P Y
RANDOM I Z A T I ON
Febrile Neutropenia
Double-blind Phase
Pegfilgrastim n 463
Open-label Phase
Docetaxel 100 mg/m2 IV given on day 1 and
blinded product given on day 2. Four 21- day
cycles were planned. Vogel C, et al. J Clin
Oncol. 2005231178-1184.
63
Clinical Benefit of Pegfilgrastim in First and
Subsequent Cycles (cont.)
Efficacy of Pegfilgrastim for Preventing Febrile
Neutropenia
Vogel C, et al. J Clin Oncol. 2005231178-1184.
64
Use of Pegfilgrastim in NSCLC

• 2 small trials performed in NSCLC patients
• A single pegfilgrastim dose per cycle maintains
  neutrophil counts after docetaxel and gemcitabine
  chemotherapy for advanced NSCLC1
• A single pegfilgrastim dose per cycle of
  dose-dense carboplatin/vinorelbine protects
  against FN2

1. Fortner BV, et al. 2003 ASCO Annual Meeting.
Abstract 2799 2. Riedel R, et al. Abstract 2826.
65
Prevention of FN Growth Factor Support
N42
40
38
35
30
N310
N157
25
20
FN rate ()
18
20
13
15
9
10
5
(n42)
(n80)
(n77)
(n156)
(n154)
0
Misset et al.
Green et al.
Holmes et al.
Misset JL, et al. Ann Oncol. 199910553-560
Green MD, et al. Ann Oncol. 20031429-35 Holmes
FA, et al. J Clin Oncol. 200220727-731.
66
Colony Stimulating Factor Support Summary

• Dose delay and dose reduction can result in care
  that is less than optimal
• Reductions in total dose and dose intensity have
  an adverse effect on DFS and OS
• Prophylactic growth-factor support appears to
  decrease treatment-related morbidity and to
  increase the likelihood of the administration of
  full-dose chemotherapy on time

Crawford J. J Support Oncol. 20042(suppl
2)36-39.
67
Growth Factor Support Unanswered Questions

• If growth factor support is provided, would the
  dose intensity delivered increase and by how
  much?
• Would the rate of neutropenic complications
  increase because of the higher chemotherapy dose
  delivered?

Crawford J. J Support Oncol. 20042(suppl
2)36-39.
68
Anemia

• Anemia defined as hemoglobin lt11 g/dL
• Anemia is a common complication of cancer and
  cancer treatment
• 50-60 patients will develop anemia
• Severity of anemia increases with the use of
  platinum combination chemotherapy
• Anemia treatment can improve quality of life
  (QOL) and clinical outcomes

Okamoto, et al. Ann Oncol. 19923819-824 Langer
C. Chemotherapy Foundation Symposium XXI 2003.
69
Causes of Cancer-related Anemia

• Disease-related anemia
• Tumor type
• Stage and duration of disease
• Presence of infection
• Treatment-related anemia
• Regimen and intensity of therapy
• Chemotherapy
• Radiation therapy
• Surgical intervention
• Prior cancer treatment

70
Hemoglobin and Performance Status

• A significant correlation was found between poor
  performance status score and low Hb level breast
  cancer (Plt0.001)

WHO Performance Score
13.0
95 CI WHO 0, 12.654-12.785 WHO 1,
12.423-12.587 WHO 2, 11.878-12.222 WHO 3,
11.484-12.223 WHO 4, 8.613-13.634
12.5
Breast cancer
12.0
Gynecologic cancer
11.5
Hb level (g/dL)
11.0
10.5
10.0
0
0
1
2
3
4
Barrett-Lee P. Oncologist, 200510743-757.
71
Clinical Consequences of Anemia
Decreased Quality of Life
Reduced Treatment Success
Decreased Survival

• Chemotherapy may be more toxic or less effective
  when patients are anemic
• Fatigue
• Full dose on time

Cella D. Semin Oncol. 19825(suppl 7)43-46
Ludwig H, et al. Semin Oncol. 19825(suppl
7)2-6 Grogan M, et al. Cancer.
1999861528-1536 Dubray B, et al. Radiology.
1996201553-558 Lee W, et al. Int. J. Radiol.
Oncol Biol. Phys. 1998421069-1075.
72
Patient-reported Areas Negatively Affected by
Fatigue
Ability to work
61
Physical well-being
60
Ability to enjoy lifein the moment
57
Emotional well-being
51
Intimacy with partner
44
Ability to take care of family
42
Relationships with family and friends
38
Concerns about mortality and survival
33
0
10
20
30
40
50
60
70
Patients ()
Vogelzang NJ, et al. Semin Hematol. 199734(suppl
2)4-12.
73
Anemia and Risk of Death
130
120
110
100
90
80
70
Relative risk of death ()
60
50
40
30
20
10
0
Lung
Head and
Prostate
Lymphoma
Overall
neck
Stasi R, et al. Oncologist. 200510539-554.
74
Management of Anemia

• Iron supplementation
• Change in chemotherapy regimen
• RBC transfusion
• Erythropoietic-stimulating agents
• Recombinant human erythropoietin (rHuEPO)
• eg, epoetin alfa, epoetin beta
• Only 50-60 of patients respond
• Darbepoetin alfa (erythropoiesis-stimulating
  protein)
• 2 to 3 times longer serum half-life than rHuEPO

Dicato M. Oncologist. 2003819-21. Gordon MS.
Oncologist. 20027331-341 NCCN. Clinical
Practice Guidelines in Oncology Cancer- and
Treatment-Related Anemia. v1.2006. 2006.
75
Erythropoietin Therapy

• Advantages
• Avoids risks of transfusion therapy
• Allergic/febrile reactions
• Transfusion-associated immunosuppression
• Formation of alloantibodies
• Disadvantages
• Response not as rapid as therapy via transfusion
• Response can take gt4 weeks
• Can cause hypertension or splenomegaly

Dicato M. Oncologist. 2003819-21. Goodnough LT,
et al. N Engl J Med. 1999340438-447Ludwig H,
et al. Semin Oncol.199825(suppl 7)2-6.
76
Erythropoietic Agents for Treatment of Anemia in
Cancer Patients

• Recombinant human erythropoietin (rHuEPO)
• eg, epoetin alfa, epoetin beta
• Has the same biological effects as erythropoietin
• Only 50-60 of patients respond
• Darbepoetin alfa
• Erythropoiesis-stimulating protein
• 2 to 3 times longer serum half-life than rHuEPO

77
Erythropoietic Therapy Recommendations

• National Comprehensive Cancer Network (NCCN)
• Initiate erythropoietic therapy in patients with
  Hg lt11 g/dL
• American Society of Hematology (ASH) and American
  Society of Clinical Oncology (ASCO)
• Initiate erythropoietic therapy in patients with
  Hg lt10 g/dL
• RBC transfusion should be considered depending on
  the severity of anemia or clinical consequences

NCCN Practice Guidelines in Oncology v.1.2006.
Rizzo JD, et al. J Clin Oncol. 200220 4083-4107.
78
Erythropoietic Intervention
Early Intervention/ Hb Maintenance
Late Intervention/ Hb Correction
Erythropoietic Treatment
11
10
Hemoglobin (g/dL)
Transfusion?
6
Chemotherapy treatment
Adapted from Rearden, TP. J Clin Oncol, 2004 ASCO
Annual Meeting Proceedings (Post-Meeting
Edition). Vol 22, No 14S (July 15 Supplement),
2004 8064.
79
Clinical Benefit of Darbepoetin alfa and Epoetin
alfa
END OF TREATMENT 2 weeks after last dose of
darbepoetin alfa or 1 week after last dose of
epoetin alfa
END OF STUDY 2 weeks after end-of-treatment visit
Darbepoetin alfa 200 mg q2 wk
Epoetin alfa 40,000 U q wk
Concurrent chemotherapy
19
1
5
9
13
17
(Baseline) Study week
Schwartzberg LS, et al. Oncologist.
20049696-707.
80
Clinical Benefit of Darbepoetin alfa and Epoetin
alfa
Combined Analysis by BaselineHemoglobin and
Overall
Individual Analysis by Tumor Type
Q2W Darbepoetin alfa
Q2W Darbepoetin alfa
70
QW Epoetin alfa
QW Epoetin alfa
45
40
60
42
27
35
50
21
18
30
17
16
40
Proportion of patients requiring a transfusion
25
21
Proportion of patients requiring a transfusion
20
30
6
17
16
15
14
20
9
10
10
5
0
0
lt10 g/dL
gt10 g/dL
Overall
Breast
Lung
Gyn
n 72 69 51 51 34 35
n 38 38 119 117 157 155
Schwartzberg LS, et al. Oncologist.
20049696-707.
81
Clinical Benefit of Darbepoetin alfa and Epoetin
alfa
Darbepoetin alfa vs Epoetin alfa for Treating
Anemia
Schwartzberg LS, et al. Oncologist.
20049696-707.
82
Noninferiority Study of Darbepoetin alfa (DA) and
Epoetin alfa (EA)

• Randomized, open-label, active-controlled,
  multicenter study
• DA at a starting dose of 200 µg Q2W over 16 weeks
  for the treatment of anemia in patients receiving
  multicycle chemotherapy
• The active control arm received EA at a starting
  dose of 40,000 U QW
• After the 16-week treatment period, patients were
  monitored for 2 weeks for adverse events,
  concomitant medications, and transfusions received

Glaspy J, et al. J Clin Oncol. 2006242290-2297.
83
Incidence of RBC Transfusions and Sensitivity
Analyses
0.6
0.6
0.5
0.5
51
45
0.4
0.4
Proportion of patients
Proportion of patients
(95 CI)
(95 CI)
0.3
0.3
27
25
26
21
0.2
0.2
22
16
0.1
0.1
0
0
Darbepoetin
Epoetin alfa
Historical
Historical
Darbepoetin
Epoetin alfa
Historical
Historical
alfa
(placebo)
(epoetin alfa)
alfa
(placebo)
(epoetin alfa)
Mean (95 CI) Difference between Treatment Groups
Noninferiority margin 11.5
11.5
Per protocol analysis set(all cohorts)
3.6
4.4
Primary transfusion analysis set/primary
analysis set(16 week cohort)
5.0
3.0
1.3
0.4
Per protocol analysis set(16 week cohort)
-16
-12
-8
-4
0
4
8
12
16
-16
-12
-8
-4
0
4
8
12
16
In favor of darbepoetin alfa
In favor of epoetin alfa
In favor of darbepoetin alfa
In favor of epoetin alfa
A Percentages of patients receiving one
transfusion B Sensitivity analysesadjusted by
screening hemoglobin category (lt10 g/dL vs 10
g/dL) and type of chemotherapy administered
(platinum-based vs nonplatinum-based) Glaspy J,
et al. J Clin Oncol. 2006242290-2297.
84
Effect of Darbepoetin alfa and Epoetin alfa on
Hemoglobin
Hemoglobin (Hb) Concentration over Treatment
Period
Achievement of Target Hemoglobin Range
(11 g/dL to 13 g/dL) by Study Week
1
Darbepoetin alfa
14
Epoetin alfa
Epoetin alfa
0.8
13
Darbepoetin alfa
11.85
11.75
11.76
Target range
0.6
12
11.44
Proportion of patients
Mean (upper 95 CI) Hb levels (g/dL)
0.4
11
10.18
10.21
10
0.2
9
0
0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
n606
n603
n433
n431
n278
n245
Time (weeks)
8
Patients at risk Darbepoetin alfa 606 606 586 521
395 360 290 266 220 194 164 150 122 116 98 86 69
42Epoetin alfa 603 603 577 515 344 302 220 195 14
7 132 106 97 66 57 48 38 30 21
Baseline
Week 9
Week 17
Glaspy J, et al. J Clin Oncol. 2006242290-2297.
85
Darbepoetin alfa and Epoetin alfa Provide
Comparable Outcomes

• Safety profiles of DA and EA were consistent with
  adverse events in anemic cancer patients
  receiving chemotherapy with no differences
  observed between groups
• The ability to extend dosing intervals represents
  an important potential benefit for patients and
  their caregivers

Mean (95 CI) Difference between Treatment Groups
FACT-fatigue
FACT-anemia
Energy
Daily activity
Overall health
-6
-5
-4
-3
-2
-1
0
1
2
3
4
5
6
In favor of epoetin alfa
In favor of darbepoetin alfa
Glaspy J, et al. J Clin Oncol. 2006242290-2297.
86
Darbepoetin alfa 300 mg Q3W Study Schema
E
E
N1225, 29 breast cancer
N
S
N
D
C
R
R
O
O
E
Darbepoetin alfa 300 mg Q3W 500 mg Q3W
F
L
Darbepoetin alfa 300 mg Q3W
E
L
N
S
M
I
T
E
N
U
N
G
D
T
Y
7 days max
4 daysmax
2
3
4
5
6
7

8
9
1
0
1
1
1
2
1
3
1
4
1
5
1
6
Study week
Darbepoetin alfa administration
Boccia R, et al. Oncologist. 200611409-417.
87
Darbepoetin alfa (DA) 200 mg Q2W vs 300 mg Q3W

• DA 200 mg Q2W has been shown to be as effective
  as epoetin alfa 40000 U QW for the treatment of
  chemotherapy-induced anemia1
• DA 300 mg Q3W is well-tolerated and effective for
  achieving and maintaining evidence-based target
  Hb levels, allowing for synchronous
  administration with common chemotherapy regimens2

1. Schwartzberg LS, et al. Oncologist.
20049696-707 2. Boccia R, et al. Oncologist.
2006 11409-417.
88
500 mg Darbepoetin alfa Q3W for
Chemotherapy-induced Anemia

• Chemotherapy-induced anemia can be treated with a
  fixed dose of 500 mg Q3W of darbepoetin alfa with
  comparable efficacy to 2.25 mg/kg weekly dosing
• Patients receiving Q3W dosing received fewer
  blood transfusions than in the weekly arm
• 84 of Q3W patients achieved the target
  hemoglobin levels (gt11 g/dL) compared with 77 QW
  patients
• Synchronous administration of darbepoetin alfa
  Q3W with many chemotherapy schedules would be
  convenient to patients and their healthcare
  providers

Canon JL et al. J Natl Cancer Inst.
200698(4)273-284.
89
Anemia and Erythropoietic Therapy Summary

• Cancer-related anemia is common but
  under-recognized and under-treated
• Anemia is associated with reduced survival
• Darbepoetin alfa has an approximate threefold
  longer half-life than epoetin alfa and is
  effective at weekly, Q2W, and Q3W dosing
  intervals
• Less frequent dosing schedules that have equal
  efficacies are an obvious benefit to patients

90
Neoadjuvant Therapy
91
Neoadjuvant Chemotherapy

• Preoperative chemotherapy may improve the
  prognosis and survival
• Goal
• Downstage the tumor before surgery, increasing
  the chances for resection

92
Neoadjuvant Therapy Plus Surgery vs Surgery Alone

• Survival improves significantly with neoadjuvant
  therapy

Rosell R, et al. N Engl J Med. 1994330(3)153-158
.
93
SWOG 9900 Trial Schema
Paclitaxel carboplatin x 3 cycles
E L I G I B L E
Surgery

• N600
• Clinical stage T2N0,
• T1-2N1, T3N0-1

Surgery
Pisters K, et al. ASCO 2005. Abstract 7012.
94
SWOG 9900 Induction Chemotherapy
100
80
Preop
60
Control
40
HR0.84 0.60-1.18 P0.32
20
0
0
12
24
36
48
60
Months
Pisters K, et al. ASCO 2005. Abstract 7012.
95
SWOG 9900 Induction Chemotherapy (cont.)

• Overall survival favors and the role of
  preoperative chemotherapy

Pisters K, et al. ASCO 2005. Abstract 7012.
96
Treatment-related Toxicities and Induction Therapy

• Death
• Neutropenia
• Esophagitis
• Nausea/emesis
• Pneumonia

97
Adjuvant vs Neoadjuvant Therapy Summary

• Preoperative treatment may have a favorable
  effect on outcome
• Aggressive neoadjuvant approaches may be
  accompanied by treatment-related toxicities,
  including death

98
Treatment of Advanced Non-small Cell Lung Cancer
99
Stage IV Disease Goals of Therapy

• Stage IV NSCLC
• Indicates presence of metastatic disease
• Largely incurable
• Properly selected patients may benefit from
  chemotherapy with regard to survival and
  palliation
• Goals of treatment are
• To prolong survival
• Palliative
• To improve quality of life

100
Best Supportive Care vs Chemotherapy in Advanced
Patients
100
Best supportive care (BSC)
90
chemotherapy
80
Supportive care
70
60
50
Percentage survival
40
30
20
10
0
0
6
12
18
24
Time from randomization (months)
No. at riskBSC chemotherapy 416
219 98 47 28Supportive care 362 125 55 28 14
Socinski M. Chest. 2003123226S-243S.
101
Best Supportive Care and Chemotherapy Prolong
Survival
No. of patients alive in the US at 1 year
20
40
15
30
10
1-y survival
20
5
10
0
BSC
CTBSC
BSC
CTBSC
Socinski M. Chest. 2003123226S-243S.
102
Current Treatment Guidelines for Metastatic NSCLC
Stage IV NSCLC

• BSC, best supportive care

PS 3, 4
PS 0-2
BSC
1st Line Platinum-based Chemotherapy
Progression
PS 0-2
PS 3, 4
2nd Line Platinum-based Chemotherapy
BSC
Progression
PS 0-2
PS 3, 4
BSC
Gefitinib or Phase I/II Clinical Trial
Adapted from NCCN Practice Guidelines in Oncology
v.2.2006.
103
ECOG E1594 Schema Efficacy in Comparable
Platinum-based Regimens
Paclitaxel 175 mg/m2/week over 24 hours, day
1 Cisplatin 75 mg/m2 day 2, every 3 weeks
(n288)
RANDOMIZE

• N1155
• Stage IIIB/IV
• PS 0-2
• Weight loss
• Brain metastases (/-)

Follow-up analysis
Gemcitabine 1000 mg/m2 day 1, 8, 15 Cisplatin 100
mg/m2 day 1, every 4 weeks (n288)
Docetaxel 75 mg/m2 day 1 Cisplatin 75 mg/m2 day
1, every 3 weeks (n289)
Paclitaxel 225 mg/m2 over 3 hours, day
1 Carboplatin AUC6 day 1, every 3 weeks
(n289)
104
ECOG E1594 Comparable Efficacy in Platinum-based
Regimens
Survival by Treatment Group
1.0
0.8
Cis/Paclitaxel Cis/Gemcitabine Cis/Docetaxel Carbo
/Paclitaxel
0.6
0.4
0.2
0
0 5 10
15 20 25
30 Months
Schiller JH, et al. N Engl J Med. 200234692-98.
105
ECOG 1594 Regimens and Efficacy
Schiller JH, et al. N Engl J Med. 200234692-98.
106
ECOG 1594 Findings

• Survival curves demonstrate comparable efficacy
  between various platinum-based regimens
• No difference in long-term survival was observed

107
Modern Agents for Treatment of Advanced NSCLC

• Paclitaxel-based regimens
• Docetaxel-based regimens
• Vinorelbine-based regimens
• Gemcitabine-based regimens
• Irinotecan-based regimens

108
Comparison of Advanced NSCLC Therapies
Wakelee H, Belani CP. Oncologist. 200510(suppl
3)1-10.
109
First-line Chemotherapy in Advanced Disease
Summary

• Platinum-based therapy is standard first-line
  treatment for advanced NSCLC
• Non-platinum regimens have similar efficacy and
  prolong survival to similar extents as
  platinum-based therapy
• Non-platinum regimens do not show substantially
  decreased toxicity but may be better tolerated

1. Georgoulias V, et al. J Clin Oncol.
2005232937-2945 2. Pujol JL, et al. Ann Oncol.
200516602-610 3. Kosmidis PA, et al. J Clin
Oncol. 200523621s 4. Gridelli C, et al. J Clin
Oncol. 2003213025-3034.
110
Stage IV Disease Second-line Therapy
Second-line Treatment for Advanced NSCLC
1. Hanna N, et al. J Clin Oncol.
2004221589-1597 2. Shepherd FA, et al. N Engl
J Med. 2005353123-132 3. Shepherd FA, et al. J
Clin Oncol. 2000182095-2103.
111
Second-line Therapy vs BSC Shepherd et al.
RANDOMIZE
Docetaxel 100 mg/m2 (n49)

• Primary endpoint
• Overall survival
• Secondary
• endpoints
• Objective tumor response
• Duration of response
• Changes in quality of life

• N204
• Stage IIIB/IV NSCLC
• Failed/intolerant to 1 prior chemotherapy
  regimen
• PS 0-2

Docetaxel 75 mg/m2 (n55)
Best supportive care (n100)
Shepherd FA, et al. J Clin Oncol.
2000182095-2103.
112
Chemotherapy Still Shows Benefits vs BSC as
Second-line Therapy
1
1
Docetaxel 100 mg/m2 (n49)
Docetaxel 75 mg/m2 (n55)
0.9
0.9
BSC100 (n51)
BSC75 (n49)
0.8
0.8
0.7
0.7
Log-rank test, P0.780
Log-rank test, P0.010
0.6
0.6
0.5
0.5
Cumulative probability
Cumulative probability
0.4
0.4
0.3
0.3
0.2
0.2
0.1
0.1
0
0
0
3
6
9
12
15
18
21
0
3
6
9
12
15
18
21
Survival time (months)
Survival time (months)
Shepherd FA, et al. J Clin Oncol.
2000182095-2103.
113
Chemotherapy Still Shows Benefits vs BSC as
Second-line Therapy (cont.)
Shepherd FA, et al. J Clin Oncol.
2000182095-2103.
114
Hematologic Toxicities Associated with Treatment
Incidence of grade 3/4 toxicity per
patient. Shepherd FA, et al. J Clin Oncol.
2000182095-2103.
115
Phase III Pemetrexed vs Docetaxel for Second-line
NSCLC
RANDOMIZE

• Primary endpoint
• Overall survival
• Secondary
• endpoints
• Toxicity
• Objective response rate
• Progression-free survival
• Time to progression
• Quality of life

Pemetrexed 500 mg/m2 Vitamin B12 Folic acid
Dexamethasone (n283)

• N571
• Stage IIIB/IV NSCLC
• Failed/intolerant to 1 prior chemotherapy regimen
• PS 0-2

Docetaxel 75 mg/m2 Dexamethasone (n288)
Hanna N, et al. J Clin Oncol. 2004221589-1597.
116
Phase III Pemetrexed vs Docetaxel for
Second-line Survival
1
Pemetrexed (n265)
Docetaxel (n276)
0.75
Survival distribution function
0.5
0.25
HR0.99 (95 CI, 0.8 to 1.2)
0
0
5
10
15
20
Survival time (months)
Patients at riskPemetrexed 283 189 78 16 0Docet
axel 288 177 78 19 1
Hanna N, et al. J Clin Oncol. 2004221589-1597.
117
Stage IV Disease Current Questions

• In which patients is chemotherapy appropriate?
• What is the optimal chemotherapeutic approach?
• Regimen?
• Duration?
• Does second-line chemotherapy improve survival?
• How do outcomes and adverse effects associated
  with chemotherapy compare with the natural
  history of the disease?

118
Treatment in the Elderly Population and Poor
Performance Status Patients
119
Elderly and Poor Performance Status Patients

• Cisplatin regimens provide a slight advantage
  over supportive care but can induce severe toxic
  effects
• Consequently, treatment is frequently
  contraindicated in the elderly and patients with
  poor PS
• Reduction in the functional reserve of many
  organs and comorbid conditions

120
CALGB 9730 Monotherapy vs Combination Therapy
Lilenbaum RC, et al. J Clin Oncol.
200523190-196.
121
CALGB 9730 Age gt70
Lilenbaum RC, et al. J Clin Oncol.
200523190-196.
122
CALGB 9730 PS 2
Lilenbaum RC, et al. J Clin Oncol.
200523190-196.
123
Efficacy of Platinum-based Doublets STELLAR 3

• Efficacy and tolerability similar in older vs
  younger patients and poor vs good PS patients

Plt0.05. Langer CJ, et al. ASCO 2005. Abstract
7011.
124
SWOG 9308 and 9509 Retrospective Analysis in
Advanced NSCLC
SWOG 9308 Vinorelbine cisplatin vs
cisplatin. SWOG 9509 Paclitaxel carboplatin vs
vinorelbine cisplatin. Kelly K, et al. ASCO
2001. Abstract 1313.
125
SWOG 9308 and 9509 Results
Kelly K, et al. ASCO 2001. Abstract 1313.
126
Poor Performance Status Patients

• ECOG E1594 adverse events
• High number of adverse events in PS 2 and PS 0-1
  groups
• Events and shorter survival in PS 2 patients
  (n64) related to disease process rather than
  treatment

Sweeney CJ, et al. Cancer. 2001922639-2647.
127
ECOG 1594 Outcome Based on Age
lt70 y ?70 y n912 n227 P- value Grade ?4
toxicity 66 71.2 0.04 OR() 22.1 24.5 0.76 PFS
(mo) PS 0-1 3.71 3.75 PFS 1-y
() 6.5 8.6 0.37 PFS 2-y () 0.5 2.2 0.04 MS
(mo) 8.15 8.25 1-y OS() 32.8 35.2 0.53
2-y OS() 10.6 13.7 0.24
Langer CJ, et al. ASCO 2003. Abstract 2571.
128
ELVIS (Elderly Lung Cancer Vinorelbine Italian
Study)

• Statistically significant benefit for patients
  receiving vinorelbine

Gridelli C. J Nat Cancer Inst. 199985365-376.
129
Efficacy of Nonplatinum Single-agent vs Doublet
Chemotherapy
MILES Comparison of Single-agent vs Double-agent
Chemotherapy
Gridelli C, et al. J Natl Cancer Inst.
200395362-372.
130
Targeted Therapy for Non-small Cell Lung Cancer
131
Targeted Therapy Goals

• Identify drug targets that
• Are responsible for tumor growth
• Are key mechanisms in cancer progression
• Are reversible by inhibition
• Are dispensable to normal cells
• Can be measured in tumor tissue
• Identify tumor-specific molecules to minimize
  risk to other cells
• Increased specificity leads to reduced toxicity

Thomas M. Chemotherapy Foundation Symposium and
Online Education Program. Advances In Research
and Practice. November 15, 2003. 
132
Tumorigenic Pathways in the Cell Are Complex
Sigma Aldrich, Inc., St. Louis, MO
133
Targets for Drug Development

• Angiogenesis
• VEGF
• VEGFR
• FGF
• Integrin
• Apoptosis
• Bcl-2
• Survivin
• XIAP
• p53
• Clusterin

• Signaling
• Ras
• Raf kinase
• MEK
• mTOR
• PKC
• HER family
• EGFR
• HER-2
• Cell cycle
• Cdks

• Extracellular
• MMP
• Receptors/kinases
• c-Kit
• PDGFR
• Abl
• Other
• DNA MTase
• HDAC
• Proteasome

134
EGFR Targeting Strategies in NSCLC
135
EGF-induced Signal Transduction and Tumorigenesis
EGF

• EGFR is a tyrosine kinase growth factor receptor
• Activated by binding of natural ligands
• TGF-?
• EGF
• Activated EGFR signals through multiple pathways
• Potential to block at various steps in the
  pathway
• Extracellular surface
• Intracellular targets

()
EGFR
X
Anti-EGFR
Raf
Ras
SOS
K
K
PI3K
pY
pY
Grb2
MEK
pY
STAT
PTEN
Akt
MAPK
Gene transcription Cell-cycle progression
p27
X
X
X
X
Proliferation
Invasion/ metastasis
Survival/ anti-apoptosis
Angiogenesis
Perez-Soler R. Oncologist. 2004958-67.
136
Anti-EGFR Targeted Agents Biological Rationale

• Activation of EGFR linked with
• Increased cell proliferation
• Angiogenesis
• Metastasis
• Agents that selectively target EGFR could inhibit
  and prevent the pathogenesis of various cancers
• EGFR expression correlates with
• Poor response to treatment
• Disease progression
• Poor survival

137
Anti-EGFR Strategies
Toxin conjugates
mAbs
TKIs
Ligand
Antisense
Cetuximab
Panitumumab
Ligand
Ligand
Ligand
mAb
Gefitinib Erlotinib
TKI
K
K
K
K
K
K
K
K
Signal transduction
Survival and metastasis
Protein synthesis
Cell death
mAb, monoclonal antibody TKI, tyrosine kinase
inhibitor. Adapted from Raymond E, et al. Drugs.
200060(suppl 1)15-23.
138
Monoclonal Anti-EGFR Antibodies
139
Monoclonal Anti-EGFR Antibodies
EGFR
Pao W, Miller VA. J Clin Oncol. 2005232556-2568.
140
Monoclonal Antibodies
141
Phase I/II EGFR Antibodies

• Cetuximab competes with endogenous ligands for
  binding at EGFR, functioning as an EGFR
  antagonist at EGFR
• Once bound to EGFR, cetuximab induces the
  internalization of EFGR

Ng M, Cunningham D. Int J Clin Pract.
200458970-976.
142
Phase II Trials of Cetuximab in Advanced NSCLC

• PR, partial response.
• 1. Rosell R, et al. Proc Am Soc Clin Oncol.
  200423618a 2. Robert F, et al. J Clin Oncol.
  2005239089-9096 3. Thienelt CD, et al. J Clin
  Oncol. 2005238786-8793.

143
Phase II Trials of Cetuximab in Advanced NSCLC

• PR, partial response TTP, time to progression.
• 1. Lynch TJ, et al. Proc Am Soc Clin Oncol.
  200423634a 2. Kim ES, et al. Proc Am Soc Clin
  Oncol. 200322642a.

144
Phase III Trial of Cetuximab in Advanced NSCLC
RANDOMIZE

• Primary endpoint
• Overall survival
• Secondary
• endpoints
• Progression-freesurvival
• Tumor response
• Disease control
• Safety
• Quality of life

Cetuximab cisplatin vinorelbine

• N1037
• Stage IIIB/IV
• EGFR-expressing NSCLC

Cisplatin vinorelbine
Von Pawel J, et al. ASCO 2006. Abstract 7109.
145
EGFR-targeted Agents Small Molecule Tyrosine
Kinase Inhibitors
146
Tyrosine Kinase Inhibitors
147
EGFR Tyrosine Kinase Inhibitors Gefitinib and
Erlotinib

• Gefitinib and erlotinib selectively inhibit EGFR
  tyrosine kinase (aka HER-1 or ErbB-1)

Pavletich N. Structural Biology Program, Memorial
Sloan-Kettering Cancer Center.
148
EGFR Tyrosine Kinase Inhibitors in Recurrent NSCLC
Phase II Trials Assessing Second-line Treatment
1. Fukuoka M, et al. J Clin Oncol.
2003212237-2246 2. Kris MG, et al. JAMA. 2003
2902149-2158 3. Perez-Soler R, et al. Proc Am
Soc Clin Oncol. 200120310a. Abstract.
149
Patient Characteristics Associated with Response
Response to Second-line Treatment with Gefitinib
Fukuoka M, et al. J Clin Oncol. 2003212237-2246.
150
ISEL Trial 709 Phase III Gefitinib in Second- or
Third-line NSCLC
RANDOMIZE
Gefitinib 250 mg/day best supportive
care (n1129)

• N1692
• Stage IIIB/IV NSCLC
• Failed/intolerant to prior chemotherapy regimen

• Primary endpoints
• Survival in overall population
• Survival in those with adenocarcinoma

Placebo best supportive care (n563)
ISEL, Iressa Survival Evaluation in Lung Cancer.
Thatcher N, et al. Lancet. 20053661527-1537.
151
ISEL Trial 709 Phase III Gefitinib in Second- or
Third-line NSCLC (cont.)
Survival
Response Rate
Adenocarcinoma
11.4
Non-adenocarcinoma
4.6
Never smoked
17.2
Ever smoked
5.2
Refractory
7.8
Intolerant
7.2
1 prior chemo
7.4
2 prior chemos
8.0
PS 0,1
8.3
PS 2,3
6.6
Female
14.0
Male
4.9
All patients
7.7
0.4
0.6
0.8
1
1.5
Hazard ratio and 95 CI
Favors gefitinib
Favors placebo
Thatcher N, et al. Lancet. 20053661527-1537.
152
Gefitinib Efficacy and Somatic Mutations in EGFR

• Gefitinib and erlotinib target the ATP cleft
  within the tyrosine kinase EGFR
• Only about 10 of patients have a rapid and
  dramatic clinical response to gefitinib
• Most NSCLC patients do not respond to gefitinib
• Efficacy may be attributed to somatic mutations
  in EGFR gene

Lynch TJ, et al. N Engl J Med. 20043502129-2139.
153
Characteristics of Patients Responding to
Gefitinib
Lynch TJ, et al. N Engl J Med. 20043502129-2139.
154
Response to Gefitinib May Be Due to Somatic
Mutation of EGFR

• Majority of patients responding to gefitinib were
  
• Women
• Had never smoked
• Had BAC
• Heterozygous mutations were detected in 8/9
  patients
• 4 mutations were in frame deletions
• No mutations were detected when matched with
  normal tissue
• Diagnostic testing may identify patients for
  gefitinib therapy

Lynch TJ, et al. N Engl J Med. 20043502129-2139.
155
EGFR Somatic Mutation Summary

• A subgroup of patients have specific mutations in
  the EGFR gene that
• Correlate with clinical responsiveness
• Lead to increased growth factor signaling
• Confer susceptibility to gefitinib
• Screening for such mutations may identify
  patients who will respond to gefitinib therapy

156
Fluorescence In Situ Hybridization (FISH) Testing

• FISH testing can detect amplification (high gene
  copy number) of EGFR in NSCLC tumors 

http//www.accessexcellence.org/AB/GG/fish.html
157
Anti-EGFR Targeted Agents EGFR Copy Number in
NSCLC
Hirsch FR, et al. J Clin Oncol.
2005236838-6845 Cappuzzo F, et al. J Natl
Cancer Inst. 200597643-655.
158
FISH and EGFR Summary

• FISH may allow for informed treatment decisions
  based on patient characteristics
• Recent data suggest an association between high
  EGFR gene copy number and favorable clinical
  benefit

159
JBR.21 Trial Phase III Erlotinib in Second- or
Third-line NSCLC
RANDOMIZE

• Primary endpoint
• Overall survival
• Secondary
• endpoints
• Time to symptom deterioration
• Progression-free survival
• Tumor response rate

• N731
• Stage IIIB/IV NSCLC
• Failed/intolerant to gt1 prior chemotherapy
  regimen
• PS 0-3

Erlotinib 150 mg/day (n488)
Placebo (n243)
Shepherd FA, et al. N Engl J Med.
2005353123-132.
160
BR.21 Trial Overall Survival
HR0.70 (95 CI, 0.58 to 0.85) Plt0.001 by
stratified log-rank test
Erlotinib
Placebo
No. at riskPlacebo 243 107 50 9 0 0Erlotinib 48
8 255 145 23 1 0
Shepherd FA, et al. N Engl J Med.
2005353123-132.
161
BR.21 Trial Progression-free Survival
HR0.70 (95 CI, 0.58 to 0.85) Plt0.001 by
stratified log-rank test
Erlotinib
Placebo
No. at riskPlacebo 243 20 3 0 0 0Erlotinib 488
115 27 2 1 0
Shepherd FA, et al. N Engl J Med.
2005353123-132.
162
BR.21 Trial Outcomes
Shepherd FA, et al. N Engl J Med.
2005353123-132.
163
BR.21 Trial Survival in Expressing vs
Nonexpressing EGFR Patients
Survival in EGFR-negative
Survival in