SMALL CELL LUNG CANCER SCLC and TKIs in NSCLC

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SMALL CELL LUNG CANCER (SCLC) and TKIs in NSCLC

• G. Giaccone
• Chief Medical Oncology Branch
• National Cancer Institute
• Bethesda, Maryland

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U.S. Cancer Mortality Men
CA Cancer J Clin 2006
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U.S. Cancer Mortality Women
CA Cancer J Clin 2006
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Worldwide Prevalence of Lung Cancer

• According to WHO, 1.2 million new cases of lung
  and bronchial cancer diagnosed each year
  worldwide, and approximately 1.1 million deaths
  annually
• Lung/bronchial cancer single largest cause of
  cancer deaths in US, accounting for 32 of cancer
  deaths in men and 25 in women in 20041
• In Europe, about 400,000 new cases of lung and
  bronchial cancer diagnosed each year,2 with
  341,800 deaths (about 20 for all cancers)
  reported in 20043
• American Cancer Society(http//www.cancer.org/doc
  root/pro/content/pro_1_1_Cancer_Statistics_2004_pr
  esentation.asp)
• Bray F, et al. Eur J Cancer. 20023899-166.
• Boyle P, Ferlay J. Ann Oncol. 200516481-488.

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Lung Cancer Demographics

• Second most frequently diagnosed cancer in the
  United States
• 12 of all new diagnoses
• 173,770 individual cases in 2004
• Median age at diagnosis is approximately 70 years
• Over 1/3 of all diagnoses are made in patients
  over 75 years of age
• Leading cause of cancer deaths in the
  United States
• 160,440 patients will die in 2004
• 32 and 25 of all cancer deaths in American men
  and women, respectively

Jemal et al. CA Cancer J Clin. 2004548. SEER
Cancer Statistics Review, 1975-2001. At
http//seer.cancer.gov/csr/1975_2001/. Accessed
October 22, 2004.
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Estimated Cancer Death Rates in the United
States 2004
Men 290,890
Women 272,810
25 Lung and bronchus 15 Breast 10 Colon and
rectum 6 Ovary 6 Pancreas 4 Leukemia
Lung and bronchus 32 Prostate 10 Colon and
rectum 10 Pancreas 5 Leukemia 4 Non-Hodgkins 4
lymphoma
Jemal et al. CA Cancer J Clin. 2004548.
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Activated proto-oncogenes in lung cancer
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Inactivated tumor suppressor genes in lung cancer
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Unbalanced translocation causing LOH in
adenocarcinoma of the lung
7 cell lines and 3 primaries
Ogiwara H et al. Oncogene 27, 4788, 2008
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Select gene mutations in NSCLC

• P53 50-70
• Kras 20 (30 adenocarcinoma)
• P16 29 (adenocarcinoma)
• EGFR 10-30 (20 adenocarcinoma)
• LKB1 26 (34 adenocarcinoma)
• NTRK 10 pulmonary NE tumors
• EML-4-ALK 6.7
• PIK3CA 1.6
• MEK1 1

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TK and relative hazard to develop metastases in
early NSCLC
Muller-Tidow C et al. Cancer Res 65 1778, 2005
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LUNG CANCER Histological Types

• Non-small cell lung cancer (85)
• Adenocarcinoma
• Squamous cell carcinoma
• Large cell carcinoma
• Small cell lung cancer (15)

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SCLC

• Mostly caused by cigarette smoke
• Kills approximately 30,000 people each year in
  the US
• Is a neuroendocrine tumor
• Highly sensitive to chemotherapy and
  radiotherapy, but recurrence is common

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SCLC

• Epidemiology
• Diagnosis and Staging
• Biology
• Treatment

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Epidemiology of SCLC

• SEER database 1978-1998
• Decrease SCLC
• 1986 17.4
• 1998 13.8

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NSCLC United States Incidence Over 3 Decades
70
60
50
40
Incidence rate
30
20
10
0
1975
1980
1985
1990
1995
2000
Year of diagnosis

• The incidence of NSCLC increased by over 26
  between 1974 and 1998
• The incidence of SCLC decreased approximately 9
  between 1998 and 2001

Rates are per 100,000 and are age-adjusted to
the 2000 US standard population. SEER Cancer
Statistics Review, 1975-2001. At
http//seer.cancer.gov/csr/1975_2001/. Accessed
October 22, 2004.
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Lung Cancer Common Signs and Symptoms

• Symptoms related to the primary tumor
• Cough, hemoptysis, wheeze and stridor, dyspnea,
  and/or pneumonitis
• Symptoms related to metastases
• Bone pain, abdominal pain, headache, weakness,
  and/or confusion
• Generalized symptoms
• Fatigue, malaise, and/or loss of appetite

American Society of Clinical Oncology. At
http//asco.org/ac/1,1003,_12-002611-00_18-0026183
-00_19-00-00_20-001,00.asp. Accessed October 26,
2004. Ginsberg et al. Nonsmall cell lung cancer.
In Cancer Principles Practice of Oncology.
2001925.
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Lung Cancer Evaluation and Diagnosis
Suspected lung cancer
Initial evaluation Chest x-ray CT scan PET scan
Peripheral tumor
Central tumor

• Options
• - Percutaneous fine needle aspiration
• - Bronchoscopy
• - Video-assisted thoracoscopy
• - Thoracotomy

• Options
• - Sputum cytology
• - Bronchoscopy
• - Percutaneous fine needle aspiration
• - Thoracotomy

Some metastases visible by CT scan only. CT
computed tomography PET positron emission
tomography. Ginsberg et al. Nonsmall cell lung
cancer. In Cancer Principles Practice of
Oncology. 2001925. Rivera et al. Chest.
2003123(suppl)129S.
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Lung cancer chest X-ray
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Lung cancer chest CT-scan
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Lung cancer bronchoscopy
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Staging of SCLC

• Physical examination
• Serum chemistries and whole blood cell counts
• CT scan of chest and upper abdomen
• US upper abdomen
• FDG PET scan
• Bone scan
• CT or MRI of the brain
• Bone marrow biopsy (optional)

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• Initiated by tobacco smoke carcinogens.
• Is SCLC derived from neuroendocrine Kulchitsky
  cells or stem cells?

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• Allelic loss (3p, 4p, 4q, 5q, 8p, 9p, 10q, 13q,
  17p, 22q)
• Microsatellite instabilities (35)
• MYC overexpression (30)
• Stem cell factor, c-kit overexpression (30)
• Bombesin/ Gastrin releasing peptide (BB/GRP),
  GRP receptor, IGF-I receptor

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• P53 inactivation (90)
• Rb inactivation (90) but not p16.
• FHIT inactivation (75)
• BCL2 expression (85)

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Small cell lung carcinoma

• Rapid growth and early metastases
• Staged in limited vs extensive disease (based on
  possibility of chest radiation in one field)
• Limited disease
• stage I resection followed by adjuvant
  chemotherapy 5y 35-45
• Stage II-III chemoradiation, PCI in CR 5y
  20-25
• Extensive disease
• Chemotherapy response 50-70, 5y

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Prognostic factors for survival
19 mo
10 mo
7 mo
2 mo
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Staging of small cell lung cancer
Limited disease (within a tolerable radiation
field)
Extensive disease (distant metastases)
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DEFINITION OF DISEASE EXTENSION

• Very-limited disease confined to one hemithorax
  without mediastinal lymph node involvement.
• Limited disease confined to one hemithorax
  including the contralateral lymph nodes (all
  within radiation field).
• Extensive disease beyond these bounderies.

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survival of SCLC

• marginally improvement of survival in 2 decades

Median survival SEER database
Extensive Disease (Chute et al. J Clin Oncol 1999)
Limited Disease (Janne et al. Cancer 2002)
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Median survivals in SCLC

• Very-limited disease 5 years
• Limited disease 18-24 months
• Extensive disease 10 months
• SCLC without treatment

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Approach to very-limited disease

• Surgery followed by chemotherapy

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Survival of patients with SCLC according to lymph
node involvement
pTN0M0 (n63)
pTN1M0 (n51)
pTN2M0 (n32)
Eur J Cardiothorac Surg, 53061991
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About half of patients with very-limited disease
may be cured with combined-modality approach that
includes surgical resection and adjuvant
chemotherapy
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preoperative SCLC

• 1 randomized study
• 328 patients (N2 excluded)
• 5 courses CAV q 3 wks radiotherapy thorax and
  brain thoracotomy
• randomized if PR
• 217 responders (90 CR, 127 PR)
• 146 randomized

Lad T et al. Chest 1994 106 320S
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-resection rate 83 -19 complete resection -9
only NSCLC as residual disease median
survival -all 12 months -randomized 16 months
Lad T et al. Chest 1994 106 320S
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Approach to limited disease
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Limited Disease - SCLC

• treatment has a small but definitively curative
  intent ( 5y survival 10 25 )
• combination chemotherapy is the backbone of
  treat-ment
• thoracic radiotherapy significantly improves long
  term survival
• early thoracic radiotherapy gives better results
  than late radiotherapy

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limited disease - SCLC

• cisplatin and etoposide are most easily combined
  within concurrent chemoradiation protocols
  (Turrisi et al )
• BID radiotherapy gives better local control and
  better long term survival than QD (5y survival
  26 Turrisi et al, NEJM 99 )
• PCI significantly improves survival by 4-5 at 5
  years when given to complete responders (Auperin
  et al )

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A meta-analysis of thoracic RT in LD-SCLC
12 phase III studies
Pignon et al NEJM 1992
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SCLC - Meta-analysis of PCI From 7 randomised
trials of PCI vs no-PCI
Patients 987 (140 patients had
ED-SCLC) Chemo- RT schemes various Overall
survival benefit 5 (95 CI 1 -10) 3 year
survival 20 vs 15 Incidence of brain metas 33
vs 59
Auperin et al. NEJM 1999
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Risk of radiation esophagitis with CT-RT

• With once-daily RT esophagitis
• With concurrent chemo-RT 25-52 acute G3-4
  esophagitis
• Risk of acute high-grade esophagitis associated
  with a length of irradiated organ of 10 cm
• Risk of late toxicity associated with 50 Gy
  delivered to 32 of the esophageal volume when
  any portion of esophageal circumference receives
  80 Gy.
• Use of involved-fields significantly reduces the
  length of irradiated esophagus.

(refs Choi 99 Hirota 01 Rusch 01 Senan 02
Vokes 02)
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Early vs Late Radiotherapy for LD SCLC. Meta
analysis
2 year survival
3 year survival
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SCLC LD Standard of treatment
Cisplatin 80 mg/m2 d1 Etoposide 120 mg/m2 d1-3
Q3wk x 4 Thoracic Radiotherapy 45 Gy 1.5
Gy/fraction bid 3 wk
Turrisi et al. NEJM 1999
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Approach to SCLC ED
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Standard of treatment for SCLC ED

• Cisplatin or Carboplatin plus Etoposide
• Median survival approx. 11 months
• 5 year survival approx 0
• No improvement achieved by
• Alternating chemotherapy
• Maintenance chemotherapy
• Novel agents (taxanes, topo 1 inhibitors)
• Biologicals

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Irinotecan
Irinotecan plus cisplatin compared with etoposide
plus cisplatin for extensive stage small cell
lung cancer

• irinotecan 60 mg/m2 d 1,8,15 cisplatin 60 mg/m2
  d 1 q 4 weeks
• etoposide 100 mg/m2 d 1,2,3 cisplatin 80 mg/m2
  d 1 q 3 weeks
• 154 patients (planned 230)
• median survival IP 12.8 months EP 9.4 months
• at 2 years 19.5 versus 5.2 alive

Noda K et al. New Engl J Med 2002
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cisplatin/irinotecan versus cisplatin/etoposide
in SCLC ED Japanese experience

Noda et al. NEJM 2002
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Randomized phase III study comparingIrinotecan/Ci
splatin (IP) with Etoposide/Cisplatin (EP) in
patients with previously untreated, ED SCLC
LBA 7004
Randomize
Cisplatin 30 mg/m2 d 1, 8 Irinotecan 65 mg/m2 d
1, 8 Q 21
N 221
Cisplatin 60 mg/m2 d 1 etoposide 120 mg/m2 d
1-3 Q 21
N 110
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IP vs EP in SCLC ED US experience


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Phase III study of oral Topotecan/Cisplatin
versus Etoposide/Cisplatin (EP) as first-line
therapy in patients with ED SCLC
abstract 7003
randomize
Cisplatin 60 mg/m2 d 5 Topotecan 1.7 mg/m2/d d
1-5 Q 21
N 389
Cisplatin 80 mg/m2 d 1 etoposide 100 mg/m2 d
1-3 Q 21
N 395
Eckardt JR et al. J Clin Oncol 2005 23 621s
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Eckardt JR et al. J Clin Oncol 2005 23 621s
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Maintenance therapyunsuccesfull

• Chemotherapy
• Biologicals
• Interferons
• Marimastat
• Vaccination
• ZD6474 (VEGFR and EGFR inhibitor)

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Rationale of the study (ctd)

• BEC 2 is an anti-idiotypic antibody that mimics
  GD3, a ganglioside which is expressed on the cell
  membrane of most SCLC
• BEC 2/BCG vaccination has been shown to be safe
  and stimulates anti-GD3 response in patients
• An impressive long-term survival was observed in
  a small pilot study

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Diseasefree progression in 15 patients vaccinated
n7
n15
n8
Grant et al., Clin Cancer Res 5, 1319, 1999
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08971-08971b Design
Observation arm BSC Vaccination arm 5
vaccinations of BEC 2BCG
R A N D O M I Z E
LD responding to 4-6 cycles of chemotherapy and
chest radiotherapy
Stratification Performance status (Karnofsky)
60-70 vs 80, CR vs. PR, Institution
Giaccone G et al. JCO 2005
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Humoral analysis of vaccinated patients (N257)

• Positive 71
• Negative 142
• Missing 44

Overal survival
By Humoral response
Overall Logrank test p0.111
O
N
Number of patients at risk
Humoral response
111
142
106
69
45
27
14
8
1
0
No
49
71
60
42
27
19
9
5
3
2
Yes
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Second line therapies

• response to first-line therapy 60
• 95 relapse after first-line treatment
• second-line treatment often considered as
  indicated as part of palliation

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Oral Topotecan vs BSC in relapsed SCLC
RANDOMIZE
Stratify PS 0/1 vs 2 Gender TTP (60
d) Liver mets
Oral Topotecan 2.3 mg/m2/day 1-5 q 3wk
Relapsed SCLC N 141
BSC
Primary end point survival Secondary QoL, ORR,
6 mo survival
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Oral Topotecan vs BSC in relapsed SCLC
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Phase III study comparing topotecan vs. CAV as
second line therapy in patients with sensitive
relapse small cell lung cancer
RANDOMIZE

• SCLC
• Measurable disease
• LD or ED
• Response to FLT
• Off therapy 60 days

Topotecan 1.5 mg/m2 daily x 5 q 3 wks
Cyclophosphamide 1000 mg/m2 Doxorubicin 45 mg/m2
Vincristine 2 mg
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Second line chemotherapy for SCLC. Symptom
improvement
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Second line chemotherapy for SCLC reinduction
chemotherapy.
Sensitive RR 61 Refractory RR 35
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Second line chemotherapy for SCLC influence of
interval and response to first-line treatment
Giaccone et al. J.Clin. Oncol. 61264,1988
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Background Brain metastases (BM) in SCLC

• High incidence 18 at diagnosis 80 at 2 years
• Major impact on physical and psychological
  functioning
• Poor response to systemic therapy and brain
  radiotherapy
• Prophylactic cranial irradiation (PCI) improves
  survival in patients in complete remission
  (Auperin et al., 1999)

Does PCI have a role in patients with ED-SCLC
after chemotherapy?
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Study Design
PCI 20-30 Gy in 5-12 fractions
Chemotherapy (4-6 cycles)
No response
Random
Any response
No PCI

4-6 weeks
Stratification Performance score and Institute
Slotman et al. NEJM 2007
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Endpoints
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Symptomatic brain metastases
100
90
1 year 14.6 vs. 40.4 HR 0.27 (0.16-0.44)
p80
70
60
50
40
Control
30
20
PCI
10
(months)
0
0
4
8
12
16
20
24
28
32
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78
Extracranial progression
79
Failure-free survival
100
90
6 months 23.4 vs. 15.5 HR 0.76 (0.59-0.96)
p0.02
80
70
PCI
60
50
40
30
20
Control
10
(months)
0
0
3
6
9
12
15
18
21
24
27
80
Overall survival
100
90
1 year 27.1 vs. 13.3 HR 0.68 (0.52-0.88)
p0.003
80
70
60
50
40
30
PCI
20
Control
10
(months)
0
0
4
8
12
16
20
24
28
32
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Summary

• PCI significantly reduces the risk of symptomatic
  brain metastases (p40.4 at 1 yr)
• No difference for the time to extra-cranial
  progression
• PCI significantly prolongs failure-free survival
  and overall survival (Overall survival p0.003
  HR 0.68 27.1 vs. 13.3 at 1 yr)
• PCI is well tolerated and does not adversely
  influence QoL/global health status

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Treatment of SCLC state of the art

• Limided 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
• PCI for responders