Systemic Therapy for Advanced Disease: Selecting Chemotherapy

1
Systemic Therapy for Advanced DiseaseSelecting
Chemotherapy
Rafael Rosell, Luis Paz-Ares on behalf of the
Spanish Lung Cancer Group
ESMO International Symposium on Chest
Tumors Geneva 31 March 2007
2
Biomarker-based approaches of targeted therapy

• SNPs
• Methylation in circulating DNA
• Mutations in tumor and circulating DNA
• Gene transcripts from RNA isolated from
  paraffin-embedded tumor tissue
• Median survival of 15 mos in stage IV NSCLC in
  selected patients

3
First-line erlotinib in EGFR mutation-positive
NSCLC

• EGFR mutation found in
• 211 / 1658 NSCLC pts (15)
• 112 / 684 (16.4) ? first-line erlotinib
• 31.6 F, 7.6 M, 35 never-smokers, 11
  ex-smokers, 3.5 smokers
• Response 90 (12 CR) independent of PS (even
  PS 3), site of metastases and age (26-86 y)
• T790M in 60 of cases

P 0.02 P 0.05
4
3 groups of tumor cells in pleural effusion
independently analyzed
Group P0
Group P1
Group P2
104 bp (del15 pb)
119 bp (wt)
Ex 19
del 15 pb
del 15 pb
del 15 pb
C
C/T
C/T
Ex 20
wt
T790M
T790M
Courtesy MA Molina
5
SEPT 2005 lung liver mets after PR with
paclitaxel/carbo
OCT 2005 CR with erlotinib (EGFR exon 19 del)
JAN 2007 long-lasting CR in 58-yr female
never-smoker with lung adenocarcinoma
Courtesy T Moran
6
GECP06/01opened February 2007

• Stage IV NSCLC
• Mutations of exon 19 or 21 of EGFR.
• Measurable or evaluable disease.
• ECOG PS 2.
• Stratified by
• ECOG PS
• In-frame del (exon 19) vs. L858R (exon 21)
• Mutation analysis in serum vs. both in serum and
  tumour tissue.

• Arm A
• Erlotinib 150 mg/day

R A N D O M I Z E
N 146 patients

• Arm B
• CDDP 75 mg/m2 plus
• Gemcitabine 1.250 mg/m2
• OR
• CDDP 75 mg/m2 plus
• Docetaxel 75 mg/m2

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Erlotinib vs Chemotherapy
EGFR mutations in tumor 14-3-3s in serum
8


Survival according to 14-3-3s serum DNA
methylation in gem/cis-treated NSCLC
Ramirez et al. JCO 2005



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14-3-3 in apoptotic pathways
Like Trx, 14-3-3 suppresses ASK-1
Porter, Khuri and Fu, Sem Cancer Biol 2006
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Translational studies 14-3-3s
SERUM DNA GEM/CIS TREATED PATIENTS
U M U M U M U M U M
U M
U M
U M U M U M U M U M
U M
U M
Pt1 Pt 2 Pt3 Pt4 Pt5
Pt6 P
t 7
Pt1 Pt 2 Pt3 Pt4 Pt5
Pt6 P
U M U M U M U M U M
U M
U M
U M U M U M U M U M
U M
U M
Pt8 Pt 9 Pt10 H
O HT-29 MP C
-
Pt8 Pt 9 Pt10 H
-
2
2
TUMOR AND PAIRED SERUM DNA NATCH TRIAL
U M U M U M U M
U M U M
T S T S
T S
Pt1 Pt 2
Pt3
U M U M U M
U M U M
T S HT-29
MP C-
Pt4
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Impairment of mitotic checkpoint genes in NSCLC
Rosell R, Santarpia M, Moran T, Salazar MF, Kaen
DL, Ramirez JL. Personalized Medicine 2007
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CHFR methylation in serum DNA of elderly NSCLC
patients

• Several lines of evidence demonstrate that CHFR
  is an early mitotic sensor in prophase of damage
  caused by antimicrotubule drugs, such as
  docetaxel
• Several studies report increased sensitivity to
  docetaxel, but not to cisplatin or etoposide, in
  cell lines with methylated CHFR
• CHFR methylation observed in serum DNA of 40 of
  NSCLC patients

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Survival in doc/cis-treated NSCLC patients gt66
years, according to CHFR methylation
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Survival in doc/cis-treated NSCLC responders gt66
years, according to CHFR methylation
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ERCC1 RRM1 mRNA in gem/cis-treated NSCLC
Rosell et al. Oncogene 2003
Lord et al. CCR 2002
Scagliotti et al. Ann Oncol 2006
Scagliotti et al. Ann Oncol 2006
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Customizing cisplatin-based chemotherapy on
quantitative ERCC1 mRNA expression a phase III
randomized trial in NSCLC
R A N D O M I Z E
Control arm
docetaxel / cisplatin
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Low genotypic group docetaxel / cisplatin
low ERCC1 mRNA
Genotypic arm ERCC1 levels
High genotypic group docetaxel / gemcitabine
high ERCC1 mRNA
Cobo et al. JCO 2007
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Customizing cisplatin-based chemotherapy on
quantitative ERCC1 mRNA expression a phase III
randomized trial in NSCLC
Cobo et al. JCO 2007
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Right paraaortic lymph node (SUV 12)

• 71-yrs
• Male
• Adeno
• low ERCC1
• doc/cis

Right adrenal SUV 11.6
June 2004
19
June 2004
Complete metabolic response in primary tumor
May 2005
20
June 2004
Complete metabolic response of paraaortic lymph
node adrenal partial metabolic response
May 2005
PFS 33 mos March 2007
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RecQ1, RAD54L ATM SNPs in pancreatic cancer
Inhibition of DNA synthesis
Li et al. JCO 2006
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Two strands of evidence for customizing therapy
based on BRCA1 mRNA levels in SCAT

• Among several DNA repair genes, BRCA1 is the most
  reliable predictive marker of chemotherapy
  outcome in stage IV and stage III NSCLC
• In early-stage chemonaive NSCLC patients, BRCA1
  is the best prognostic marker of survival
• BRCA1 has been selected as the marker for
  assigning chemotherapy in the SCAT experimental
  arm
• Low BRCA1 ? gem/cis
• Intermediate BRCA1 ? doc/cis
• High BRCA1 ? doc

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Gene expression according to histology in NSCLC
Clinical data from M Skrzypski, E Jassem, J Jassem
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Outcome according to BRCA1, ERCC1 RRM1 mRNA in
early NSCLC
Clinical data from R Bartolucci, F Puma, R Farabi
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Survival to neoadjuvant gem/cis according to
BRCA1 expression in stage III NSCLC
q1
q2q3
q4
HAZARD RATIO
Taron, Rosell, Felip, et cla. Hum Molec Genet 2004
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Survival in early-stage NSCLC patients
Rosell et al. ASCO 2007
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Spanish Customized Adjuvant Therapy in completely
resected N1 N2 NSCLC
Docetaxel/Cis
CONTROL

• Resected
• NSCLC
• pN1 / pN2

Gem/Cis
Q 1 BRCA1
Q 2 3 BRCA1
EXPERIMENTAL
Docetaxel/Cis
Docetaxel
Q 4 BRCA1

• EGFR mutations in adenocarcinomas
• patients stratified by invasive gene signature
  (CSF-1, EGFR CA IX) tumor size

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Customized adjuvant chemotherapy in stage II-IIIA
NSCLC
Spanish Lung Cancer Group
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Customizing cisplatin-based chemotherapy on
quantitative ERCC1 mRNA expression a phase III
randomized trial in NSCLC
Cobo et al. JCO 2007
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Stage IV NSCLC treated with gem/cis or doc/cis
Spanish Lung Cancer Group
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Survival in carriers of XRCC3 241 MetMet
according to age chemotherapy regimen 1000
stage IV NSCLC patients
Rosell et al. ASCO 2006
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Diagnostic testing to guide treatment decisions
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Stage IIIA N2 lung adenocarcinoma in 62-yr-old
male heavy smoker with emphysema
14.3.3 s unmethylated XRCC3 met/met No tumor
tissue to study BCRA1 EGFR mutations
4 cycles induction cis/gem ? 75 PR in primary
tumor
Courtesy T Moran
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Courtesy T Moran
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May 2006 upper left lobectomy ? pT1N0M0 low
BRCA1 levels wild-type EGFR September 2006 CEA
15 CT liver mets October 2006 PET-CT
tracheal, bronchial aortopulmonary lymph nodes
(SUV7/8) and liver M1 (SUV 23)
Repeated blood tests 14.3.3 s unmethylated XRCC3
met/met Serum EGFR mutations del 19
Courtesy T Moran
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04/2006
10/2006
Liver and lymph node relapse November 2006 EGFR
mutations in serum ? erlotinib
Courtesy T Moran