Customization of NSCLC treatment

1
Customization of NSCLC treatment

• Prof Zarogoulidis K
• Lung Tumour Research Section,
• Aristotle University Pulmonary Clinic,
• G. Papanikolaou Hospital, Thessaloniki

2
Disclosure Information

• Prof Zarogoulidis P Konstantinos
• I have no potential conflict of interest with the
  topics that I am going to discuss

3
General information about NSCLC I

• Accounts for the 80 of all lung cancers
• Main types
• adenocarcinoma (including BAC) 32-40
• squamous 25-30
• large cell 8-16

4
General information about NSCLC II

• Till lately there were obscure guidelines for the
  management of NSCLC
• Now there is a global attempt to tailor the
  management of the cancer according to the
  specific patients characteristics, such as the
  extent of the disease and a number of prognostic
  and predictive factors.

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Management of NSCLC according to the extent of
the disease
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Stages of NSCLC

• Stage Ia 13.1
• Stage Ib 22.7
• Stage IIa 0.6
• Stage IIb 6.8
• Stage IIIa 9.8
• Stage IIIb 19.7
• Stage IV 27.3

7
Definition of stage I

• A T1 or T2 tumor of the lung
• More than 2cm distant to the carina
• No nodal (N1 or N2) disease
• No metastatic (M1) disease

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Survival

• Combining the 2 largest published series, over
  1500 patients.
• Post-surgical survival
• Stage Ia 71
• Stage Ib 57

12

• All patients undergoing resection for stage I
  NSCLC (Ia and Ib) should have intraoperative
  systematic surgical mediastinal lymph node
  evaluation for accurate pathologic staging.

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Mo
Ia
?1?0 T2N0
Ib
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Which of the following is the best management
according to your decision for stage Ia and Ib?

• Surgery
• Surgery Chemotherapy
• Surgery Radiation
• Chemotherapy alone
• Radiation alone
• Chemotherapy Radiation
• Surgery Chemotherapy Radiation

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Surgery vs. other treatment modalities

• To date, there have been no large randomised
  trials evaluating surgical resection vs. other
  treatment modalities for Stage I NSCLC
• Evaluation of independent and combined modality
  data, however, do not support the routine use of
  neoadjuvant or adjuvant chemotherapy or
  irradiation in Stage I NSCLC

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Mo
Ia
?1?0 T2N0
Ib
Surgery
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Definition of stage II

• Stage IIa T1N1 cancers
• 1-5 of patients present with clinical stage IIa
• Stage IIb T2N1 and T3N0 cancers
• 15-25 of resected cancers

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Intraoperative staging

• Systematic lymph node sampling
• Routine biopsy of representative nodes from all
  lymph node stations
• Mediastinal lymph node dissection
• Removal of all lymph node bearing tissue in each
  nodal station.

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Mo
IIa
?1?1
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Which of the following is the best management
according to your decision?

• Surgery
• Surgery Chemotherapy
• Surgery Radiation
• Chemotherapy alone
• Radiation alone
• Chemotherapy Radiation
• Surgery Chemotherapy Radiation

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Adjuvant (postoperative) therapy (Stage II)

• Radiotherapy Reduces local recurrence, but
  offers no improved survival
• Chemotherapy Has a mild biologic effect. Adds
  approximately an additional 5 cure rate when
  given alone.
• Randomized adjuvant trials No survival benefit
  adding chemotherapy to radiotherapy.

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5-Year survival
Based on pathologic staging
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Surgery vs. surgery adjuvant RT
Randomised clinical trials in patients with
completery resected stage in NSCLC
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Adjuvant chemotherapy and radiation
P0.56 Keller SM, et al. N Eng J Med 2000 343
1217-22
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Mo
IIa
?1?1
Surgery
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Mo
I?b
?2?1 ?3?0
15-25 of resected cancers
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Which of the following is the best management
according to your decision?

• Surgery
• Surgery Chemotherapy
• Surgery Radiation
• Chemotherapy alone
• Radiation alone
• Chemotherapy Radiation
• Surgery Chemotherapy Radiation

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Mo
?Ib
?3?0
Surgery
CHT with Vinorelbinecisplatin Gemcitabineplatin
um analogues or Taxanes platinum analogues
Radiotherapy
Local recurrence
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Mo
I?b
?2?1
Surgery
CHT with Vinorelbinecisplatin Gemcitabineplatin
um analogues or Taxanes platinum analogues
CHT with Vinorelbinecisplatin Gemcitabineplatin
um analogues or Taxanes platinum analogues
Radiotherapy
Radiotherapy
Local recurrence
Distant metastasis
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Mo
IIIa
?1-3?2 T3N1
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Which of the following is the best management of
stage IIIa according to your decision?

• Surgery
• Surgery Chemotherapy
• Surgery Radiation
• Chemotherapy alone
• Radiation alone
• Chemotherapy Radiation
• Surgery Chemotherapy Radiation
• Induction chemotherapy

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Management of IIIa stage

• IIIA1 Nodal metastases found postoperative
  consider adjuvant radiotherapy which will reduce
  local recurrence but not improve survival
• IIIA2 Single station nodal metastases recognized
  intraoperative consider
• a) adjuvant radiotherapy to reduce local
  recurrence
• b) consider adjuvant chemotherapy alone
  preferable in a clinical trial
• c) combination a b

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Management of IIIa stage

• IIIA3 Mediastinal node metastases documented
  preoperatively (potentially resectable N2
  disease)
• Bi- or tri-modality therapy is better than
  surgery alone for locally advanced stage IIIA
  lung cancer
• Induction therapy

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5-Year survival
Based on pathologic staging
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Induction Therapy
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Induction chemotherapy plus surgery
Randomised Trials
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Significant milestones in lung cancer therapy
2000s
Increasing evidence for adjuvant chemotherapy in
early-stage NSCLC
Arriagada R, et al. N Engl J Med
200435035160Winton TL, et al. N Engl J Med
2005352258997Rosell R, et al. Lung Cancer
200549(Suppl. 2)s3 (Abs. Pr3)Strauss GM, et
al. J Clin Oncol 200624(Suppl. 18) 365 (Abs.
7007)
1930
1940
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1960
1970
1980
1990
2000
2010
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IALT studyadjuvant chemotherapy
100 80 60 40 20 0
Overall survival
Chemotherapy Control
Patients ()
HR0.86 (0.760.98) plt0.03
0 1 2 3 4 5
Years
At risk
The IALT Collaborative Group. N Engl J Med
200435035160
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Mo
I??a
?1-3?2
Surgery
CHT with Vinorelbinecisplatin Gemcitabineplatin
um analogues or Taxanes platinum analogues
CHT with Vinorelbinecisplatin Gemcitabineplatin
um analogues or Taxanes platinum analogues
Radiotherapy
Radiotherapy
Distant metastasis
Local recurrence
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Mo
I??a
T3N1
Surgery
CHT with Vinorelbinecisplatin Gemcitabineplatin
um analogues or Taxanes platinum analogues
CHT with Vinorelbinecisplatin Gemcitabineplatin
um analogues or Taxanes platinum analogues
Radiotherapy
Radiotherapy
Distant metastasis
Local recurrence
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Management of advanced NSCLC Stages IIIb IV
43
Mo
??Ib
T4N0 T4N1 T4N2 T1-4N3
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Which of the following is the best management
according to your decision?

• Surgery
• Surgery Chemotherapy
• Surgery Radiation
• Chemotherapy alone
• Radiation alone
• Chemotherapy Radiation
• Surgery Chemotherapy Radiation

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Stage IIIb

• At least 3 meta-analyses on the randomized trials
  have been performed
• Lung cancer collaborative group evaluated 11
  trials with cisplatin-based chemotherapy regimens
• Significant overall benefit of chemoradiotherapy
• 13 reduction in the risk of death
• Absolute benefit of 4 at 2 years and 2 at 5
  years (p0.005)

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Stage IIIb NSCLC
Concurrent vs. Sequential chemoradiotherapy

• Several phase III randomized trials of concurrent
  vs. sequential chemo-radiotherapy have revealed
• In the concurrent arm
• Improved median survival time (average of 15.7
  months vs. 14 months)
• Improved 2-year survival rates (35 vs. 23)
  French Cooperative Group Study ASCO Proc 2001
• Improved 5-year survival (15.8 vs. 8.9,
  p0.039) The West Japan Lung Cancer Group Study
  JCO 1999
• Increased toxicity acute esophagitis incidence
  of 26

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Prognostic factors in Stage IV NSCLC

• Performance status remains the most important
  factor
• Careful assessment is crucial to appropriately
  select patients for chemotherapy
• Benefits of therapy and therapeutic index best
  in ECOG PS 0-1 patients
• ECOG PS 3-4 are not candidates for chemotherapy
• Optimal approach in ECOG PS 2 remains
  controversial

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Advanced NSCLC

• Is survival improved with chemotherapy?
• Ten trials of platinum-based chemotherapy vs..
  BSC
• In all 10 trials, survival numerically better
  with chemotherapy vs. BSC
• In 6 of 10 trials, the survival advantage was
  statistically significant
• Four separate meta-analyses have all concluded
  that survival in advanced NSCLC is improved as a
  result of chemotherapy

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Standard regimes in advanced NSCLC

• Currently, outside a clinical trial, standard
  regimes must include a platinum (cisplatin or
  carboplatin) and
• Paclitaxel, docetaxel, gemcitabine, irinotecan or
  vinorelbine
• Non-platinum doublets or platinum-based triplets
  should be considered investigational in this
  setting
• Monotherapy is an option for special groups of
  patients (eg, elderly, poor PS)

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Duration of therapy in advanced NSCLC

• Chemotherapy is palliative
• Major palliative benefit occurs early (3-4
  cycles)
• All regimens/ agents have cumulative toxicities
• 1997 ASCO guidelines recommended 2-8 cycles in
  the absence of data from randomized clinical
  trials

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Significant milestones in lung cancer therapy
1990s
Platinum-based doublets based on new agents
established in first-line treatment of advanced
NSCLC
Platinum-based doublets (3rd generation)810
months
Median survival (months)
Cisplatin-based regimens68 months
BSC 24 months
1970s
1980s
1990s
1930
1940
1950
1960
1970
1980
1990
2000
2010
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Phase II studies new drugs cisplatin or
carboplatin
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Significant milestones in lung cancer therapy
1.0 0.8 0.6 0.4 0.2
1990s
Cisplatin/paclitaxel Cisplatin/gemcitabine Cisplat
in/docetaxel Carboplatin/paclitaxel
Chemotherapy for first-line advanced NSCLC
reaching a plateau in efficacyUrgent need for
new treatment options
Survival distribution function
0 5 10 15 20 25 30
Months
Schiller JH, et al. N Engl J Med 2002346928
1930
1940
1950
1960
1970
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1990
2000
2010
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Genetic Determinants of Pemetrexed (antifolate)
Activity

• In several phase II and III studies superior
  clinical activity in non-squamous histology
• Baseline expression of the TS gene and protein
  were significantly higher in squamous cell
  carcinoma when compared with adenocarcinoma.
  (Ceppi et al. Cancer 2006)
• Preclinical data indicate that high expression of
  TS correlates with reduced sensitivity to
  Pemetrexed. (Sigmond et al. Biochem. Pharmacol.
  2003 Giovannetti et al. Mol. Pharmacol. 2005)

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Significant milestones in lung cancer therapy
1.0 0.75 0.50 0.25 0
2003
Pemetrexed Docetaxel
Phase III study suggests equivalent efficacy for
pemetrexed and docetaxel in relapsed advanced
NSCLC
HR0.99 (95 CI 0.8, 1.2)
Survival distribution function
Hanna N, et al. J Clin Oncol 200422158997
0 5 10 15 20 25
Months
EUUS approvals
1930
1940
1950
1960
1970
1980
1990
2000
2010
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Mo
??Ib
?2?2 T4N0 T4N1 T4N2 T1-4N3
CHT with Vinorelbinecisplatin Gemcitabineplatin
um analogues or Taxanes platinum analogues or
Pemetrexedplatinum analogues
CHT with Vinorelbinecisplatin Gemcitabineplatin
um analogues or Taxanes platinum analogues or
Pemetrexedplatinum analogues
Radiotherapy
Radiotherapy
Local recurrence
Distant metastasis
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M1
IV
any T any N
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Which of the following is the best management
according to your decision?

• Surgery
• Surgery Chemotherapy
• Surgery Radiation
• Chemotherapy alone
• Radiation alone
• Chemotherapy Radiation
• Surgery Chemotherapy Radiation

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• Is there an optimal regiment for advanced NSCLC?
• Short answer NO

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M1
T4 ?3 ?2 ?1 ?0 ?1 ?2 ?3
CHT with Gemcitabineplatinum analogues or
Taxanes platinum analogues or
Pemetrexedplatinum analogues
Radiotherapy
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Management of NSCLC according to prognostic and
predictive factors
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Biomarkers for chemotherapy

• High RRM1 and ERCC1 expression is associated with
  longer survival after resection of early stage
  NSCLC (prognostic).
• High RRM1 and ERCC1 are predictors of lower
  tumour response rate and shorter survival for
  treatment with gemcitabine and cisplatin
  (predictive)
• Low ERCC1 expression is associated with survival
  benefit from adjuvant chemotherapy for NSCLC
  (predictive)
• These biomarkers have not been prospectively
  validated

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Test of interaction between ERCC1 and treatment
plt0.009

• For ERCC1 ve tumours
• 14-month benefit in overall survival for CT vs
  control
• 6-month benefit in overall survival for CT vs
  ERCC1 ve tumours

Olaussen KA, et al. N Engl J Med 200635598391
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Prognostic value of RRM1 ERCC1 expression (AQUA)
HR1.8 p0.02
NEJM 356 800, 2007
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RRM1 mRNA expression prognostic and predictive
factor
high RRM1
RRM1 as a Prognostic marker in Surgically
Resected NSCLC
low RRM1
RRM1 as a Predictive marker for Chemotherapy
Survival in NSCLC
low RRM1
regulatory subunit of ribonucleotide reductase
provides deoxyribonucleotides for DNA-synthesis
also for DNA-repair
high RRM1
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Question

• In patients with squamus carcinoma and high
  levels of ERCC1, which of the following
  combinations would you administrate?
• Gemcitabine cisplatin
• Docetaxel cisplatin
• Docetaxel gemcitabine
• Pemetrexed cisplatin

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Answer

• In patients with squamus carcinoma and high
  levels of ERCC1, which of the following
  combinations would you administrate?
• Gemcitabine cisplatin
• Docetaxel cisplatin
• Docetaxel gemcitabine
• Pemetrexed cisplatin

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Question

• In patients with squamous Ca with low levels of
  ERCC1 and RRM1, which combination therapy you
  would NOT administrate?
• Docetaxel cisplatin
• Docetaxel gemcitabine
• Docetaxel cisplatin anti-EGFR
• Pemetrexed cisplatin
• cd

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Answer

• In patients with squamous Ca with low levels of
  ERCC1 and RRM1, which combination therapy you
  would NOT administrate?
• Docetaxel cisplatin
• Docetaxel gemcitabine
• Docetaxel cisplatin anti-EGFR
• Pemetrexed cisplatin
• cd

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Question

• In patients with adenocarcinoma with low levels
  of ERCC1 and RRM1, which one would be the best
  choice of treatment?
• Docetaxel cisplatin
• Docetaxel gemcitabine
• Docetaxel cisplatin anti-EGFR
• Pemetrexed cisplatin
• All the above

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Answer

• In patients with adenocarcinoma with low levels
  of ERCC1 and RRM1, which one would be the best
  choice of treatment?
• Docetaxel cisplatin
• Docetaxel gemcitabine
• Docetaxel cisplatin anti-EGFR
• Pemetrexed cisplatin
• All the above

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Question

• In patients with adenocarcinoma with high levels
  of ERCC1 and RRM1, which one would be the best
  choice of treatment?
• Docetaxel cisplatin
• Docetaxel gemcitabine
• Docetaxel cisplatin anti-VEGFR
• Pemetrexed cisplatin

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Answer

• In patients with adenocarcinoma with high levels
  of ERCC1 and RRM1, which one would be the best
  choice of treatment?
• Docetaxel cisplatin
• Docetaxel gemcitabine
• Docetaxel cisplatin anti-VEGFR
• Pemetrexed cisplatin

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More effective treatment strategies are needed

• Chemotherapy in advanced NSCLC has reached a
  plateau
• Triplet chemotherapy regimens do not appear to
  improve survival substantially, and are
  associated with increased toxicity1
• Novel chemotherapy combinations are not likely to
  confer substantial improvements in survival
• Chemotherapy results in unacceptable levels of
  toxicity for patients with poor PS (gt2), thus
  outweighing potential improvements in survival2
• Quality of life and symptom improvement are
  crucial aspects to consider in lung cancer
  patient management

1Delbaldo C, et al. JAMA 200429247084 2National
Comprehensive Cancer Network (NCCN) clinical
practice guidelines in oncology. Non-small cell
lung cancer, version 1 2007. Available at
http//www.nccn.org/professionals/physician_gls/PD
F/nscl.pdf
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Conclusions

• An increased understanding of tumour biology has
  led to the rational development of novel agents
  that target specific tumorigenic processes
• In recent years, research effort has focused on
  agents targeting the VEGF and EGFR pathways
• The preclinical and clinical results achieved for
  agents targeting VEGF and EGFR to date have set a
  precedent for targeting specific molecular targets

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Significant milestones in lung cancer therapy
2004
Tarceva significantly prolongs survival in
relapsed advanced NSCLC Only EGFR inhibitor
proven to provide an overall survival benefit in
this disease
EUUS approvals
Shepherd FA, et al. N Engl J Med 200535312332
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1940
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2000
2010
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Concurrent administration of erlotinib and CHT
did not improve overall survival
TALENT Erlotinib cisplatin/gemcitabine
TRIBUTE Erlotinib carboplatin/paclitaxel
Gatzemeier et al. JCO 2007 Herbst et al. JCO 2005
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Possible explanation pharmacodynamic antagonism
Erlotinib docetaxel
Docetaxel Erlotinib
Apoptosis
Apoptosis
M
M
G2
G2
Cell cycle
Cell cycle
G1
G1
S
S
Apoptosis
Docetaxel induces M-phase arrest and apoptosis,
enhanced by the anti-cell survival effect of
erlotinib
Erlotinib induces G1 arrest, which can block the
M-phase activity of docetaxel
Gandara D, et al. Clin Cancer Res 200511(Suppl.
13)5057s62s
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TALENT gemcitabine cisplatin plus continuous
Tarceva improved survival in never smokers
1.00 0.75 0.50 0.25 0.00
Tarceva (NS)
Tarceva (F/CS)
Placebo (NS)
Placebo (F/CS)
Survival distribution function
0 100 200 300 400 500 600
Study day
NS never smokedF/CS former/current smokerNR
not reached
1Gatzemeier U, et al.J Clin Oncol 200523(Suppl.
16S Pt I)627s (Abs.7028)
80
TRIBUTE carboplatin paclitaxel plus continuous
Tarceva improved survival in never smokers
1.0 0.8 0.6 0.4 0.2 0
Tarceva Placebo
Survival rate
0 5 10 15 20 25
Months on study
Miller V, et al. J Clin Oncol 200422(Suppl.
14S)628 (Abs. 7061)
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EGFR mutations in NSCLC

• EGFR mutations are over-represented in
  responders to EGFR inhibitors
• These mutations include
• exon 19 small in-frame deletions
• exon 21 point mutationse.g. EGFR L858R
• Mutations known to cause resistance to
  first-generation EGFR include
• exon 20 in-frame insertions
• exon 20 point mutations (e.g. T790M)

Extracellular ligand-binding domain
Deletions (vIII) 1
TM
TM
Exon 18
19
20
Tyrosine kinasedomain
21
22
23
24
Sharma et al. Nature Rev Cancer 20077169 Ji et
al. Proc Natl Acad Sci USA 20061037817 Stephens
et al. Nature 2004431525
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FLEXStudy design
Maintenance
Cetuximab until PD or intolerable toxicity
Chemotherapy Cetuximab
NSCLCwet IIIB/IV EGFR- expressing
Chemotherapy
Pirker R et al. J Clin Oncol 2008, 18S (abstract
3)
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Question

• What are the eligibility criteria for the
  administration of anti-EGFR biological agents?
• Performance status
• Gender
• Histology
• Smoking status
• Ethnicity
• All the above

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Answer

• Performance status
• Gender
• Histology
• Smoking status
• Ethnicity

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Lessons from FLEX General findings

• EGFR is clinically relevant in NSCLC
• EGFR-targeted antibodies in combination with
  1st-line chemotherapy do work in advanced NSCLC
• Survival benefit can be achieved in advanced
  NSCLC
• Acceptable toxicity profile of cetuximab
• Step-wise progress but no huge leaps

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Lessons from FLEX Prognostic factors

• FLEX demonstrated the following prognostic
  factors
• Performance status
• Gender
• Histology
• Smoking status
• Ethnicity ?
• Patient populations have to be considered when
  comparing different trials

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What did we learn from FLEX?

• Cetuximab improves survival when added to
  first-line chemotherapy in advanced NSCLC
• EGFR is a clinically relevant target in advanced
  NSCLC
• Predictive factors
• Rash ?
• Others not (yet ?) available

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Angiogenesis Plays a Critical Role in Tumor
Development
Somatic mutation
Smallavascular tumor
Tumor secretion of proangiogenic factors
stimulates angiogenesis
Rapid tumor growth and metastasis
Angiogenic inhibitors may reverse this process
91

• Tumour growth beyond 1mm3 requires new blood
  vessel formation (neo-angiogenesis)
• Intense basic and translational research in the
  field of tumour-neo-angiogenesis over the past
  few decades has led to incorporation of
  angiogenesis inhibitors into the cancer treatment
  armamentarium.

92
Question

• What are the eligibility criteria for the
  administration of anti-VEGFR biological agents?
• Performance status
• Gender
• Histology
• Smoking status
• Ethnicity
• All the above

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Answer

• Histology

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E4599 trial improvement in PFS when Avastin is
added to standard first-line therapy
1.0 0.8 0.6 0.4 0.2 0
CP Avastin CP
HR0.66 (0.570.77) plt0.001
Probability
4.5
6.2
0 6 12 18 24 30
Time (months)
Sandler A, et al. N Engl J Med 2006355254250
95
BR.21 and E4599 trials overall survival
1.0 0.8 0.6 0.4 0.2 0
Carboplatin/paclitaxel Avastin Carboplatin/pacli
taxel
Shepherd FA, et al. N Engl J Med
200535312332 Sandler A, et al. N Engl J Med
2006355254250
HR0.79, p0.003
Probability
10.3
12.3
0 6 12 18 24 30 36 42
Time (months)
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Mo
M1 (any T any N)
T4 ?3 ?2 ?1 ?0 ?1 ?2 ?3
Surgery
CHT with Gemcitabineplatinum analogues or
Taxanes platinum analogues or
Pemetrexedplatinum analogues Biological
agents ANTI-EGFR Tarceva, Cetuximab or
ANTI-VEGFR Avastin, VEGF-Trap
CHT with Gemcitabineplatinum analogues or
Taxanes platinum analogues or
Pemetrexedplatinum analogues Biological
agents ANTI-EGFR Tarceva, Cetuximab or
ANTI-VEGFR Avastin, VEGF-Trap
Radiotherapy
Radiotherapy
Vaccines?
Local recurrence
Distant metastasis
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Which is the best treatment?
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