Established first, second and third line therapies base

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Targeted Therapies in Lung Cancer

• Martin J.Edelman, MD
• University of Maryland

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Thoracic Oncology Not Feeling Guilty Any More

• Established first, second and third line
  therapies based upon solid evidence.
• Increasing cure rates in stage III disease.
• Dramatic benefit from platinum based chemotherapy
  in the adjuvant treatment of stage Ib-IIb disease.

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Current Challenges

• Targeting therapies
• Current drugs
• Current targeted drugs
• Moving forward issues in future trials
• Tumor heterogeneity
• Populations heterogeneity

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Martha Stewart Investment Advice or New Agents in
Development
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EGFR Family of Tyrosine Kinases
Adapted with permission from Ritter CA, Arteaga
CL. Semin Oncol. 200330(suppl 1)3-11.0
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Iressa Not Exactly a Homerun
INTACT-2
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rhuMAb VEGF (Recombinant Humanized Monoclonal
Antibody to VEGF)

• Humanized to avoid immunogenicity (93 human, 7
  murine).
• Recognizes all isoforms of vascular endothelial
  growth factor, Kd 8 x 10-10 M
• Terminal half life 17-21 days

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Randomized Phase II Trial of Rhumab VEGF
PASCO 2000 1896
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ECOG4599 Phase III Trial
Stage IV NSCLC -Non-squamous histology - No
CNS - No hemoptysis - PS 0-1
Carboplatin/Paclitaxel/anti-VEGF
Carboplatin/Paclitaxel
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ECOG 4599
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VEGF
VEGF as a target for the tratment of Lung Cancer
TUMOR
Ineffective Vasculature
High Interstitial Pressure
Effective Vasculature
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Anti-VEGF
VEGF as a target for the tratment of Lung Cancer

TUMOR
Ineffective Vasculature
Low Interstitial Pressure
Effective Vasculature
Jain et al, Nature Medicine, 2004
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Why the Disappointment Problems with Trial Design

• Unjustified approach combination not really
  justified by Phase II data.
• Phase I/II trials frequently utilize
  unrepresentative populations.
• Unrecognized tumor heterogeneity
• Unrecognized population heterogeneity

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Hype and Hope The Problem of Single Center
Studies
Langer et al. J Clin Oncol. 1995131860-1870.
Langer et al. ECCO, 2001 Natale et al. Semin
Oncol. 199623(6 suppl 16)51-54. Belani et al.
PASCO, 1998 Schiller et al. PASCO 2000
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Referral Populations

• Referral populations inherently do better.
• Possible reasons
• Socioeconomics
• Nutrition
• Inherent biology

JNCI 2001
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Molecular Heterogeneity and Trial Outcome

• Cancer has two genetic subtypes
  indistinguishable by histology.
• What if there are subtypes with variable
  sensitivities to therapy?

R.A. Betensky et al. J Clin Oncol 202495,2002
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Hypothetical TrialSample Size Required for 80
Power
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Identifying the Target Population

• Refined classification of tumors based upon new
  methods of evaluating tumor DNA, RNA, protein.
• Novel approaches with radiopharmaceuticals
• Targeting specific patient populations.

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Identify Specific Subsets

• The promise of genomic and proteomic technology.
• We already do this
• PML
• CML
• Breast cancer
• Need to limit the markers

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EGFR Mutations
NEJM 2004
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CALGB 30406 Randomized Phase IIStudy Trial
Design
Chemotherapy naive patients with stage III/IV
adenocarcinoma or BAC who are never or light
former smokersECOG PS 0-1
Daily oral erlotinib
Daily oral erlotinib 6 cycles
carboplatin/paclitaxel
Daily oral erlotinib
Daily oral erlotinib

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

never smoker ? 100 cigarettes/lifetime light
former smoker quit ? 1 year ago and ? 10 pack
years
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The TARGET Trial Trial to Assess Response to
Gefitinib in EGFR-mutated Tumors
S C R E E N I N G
M U T A T I O N
Enroll to Treatment (up to 35)
Positive
Eligible Patients Enter
Negative
Off-Protocol
Patients eligible to be screened adenocarcinoma,
female, non-smoker, Japanese/Chinese Primary
endpoint RR (estimate 60) Dana Farber/MGH
P.Janne
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Molecular correlates of drug response

• Beta-tubulin isoforms predict response to
  taxanes, vinca alkaloids.
• ERCC1 predicts response to platinum agents.

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Isolation of Circulating Cancer Cells
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Target Identification in Circulating Cancer Cells
ERCC1
Her2-neu
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Continual Reassessment Study Design

R E GiSTER
Marker A Marker B -
- A/B -
A/C - B/C
C/D
Marker A Marker B -
- A/B -
A/C - B/C
C/D
Resampling
(every 21 days)
Marker A- marker of resistance to drug A Marker B
marker of resistance to drug B
Potential agents Carboplatin, paclitaxel,
gemcitabine, CPT-11, Premetrexed
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Rhenium Re 188 P2045
Re-188 P2045
Tc-99m 2045
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Scintigraphic images of prostate tumor bearing
mice 70 min 24 hrs post injection of
99mTc-HPMA copolymer-RGD4C/RGE4C conjugates.
70 min
70 min
24 hrs
24 hrs
TUMOR
TUMOR
LIVER
LIVER
KIDNEY
KIDNEY
BLADDER
BLADDER
HPMA copolymer-RGE4C conjugate
HPMA copolymer-RGD4C conjugate
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The fault may not be in the tumor , but in the
patient

• Boys are different from girls.
• Political correctness aside, there are ethnic
  differences in toxicity and outcome.
• Heterogeneity within specific populations may be
  considerable.

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Cancer Deaths Women
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Gender Differences and Prognostic Markers
ASCO 2004, 7008
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Treatment Outcomes Female vs. Male
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Pharmacogenomics
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Japan-SWOG Common Arm Study
ASCO 2004 7007
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New Drug Development Traditional Algorithm
Phase I Pk, pd
Preclinical
Phase II
Phase III
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New Drug Development An Algorithm
Phase I w. other agents XRT
Clinic Phase I trial -pk, pd -assessment of
targeting
Phase III

• Phase II defined populations
• required correlative studies
• Dose ranging
• Randomized Phase II

Lab -preclinical w.other agents -XRT -development
of assays -define and redefine mechanism Imaging S
tatistics
Alternative schedules
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Conclusions

• Current therapy of advanced NSCLC is beneficial
  but limited.
• We still do not understand current, validated
  agents.
• Trials of targeted agents will need to
  incorporate assessment of the target into the
  trial. Targeted agents may be less effective
  overall.
• Successful future trials will need to be targeted
  and assessed for specific populations.