Molecularly Targeted Therapy in Lung Cancer: Hype, Hope, Myths and Reality

1
Molecularly Targeted Therapy in Lung Cancer
Hype, Hope, Myths and Reality

• Martin J. Edelman, MD
• University of Maryland Greenebaum Cancer Center

2
Advanced NSCLC The State of the Art
3
What is Targeted Therapy?

• If we use the analogy of pesticides empiric
  therapy would be Raid while targeted therapy is
  the Roach Hotel.
• Dr. David Gandara
• A smart bomb versus a cluster bomb.
• Dr. Nevin Murray

4
Targeted Therapy A definition

• Drugs targeted at pathways, processes and
  physiology which are uniquely disrupted in cancer
  cells
• Receptors
• Genes
• Angiogenesis
• Tumor pH
• Get real, these pathways etc. are not so
  distinct.

5
Six Essential Alterationsin Cell Physiology in
Malignancy
Hanahan Weinberg, Cell 10057 (2000)
Targets for classical drugs?
Targets for novel drugs?
6
Myth 1 Targeted therapy is new (or what were we
thinking?)

• DNA is not a bad target.
• Tubulin is a very good target.
• Specific receptor targeting tamoxifen etc.
• Sometimes you design for one target and hit
  another estramustine.

7
Survival by B-Tubulin III Phenotype In
Taxane-treated NSCLC


8
Better Identify and Utilize the Drugs We Already
Have GILT
Standard Arm Docetaxel/Cisplatin
RANDOMIZE
Genomic Arm Beta tubulin
ERCC1 Regimen - -
Doc/CDDP -
Doc/Gem -
Gem/CDDP
Gem/CPT-11
9
New Anti-tubulins Epothilones
Computer model of beta-tubulin
mutations Taxane Epothilone
Giannakakou et al. Proc. Natl. Acad. Sci. USA
2000, 97, 2904
10
Myth 2 Imatinib Mesylate is the Proof of
Principle for these Drugs

• Imatinib Mesylate targets the bcr-abl TK very
  specifically.
• Bcr-abl is the root cause of CML, essentially a
  monogenetic disease

11
Imatinib Mesylate The Exception that Proves the
Rule
Time to Relapse in Patients with Myeloid or
Lymphoid Blast Crisis Who Had a Response to STI571
Probability of Relapse

• Orange arrows indicate patients still enrolled
  in the study and in remission at the
• time of the last follow-up
• White arrows indicate the day on which patients
  were removed from the study

NEJM 344 1038, 2001
12
Targeted Therapy in the Common Solid Tumors The
Reality
13
But what about Trastuzumab?

• Degree of benefit is relatively modest.
• Population is enriched by Herceptest.
• Drug would have lt10 RR if entire population
  treated

14
Why the Difference?

• Most solid tumors have complex genetics, not one
  or two hits but 20. The more advanced the tumor,
  the greater the heterogeneity.
• Molecular heterogeneity.
• Hitting one narrow target is not likely to be
  that beneficial.

15
Tumors Progressively Make More Angiogenesis
Stimulators
bFGF
bFGF VEGF
bFGF VEGF PDGF
bFGF VEGF PDGFIL-8
Relf et al., Cancer Research, 57953, 1997
16
How to hit the target

• If you know the target, and there is only one
  target you can be very specific.
• If you dont really know or its a really big
  target, a larger weapon may be needed.

17
But all is not lost

• Return to the fundamental assumption.
• Targeted therapy works when you can identify and
  validate the target.
• Need to enrich the population for the target
  Herceptin
• May need to hit more than one target
• Importance of trial design

18
Leveraging your opponents weight, or how targeted
therapy can work with other treatments and toss
the opponent out of the ring
19
Arachidonic Acid Metabolism
Cell membrane phospholipids
Sphingomyelin
Neutral sphingomyelinase
Arachidonic Acid
Ceramide
COX 1,2
5-HPETE
12-HPETE
15-HPETE
Celecoxib
5LO
Prostaglandins
12HETE
15HETE
5HETE
Zileuton
LTA4
LTB4
LTC4
LTD4
LTE4
20
CALGB 300203Gemcitabine/ Carboplatin
Eicosanoid Modulators
PD
Off study
Carboplatin AUC 5.5 Gemcitabine 1000
mg/m2 Zileuton 600 mgpo qid
Stage IIIB (pleural effusion), IV NSCLC PS
0-1 Adequate organ fcn
SD, PR CR
Eicosanoid modulator until progression
Carboplatin AUC 5 Gemcitabine 1000
mg/m2 Celecoxib 400 mg po bid
Carboplatin AUC 5.5 Gemcitabine 1000
mg/m2 Zileuton 600 mgpo qid Celecoxib 400 mg po
bid
Correlates IHC, CYFRA VEGF levels
MJ Edelman, PI
21
Issues in Trial Design

• How to screen drugs
• Identify logical targets
• Identify whether target acquired and neutralized.
• Identify the population with the target.
• Was the target important.
• Beware collateral damage.

22
The Phase I Trial

• Traditionally, based upon the idea that good
  medicine tastes bad.
• A little is good, more is better.
• Clearly false
• If you know the target, you can find the dose.
• Demonstrate target inhibition
• Downstream effects
• Pharmacokinetic parameters

23
Molecular Target Measurements

• Enzyme activity measurements
• e.g., DT-diaphorase, P450s
• Gene mutation status
• e.g., Ras, p53
• Protein levels
• e.g., Thymidylate synthase
• mRNA levels
• e.g., Microarray
• Other
• e.g., Phosphorylation status of a protein

24
Clinical Trial Design WithBiologic Endpoints

• Evaluate for target effect as active
  concentration is approached
• Expand cohort when any biologic effect seen
• reproducibility of effect
• importance of well defined confidence interval
• Escalate dose
• until maximal expected effect is seen
• until maximal effect occurs in maximal fraction
  of patients
• Additional steps to confirm
• effect is maximal
• rate of effect is maximal

25
Phase I of Targeted Agent Use of Enzyme
Inhibition to Determine Dose
The Oncologist, 2002 7401-409
26
Phase I Trial of a Targeted Agent Use of Target
Inhibition to Determine Dose
27
Trial Design The Value of the Phase II Study

• Early optimism led to the assumption that one
  could go directly from Phase I to III.
• Unless a home run is assured, not a good idea.
• Decisions made in haste are repented at leisure
• Phase II designs with go and no go endpoints.
• New Phase II designs
• Randomized Phase II
• Enrichment designs
• Discontinuation designs

28
Powering the Phase II Trial

• Response rate is a crude intermediate marker.
  The various Phase II approaches are adaptable to
  any endpoint.
• Power for TTP, survival or a molecular marker.
• But whatever you do, identify an endpoint.

29
False Positive Trials

• Patient self-selection
• Physician selection incentives for entry
• Assessment of responses the power of wishful
  thinking
• And of course, inadvertent enrichment for the
  target

30
Phase III Trials The Problem of Molecular
HeterogeneityImpact on Clinical Trials Outcome

• Histologic diagnosis remains a key eligibility
  criterion.
• Tumors with indistinguishable histology
  demonstrated quite different responses to
  therapy.
• Do solid tumors possess different destinies
  based on their molecular profiles?

31
Anaplastic Oligodendroglioma

• Proportion of genetic subtypes differ in
  different cohorts of patients.
• in recurrent disease 90 1p LOH
• in newly dxd disease 60 1p LOH
• Genetic subtype is age dependent.
• 1p LOH more common in young pts
• older pts predominate in trials

32
Molecular Subtypes of Anaplastic
Oligodendrogliomas Implication for Patient
Management at DiagnosisY. Ino et al. Clin
Cancer Res 7839,2001
33
False Negative Trials

• Overestimation of a therapeutic effect due to
  enrichment of phase II studies for a treatment
  sensitive subtype.
• Dilution of a beneficial effect in responding
  patients by large numbers of nonresponding
  patients.
• Reversal of a beneficial effect in responders by
  negative effect in nonresponders.

34
Identify Specific Subsets

• The promise of genomic and proteomic technology.
• This enriches the population.
• We already do this
• PML
• CML
• Breast cancer

35
Pharmacogenomics
36
Targeted Therapy The Future

• Modern biology has identified a host of new
  potential targets for cancer therapy
• Drugs interacting with these targets are
  available.
• The benefit of these agents is dependant upon the
  criticality of the target. More than one target
  may need to be inhibited.
• New agents may tip the balance when combined
  with chemotherapy, radiation.

37
Targeted Therapy The Future (contd)

• The design and careful assessment of new agents
  in Phase I and II trials will result in better
  understanding of the potential population and
  magnitude of benefit for any particular agent.
• Phase II trials should guide the decision for
  Phase III.
• Phase III trials with a good chance of success
  can then be accomplished.