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Targeted Drug Development: Wrong Turns and Blind Alleys On The Road to Success. Janet E. Dancey, MD Investigational Drug Branch Cancer Therapy Evaluation Program National Cancer Institute March 3, 2004.

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targeted drug development wrong turns and blind alleys on the road to success

Targeted Drug Development: Wrong Turns and Blind Alleys On The Road to Success

Janet E. Dancey, MD

Investigational Drug Branch

Cancer Therapy Evaluation Program

National Cancer Institute

March 3, 2004

how have we approached targeted agent development how should we approach targeted agent development

How have we approached targeted agent development?How should we approach targeted agent development?

phase iii trials results
Phase III Trials Results

Agent

Tumor

Selection

Combo

Results

Trastuzumab

Breast

Y

Y

Positive

Imatinib

CML - CP

Y

N

Positive

Gefitinib

NSCLC

N

Y

Negative x 2

Erlotinib

NSCLC

N

Y

Negative x 2

Cetuximab

Colorectal

SCCHN

Y

Y

Y

Y

Positive (Phase 2)

Negative

Bevacizumab

Breast

Colorectal

N

N

Y

Y

Negative

Positive

SU5416

Colorectal

N

Y

Negative

R115777

Colorectal

Pancreas

N

N

N

Y

Negative

Negative

G3139

Melanoma

N

Y

Negative

ISIS 3521

NSCLC

N

Y

Negative

Marimastat

SCLC

N

N (post Rx)

NegativeX2

Prinomastat

NSCLC

N

Y

Negative

BAY 12-9566

Pancreas

N

N

Negative

what we know entering the clinic
What we know entering the clinic
  • From clinical investigations
    • Expression of the target in human malignancy
      • What the samples?
      • Prognostic importance?
  • From non-clinical models
    • Target Credentials
      • Types of models?
  • From pre-clinical investigations of inhibitors
    • “Druggable” target
      • Agents had favorable pharmacology and toxicity
      • Inhibition of the target
      • Inhibition of the pathway
      • Inhibit tumor cell growth/induction of apoptosis
      • Enhance chemotherapy and radiotherapy antitumor effects
what we often don t know
What we often don’t know
  • Molecular epidemiology of the target in the proposed study of population
  • The role of the target in pathophysiology of human cancers
  • Effectiveness of the agent(s) on target inhibition in human cancers
  • The molecular phenotype predictive of activity
  • Interactions with chemotherapy and radiation in human cancers
what we knew before the phase iii trials were initiated selected approved agents
What we knew before the Phase III trials were Initiated:Selected Approved Agents
slide7

What we knew before the Phase III trials were Initiated:Selected Unapproved Agents

development of imatinib mesylate
Development of Imatinib Mesylate

Phase I CML

Phase II

Phase III

Positive - Approved1st Line

Phase 1 CML

Toxicity

PD (WC)

Positive -Approved(Relapse)

Phase I GIST

Phase II

Phase III (Assessing dose)

Phase 1 CML

Toxicity

Positive - Approved

Role to be defined

Phase II

Other tumors

  • Dermatofibrosarcoma protuberans
    • T(17;22)(q22;q13) fuses collagen gene to PDGFR gene
    • 2 patients responded, 1 with sustained PR
  • SCLC 0/19 responses
    • Only 28% (4 patients) were c-kit positive
development of vegf and rtk inhibitors
Development of VEGF and RTK Inhibitors

Phase I Bevacizumab

Phase II

Phase III

Positive

Approval

PK

No ORR

Toxicity – HTN, proteinuria

Randomized with CT in CRC

Single agent

MBC

Randomized with CT in NSCLC

Toxicity bleeding

Single Agent RCC

Toxicity – HTN, proteinuria

GI perforation

Negative

Phase III

?

Phase III

?

Phase III

Negative ABANDONED

Phase I SU5416

Phase II/III

PK

Toxicity – HA, N/V

No ORR

With CT in CRC

SU11248

Phase I SU6668

Phase II

ABANDONED

Phase I PTK/ZK

Phase II

Phase III

PK

Toxicity – HTN, proteinuria, bleeding

No ORR

PD- DCE-MRI

Phase I ZD6474

Phase II

development of egfr is in nsclc

Positive

Approval

Phase I gefitinib

NSCLC Phase II

Negative

Phase I/II Combination

Phase III

Expanded Access Program

ORRs in phase I

PK, toxicity, PD in skin supported phase II doses/schedule

?

Phase I erlotinib

NSCLC Phase II

Phase III

Negative

Phase III

Phase I Combination

No ORR’s in phase I

PK, MTD supported phase II dose/schedule

Development of EGFR-Is in NSCLC

Phase I cetuximab

Phase I Combination

Phase II Combination

X

Phase I PKI166

Phase I CI1033

Phase II

Phase I GW572016

Phase I EKB569

why have these trials failed to show a difference
Why have these trials failed to show a difference?
  • Was it the patient population?
    • “Three drugs don’t work better than two drugs in advance NSCLC patients”
    • EGFR driven NSCLC is a small subset of NSCLC
  • Was it concurrent administration with chemotherapy?
    • Overlapping sensitivities
    • Antagonism
  • Was it the agents?
    • Effectiveness of target inhibition
      • Delivery to tumor
      • Intracellular uptake
      • Target modulation
phase 2 single agent egfr i studies
Phase 2 Single Agent EGFR-I Studies

1Fukuoka et al, J Clin Oncol 2003; 2Kris et al, JAMA 2003; 3Perez-Soler P ASCO, 2001; 4Shepherd et al J Clin Oncol 2002

ideal 1 factors associated with an objective response to gefitinib by multivariate analysis

What we’ve learned about activity in patients

IDEAL 1: Factors Associated with an Objective Response to Gefitinib by Multivariate Analysis

Fukuoka et al, J Clin Oncol 21:2237-2246, 2003

response rates by sub groups in ideal 2
Response Rates By Sub-GroupsIn IDEAL 2

Kris et al, JAMA 290:2149-2158,2003

intact 1 and 2 demography
INTACT 1 and 2: Demography

Placebon=345

Placebon=363

ZD1839500 mg/dayn=347

ZD1839250 mg/dayn=345

ZD1839 500 mg/dayn=365

ZD1839250 mg/dayn=365

38.6/61.4

Female/male, %

Squamous

Adenocarcinoma

Mixed

Bronchoalveolar

Undifferentiated

Large-cell

27.9/72.1

28.8

43.3

2.7

1.1

11.5

11.5

23.3/76.7

32.1

48.5

1.4

0.8

9.3

7.7

27.8/72.2

29.2

46.6

1.4

0.3

11.8

8.8

40.1/59.9

42.3/57.7

16.7

57.9

2.9

2.9

11.5

7.2

20.3

55.7

2.3

2.6

9.6

8.7

19.4

51.9

1.7

3.2

11.3

11.0

ODAC September 2002

sample sizes for a trial of a targeted agent in a unselected study population
Sample sizes for a trial of a targeted agent in a unselected study population

Shading = number of patients required to be randomized

Dancey and Freidlin, Lancet 362:62-64, 2003

criteria for go no go for phase iii study
Criteria for Go/No Go for Phase III Study
  • Molecular epidemiology of target
    • known/not known?
  • Predictive marker/profile
    • known/unknown?
  • Assay to select patients
    • available/not available
  • Proof-of-Target/Pathway inhibition
    • shown/not shown
  • Anti-tumor activity in early studies
    • seen/not seen?
reasons for limited use of biomarkers to date
Reasons for Limited Use of Biomarkers to Date
  • Target not known
  • Assay(s) not available
  • Assays/their interpretation not standardized
  • Effect of agent on target not sufficiently characterized
  • Additional resources, costs required for specimen collection and analysis not available
    • Sample size per cohort (may) need to be greater to observe dose effect
    • Difficult to obtain serial biopsies of tumor
    • Relevance of “surrogate tissue” (e.g. PBMC) unclear
phase 1trial assessment of target effects requirements
Phase 1Trial Assessment of Target Effects - Requirements
  • Known association of target effect and tumor activity
  • Well-characterized assay
      • Optimal dose/concentration/schedule
      • % change in target or target level associated with efficacy
      • Concentration required for target effect
      • Time course for effect on target, duration, recovery
      • CV of target measurements
      • Target effect on tumor vs other tissues (eg PBMC, Skin, Buccal)
  • Usual target values and variability in human tissue known
    • (Tumor and/or surrogate)
  • Patients’ tumors must have relevant target
  • Commitment from investigators/patients for tissue
      • mandatory requirement (just like PK)
      • assess adequacy of specimen at time of biopsy
      • on-treatment assessment should be earlier rather than later
dose escalation study identifying biologically effective dose
Dose Escalation Study Identifying Biologically Effective Dose
  • Preclinical data allow determination of dose increments, target sampling time, desired target responses
  • Eligible patients have tumor with target
    • Escalate in cohorts of 3 if no more than 1 “biological effect”
    • If at least 2 “biological effects” expand cohort to 6
    • Identify dose with at least 5 of 6 “biological effects”
  • .96 probability of dose  for dose with < 40% target rr
  • at least .89 probability of halting dose  for a dose associated with at least 90% “target response” rate
phase 2 designs of targeted agents critical questions
Phase 2 Designs of Targeted Agents – Critical Questions
  • Should patients be pre-selected?
    • Is there a marker predictive of anti-tumor effect?
      • Strength of supporting data
      • Robustness of assay
    • Is predictive marker frequently expressed?
    • Is the predictive marker consistent across tumor histologies?
  • Is the likely anti-tumor effect to be tumor regression or tumor stabilization?
phase 2 trials of targeted agents
Phase 2 Trials of Targeted Agents

Yellow = Agents receiving FDA approval based on these RRs

a caveat target vs biological effect vs clinical efficacy
A Caveat: Target vs Biological Effect vs Clinical Efficacy
  • Selection criterion/criteria may be difficult to identify
  • Target and target effect may be necessary but not sufficient for clinical activity
    • Target presence does not always correlate well with activity
      • VEGF and bevacizumab
      • EGFR and ZD1839
    • Target effect does not always predict clinical activity
      • Proteasome inhibition vs tumor response
      • O6BG inhibition vs increased sensitivity to alkylator
      • Rapamycin inhibition of phosphorylation of 4E-BP1 vs decreased proliferation
  • Patient enrichment can be by selecting based on markers of activity or eliminating based on markers of inactivity
slide24

Phase 2 Trial Design – Histologically Defined and Molecularly Defined Patient Population

Initial Strata

Initial Screen

Outcome

Marker Present

Objective Tumor Response

Histology

Marker Absent

  • Trial is designed to assess activity in both strata or only +marker cohort
    • (depends of strength of supporting data and resource availability)
  • In the absence of historical data for marker+ subset, may have to randomize to assess time to progression endpoints or develop a surrogate marker of drug effect in the setting of stable disease
phase 2 trial molecularly defined patient population
Phase 2 Trial – Molecularly Defined Patient Population

Initial Screen

Initial Strata

Outcome

Histology A

N=15/30

Marker Present

Histology B

N=15/30

Objective Tumor Response

Histology C

N=15/30

  • Trial is designed to assess activity in molecularly defined cohort
  • If relevance of marker across histologies is uncertain, assess activity within histologies with two-stage design and close stratum early for inactivity
  • In the absence of historical data for subset, may have to randomize to assess time to progression endpoints or develop a surrogate marker of drug effect in the setting of stable disease
summary for phase 2
Summary for Phase 2:
  • Patient selection to enrich for tumor response is the most efficient strategy
  • Alternative endpoints for response remain problematic
    • None proven valid
    • Before using a non-validated endpoint in phase 2 consider:
      • Would “negative” trial be sufficient to stop development?
      • If no (i.e. would proceed to phase 3 anyway) why bother with phase II?
slide27

Phase 3 Trial – Histologically Defined and Molecularly Defined Patient Population

Randomization

Second Selection

Outcome

Initial Selection

Standard Rx

Histology/Stage

Marker Present

Survival

Experimental Rx

Marker Absent?

(Target Agent or

Standard + Target)

  • Trial designed to assess active in the marker+ group
    • both marker +ve and –ve groups could be assessed for effect independently but issues of size of the trial, power, likelihood of benefit should be considered
  • Marker assessment could be done prospectively or retrospectively if prospectively planned analyses and collected specimens
slide28

Phase 3 Trial – Molecularly Defined Patient Population

*All patients have similar stage of disease

Initial Selection

Strata

Randomization

Outcome

Standard Rx

(for histology

stage)

Histology A

Marker Present

Survival

Histology B

Experimental Rx

Histology C

(Target Agent or

Standard + Target)

what have we learned from phase 3 clinical trials with agents
Targeted anti-cancer therapy works (sometimes);

Target is absent or biologically irrelevant

Redundant pathways

Tumor cells molecular profiles evolve

Target mutation, overexpression, compensatory pathways

Single agent is unlikely to confer clinical benefit

Exception: Disease state defined by the molecular target

Efficacy of single agent or in combination may vary with tumor types, stages and between individual patients

Eg bevacizumab in breast ca versus colorectal ca

Tumor resistance or escape occurs (inevitable?)

Strategies: Patient selection

Rational combinations

What have we learned from phase 3 clinical trials with agents?
slide30

Antibody to

Receptor

e.g. Herceptin(R)

EGFR antibody

Receptor Tyrosine Kinase

Growth Factor Mutation, Translocation,

Amplification

RTK Inhibitor

e.g. ZD1839

Ras

mutation - active

PI3K

PTEN

mutation - inactive

Raf

Akt

MEK

mTOR

Raf Inhibitor

e.g. BAY 43-9006

FTI

e.g. R115777

MEK Inhibitor

e.g. CI-1040

CCI-779

If single agents are unlikely to be effective, what combinations should be evaluated?

Cell Proliferation

Survival

Migration

Angiogenesis

CDK Inhibitor

e.g. Flavopiridol

BCL-2 Inhibitor

e.g. G3139

MET Inhibitor

Src Inhibitor

VEGF Inhibitor

e.g. Bevacizumab

optimizing targeted therapy by combination strategies
Optimizing Targeted Therapy by Combination Strategies --
  • 3 Strategies (not mutually exclusive):
    • Maximize the target inhibition
      • Antibody + small molecule TK to same target
    • Maximize inhibition of a pathway
      • Ras + Raf inhibitor
    • Target multiple cellular mechanisms/pathways
      • GF inhibitor + anti-antiangiogeneic (+ others)
  • No adverse pharmacological interaction(s)
  • Non-overlapping mechanisms of resistance
  • Non-overlapping toxicities
challenges in the development of combination regimens
Challenges in the development of combination regimens

Critical questions:

  • Mechanisms of action, interaction and resistance
  • Predictive markers for specific agents AND combinations
    • Markers predictive of activity of the individual agents may not be the same as those of the combination
  • Effective preclinical and clinical evaluation for proof of principle, optimization of doses/schedule
3 target agents in combinations possible outcomes in unselected patients
3 Target Agents in Combinations: Possible Outcomes in Unselected Patients

Study Population

Study Population

Study Population

A

10%

B

10%

A

10%

B

10%

A

10%

B

10%

C

10%

C

10%

C

10%

A+B+C < 30%

Unfavorable interaction

Overlap of sensitivities

A+B+C = 30%

Patients benefiting only from 1 agent

A+B+C > 30%

(or there are cures)

True synergy but can this be predicted preclinically?

phase 2 combinations possible outcomes in unselected patients
Phase 2 Combinations: Possible Outcomes in Unselected Patients
  • Randomized phase 2 “pick the winner” design limitations
    • Assumptions
      • Agents have different targets
      • Target expression is unknown

Outcome

Eg response rate

R

A

N

D

O

M

I

Z

E

35%

Drug A + Drug B

Drug B + Drug C

50%

Drug D + Drug E

20%

  • RR may vary depending on the number of patients with targets in the treated groups.
  • All combinations may be beneficial to subset of patients with responsize tumors
do non clinical combination studies reflect clinical realities
Do non-clinical combination studies reflect clinical realities?
  • In clinical trials,
    • Drugs are administered at MTDs
    • Drugs are administered with standard treatment combinations or must be compared to standard treatment combinations
      • Exception: no standard treatment exists
    • Combinations may improve outcome by circumventing heterogeneity within patient or between patients
  • Non-clinical studies do not necessarily reflect these clinical realities
    • Synergy defined within a model based sub-MTD doses
    • Interactions assessed with single chemotherapy agent or radiation
    • Combinations assessed in limited numbers of models
what can we learn from examples
What can we learn from examples?
  • Target and Tumor:
    • Limited information of epidemiology and pathophysiology of target in human cancers
    • Little information on impact of agent on target in tumor
      • Underdosing may be minimized by dosing to toxicity
    • Most trials have not restricted entry to only those patients with target expression, except as inferred by histology
      • Exceptions: GIST, CML, HER2
    • Limited understanding of interactions with standard treatments prior to launching phase 3 studies
  • However, patient and dose/schedule selection are key to successful evaluation of clinical benefit
  • Start evaluating at preclinical stage or the opportunity is missed