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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.

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

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  1. 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

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

  3. 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

  4. 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

  5. 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

  6. What we knew before the Phase III trials were Initiated:Selected Approved Agents

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

  8. 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

  9. 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

  10. 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

  11. 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

  12. 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

  13. 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

  14. Response Rates By Sub-GroupsIn IDEAL 2 Kris et al, JAMA 290:2149-2158,2003

  15. 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

  16. 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

  17. 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?

  18. 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

  19. 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

  20. 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

  21. 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?

  22. Phase 2 Trials of Targeted Agents Yellow = Agents receiving FDA approval based on these RRs

  23. 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

  24. 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

  25. 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

  26. 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?

  27. 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

  28. 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)

  29. 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?

  30. 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

  31. 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

  32. 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

  33. 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?

  34. 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

  35. 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

  36. 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

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