Lessons From Clinical Trials of Targeted Therapies for Cancer - PowerPoint PPT Presentation

lessons from clinical trials of targeted therapies for cancer n.
Download
Skip this Video
Loading SlideShow in 5 Seconds..
Lessons From Clinical Trials of Targeted Therapies for Cancer PowerPoint Presentation
Download Presentation
Lessons From Clinical Trials of Targeted Therapies for Cancer

play fullscreen
1 / 72
Lessons From Clinical Trials of Targeted Therapies for Cancer
373 Views
Download Presentation
colby
Download Presentation

Lessons From Clinical Trials of Targeted Therapies for Cancer

- - - - - - - - - - - - - - - - - - - - - - - - - - - E N D - - - - - - - - - - - - - - - - - - - - - - - - - - -
Presentation Transcript

  1. Lessons From Clinical Trials of Targeted Therapies for Cancer George W. Sledge M.D. Indiana University Simon Cancer Center

  2. What is Targeted Therapy? • Well-defined molecular target • Target is correlated with tumor biology • Target is measurable in the clinic, or so common it doesn’t need to be • Target is correlated with therapeutic effect

  3. The HER Family of Receptors TGF-α EGF Epiregulin Betacellulin HB-EGF Amphiregulin No ligand-binding activity* Ligands Heregulin (neuregulin-1) Epiregulin HB-EGF Neuregulins-3, -4 Heregulin Ligand- binding domain Tyrosine kinase domain Erb-B3 HER3 Erb-B1 HER1 EGFR Erb-B2 HER2 neu Erb-B4 HER4 *HER2 dimerizes with other members of the HER family. Roskoski. Biochem Biophys Res Commun. 2004;319:1. Rowinsky. Annu Rev Med. 2004;55:433.

  4. Fluorescence In Situ Hybridization Test Measures HER2 Gene Amplification • FISH tests are designed to detect amplification of the HER2 gene Chromosome 17 centromere HER2 gene HER2-normalRatio <2.0 HER2-amplifiedRatio ≥2.0 PathVysion® PI. Revised May 2004.

  5. Disease-Free Survival ACTH 87% 85% ACT 75% % 67% N Events ACT 1679 261 ACTH 1672 134 HR=0.48, 2P=3x10-12 B31/N9831 Years From Randomization

  6. Targets for which Targeted Therapies exist • Steroid receptors: for ER+ breast cancer, prostate cancer, and lymphoma • HER2: for breast and gastric ca • ALK: for NSCLC • CD20: for lymphoma • bcr/Abl: for CML • c-Kit: for GIST • Hedgehog: for basal cell and medulloblastoma • RET: for medullary thyoid ca • b-RAF: for melanoma

  7. Sort-of Targeted Therapy • VEGF-targeted therapies (except renal cell ca) • rarely drives tumor; hard to predict benefit • EGFR (colon, lung, H&N ca) • ras, EGFR mutations • CMF chemotherapy in high RS breast cancer • redefining targted therapy?

  8. EGF Receptor: Role in CRC Therapy Meyerhardt & Mayer, N Engl J Med 2005 Venook, Oncologist 2005 pY PI3K pY pY pY PTEN STAT mTOR AKT Ligand Antibodies to EGFRcetuximab, panitumumab RAS RAF EGFR-TK MEK MAPK Gene transcription Cell-cycle progression Proliferation Survival (anti-apoptosis) Chemotherapy /radiotherapy resistance Invasion and metastasis Angiogenesis

  9. Mutant – 7.4 vs 7.3 weeks Wild type – 12.3 vs. 7.3 weeks P= <0.0001

  10. Oncotype DX 21 Gene Recurrence Score (RS) Assay 16 Cancer and 5 Reference Genes From 3 Studies PROLIFERATION Ki-67 STK15 Survivin Cyclin B1 MYBL2 ESTROGEN ER PR Bcl2 SCUBE2 GSTM1 BAG1 INVASION Stromolysin 3 Cathepsin L2 CD68 REFERENCE Beta-actin GAPDH RPLPO GUS TFRC HER2 GRB7 HER2

  11. 40 35 95% C.I. 30 Recurrence Rate 25 20 Rate of Distant Recurrence at 10 years 15 10 5 0 0 5 10 15 20 25 30 35 40 45 50 Recurrence Score Recurrence Score and Distant Recurrence-Free Survival Low RS < 18 Rec. Rate = 6.8% C.I. = 4.0% - 9.6% Intermediate RS 18 - 31 Rec. Rate = 14.3% C.I. = 8.3% - 20.3% High RS  31 Rec. Rate = 30.5% C.I. = 23.6% - 37.4% Paik .S. et al. N Engl J Med 2004;351:2817-26

  12. B-20: Absolute % Increase in DRFS at 10 Years • Benefit of Chemo Depends on RS n = 353 Low RS<18 n = 134 Int RS18-30 n = 164 High RS≥31 0 10% 20% 30% 40% % Increase in DRFS at 10 Yrs (mean ± SE)

  13. Targeted Therapies Vary in Effectiveness • Based on degree of “pathway addiction” • Is there an ideal target? • Based on drug-related issues

  14. The Ideal Target? • Driving mutation in a • “Dumb tumor” that is • Easily druggable • and the mutation is really common

  15. Dumb Tumors vs. Smart Tumors • CML, MTC, GIST • Non-Small Cell Lung Cancer: • Responses to EGFR and ALK-targeted therapy seen predominantly in non-smokers • Bronchial epithelium of smokers are loaded with mutations (~1 mutation/cell/3 cigarettes) • Breast Cancer: ER-neg vs. ER-pos • BRCA and BRCA-ness of TNBC; large mutational load • ER-pos: less LOH, more well-differentiated

  16. Clinical Trial Implications of Biomarker-Driven Therapy • Number needed to study vs. Number needed to treat: a source of tension • Laboratory implications that follow from this

  17. A Simulation of a Phase III Trial: Assumptions: Two subgroups (A and B) A is sensitive to targeted therapy and will have a 25% improvement in median survival from 2227 mo. B is insensitive to targeted therapy Three scenarios: A representing 100, 50, and 25% of the study population.

  18. The Crizotinib Story:How It’s Supposed to Work

  19. Crizotinib: Rationale for Development of a c-MET inhibitor • c-MET is potentially one of the most frequently genetically altered receptor tyrosine kinases in human cancers • Activating mutations • Hereditary papillary RCC: 100%, sporadic papillary RCC (13%) • HNSCC: 10% • NSCLC (8%) and SCLC (13%) • Gene amplification • Gastric carcinoma: 5-10% • Colorectal carcinoma: 4% primary tumors, 20% liver metastases • Esophageal adenocarcinoma: 5-10% • Anaplastic Lymphoma Kinase (ALK) (2 target for crizotinib) • Anaplastic lymphoma is very sensitive to chemotherapy • ALK point mutations and gene amplification are implicated in neuroblastoma … a rare tumor • ALK translocations in inflammatory myofibroblastic tumors … a very rare tumor

  20. Crizotinib: Kinase Inhibition Profile Upstate 102 kinase Cellular selectivity on 10 of 13 relevant hits Crizotinib (PF-02341066) 13 kinase “hits” <100X selective for c-MET • Selectivity findings • ALK and c-MET inhibition at clinically relevant dose levels • Low probability of pharmacologically relevant inhibition of any other kinase at clinically relevant dose levels *The cellular kinase activities were measured using ELISA capture method Pfizer Inc. Data on file

  21. A8081001: Phase I Trial of Crizotinib Cohort 6 250 mg BID MTD/RP2D Cohort 5 300 mg BID MDZ sub-study Cohort 4 200 mg BID Cohort 3 200 mg QD Cohort 2 100 mg QD MDZ sub-study Cohort 1 MTD = Maximum tolerated dose; RP2D = Recommended phase 2 doseMDZ = Midazolam (in-vitro data indicated that PF-02341066 is a major substrate and inhibitor of CYP3A activity) 50 mg QD Kwak EL, et al. ESMO/ECCO 2009(Abstract G6 and oral presentation)

  22. Most Common Treatment-related Adverse Events (≥10%): Dose Escalation Cohorts (N=37) DLTs 3 objective responses observed in this part of the Phase I trial Kwak EL, et al. ASCO 2009 (Abstract 3509 and oral presentation)

  23. First Description of EML4-ALK Translocation in NSCLC

  24. Evidence for EML4-ALK as a Lung Cancer Oncogene • Insertion of EML4-ALK into NIH 3T3 fibroblasts was tumorigenic when implanted subcutaneously into nude mice • Engineered the specific expression of EML4-ALK fusion gene in lung progenitor cells using a surfactant protein C gene promoter • 100% of EML4-ALK transgenic mice developed lung adenocarcinoma that were + for ALK by IHC. No other primary cancers were observed. • Following IV injection of EML4-ALK/3T3 • cells into nude mice, all developed lung • cancer. Ten animals were treated with an • ALK-specific TKI and 10 were observed:

  25. Key CollaborationPfizer and Massachusetts General Hospital Kwak EL, et al. ESMO/ECCO 2009 (Abstract G6 and oral presentation) • Of the 3 objective responders, all had ALK translocations: • Inflammatory myofibroblastic sarcoma: NPM-ALK translocation • NSCLC (2): EML4-ALK translocation

  26. Clinical and Demographic Features of Patients with ALK-positive NSCLC Y Bang et al: ASCO 2010

  27. Tumor Responses to Crizotinib for Patients with ALK-positive NSCLC Objective RR = 57% (95% CI: 46-68%) DCR (CR+PR+SD): 87% (95% CI: 77-93%) 60 40 20 0 –20 –40 –60 –80 –100 Progressive disease Stable disease Confirmed partial response Confirmed complete response Maximum change in tumor size (%) –30% * Y Bang et al: ASCO 2010 *Partial response patients with 100% change have non-target disease present

  28. 77% of Patients with ALK-positive NSCLC Remain on Crizotinib Treatment Individual patients • Reasons for discontinuation • Related AEs 1 • Non-related AEs 1 • Unrelated death 2 • Other 2 • Progression 13 0 3 69 12 15 18 21 Treatment duration (months) N=82; red bars represent discontinued patients Y Bang et al: ASCO 2010

  29. Median PFS Has Not been Reached 1.00 0.75 0.50 0.25 0.00 PFS probability at 6 months: 72% (95% CI: 61, 83%)  Progression-free survival probability Median follow-up for PFS: 6.4 months (25–75% percentile: 3.5–10 months) 95% Hall–Wellner confidence bands 0 2.5 5.0 7.5 10.0 12.5 15.0 17.5 Progression-free survival (months) Y Bang et al: ASCO 2010

  30. Current Crizotinib Clinical Trials PROFILE 1007 • Crizotinib 250 mg BID (n=159) • administered on a continuous • dosing schedule RANDOMIZE • Key entry criteria • Positive for ALK by central laboratory • 1 prior chemotherapy (platinum-based) • Pemetrexed 500 mg/m2or • docetaxel 75 mg/m2 (n=159) • infused on day 1 of a 21-day cycle N=318 PROFILE 1005 • Key entry criteria • Positive for ALK by central laboratory • Progressive disease in Arm B of study A8081007 • >1 prior chemotherapy • Crizotinib 250 mg BID (N=250) • administered on a continuous • dosing schedule N=250 PROFILE 1007: NCT00932893; PROFILE 1005: NCT00932451

  31. Crizotinib: The Good News • Important unmet medical need • Straightforward, biology-based biomarker predicting response • High response rate in heavily pre-treated patients (i.e., low NNT) • Relatively non-toxic A triumph for targeted therapy

  32. Crizotinib as an Example: The Bad News • 4-5% of Non Small Cell Lung Cancer, so… • 20-25 patients screened for every EML4-ALK+ patient • Not all patients are trial eligible • Not all patients give informed consent • Best guess: 50+ patients screened for every patient entered on trial • Screening = FISH, which requires trained lab tech, time, and supply money • Lab requires CLIA certification

  33. A Thought Experiment:Imagine ALK in Esophageal Cancer • Esophageal cancer = 16,640 cases/year, with 14,500 deaths • Assume ALK-like rates of gene expression of 5% • .05 X 16,640 = 832 patients/year in the US • Only 3% of patients with cancer go onto clinical trials • .03 X 832 = 25 patients/year entering trial

  34. Medullary Thyroid Cancer • Thyroid cancer: 2% of all cancers • MTC: 5% of all thyroid cancers • RET proto-oncogene mutations drive • all hereditary MTC and ~50% of sporadic • RTKi’s for RET exist

  35. Vandetanib • Inhibits VEGFR1,2, and RET • A dud in lung cancer • ASCO 2010: Phase III trial of 331 MTC patients • 54% reduction in rate of progression, p = 0.0001 • ORR 45% vs. 13% • International trial required; accrued in 1 year • NB: the “biomarker” was the diagnosis of MTC

  36. It Gets Worse Multiple kinases are activated Optimal cell kill requires inhibition of multiple kinases Stommel et al. SCIENCE VOL 318: 287,2007

  37. It Gets Worse • Assume: Cancers have multiple drivers • Targeting multiple RTK’s increases benefit • So now imagine esophageal cancers with two drivers, requiring two different targeted therapies • What is the number needed to screen to perform a trial of a combination of 2 RTKi’s?

  38. Number Needed to Study:A New Concept for Biomarker-Driven Clinical Research • NNS = ___________1________ (fraction with biomarker X assay specificity X fraction trial-eligible X fraction giving informed consent X) Example: HER2+ = 1/(0.25 X 0.9 X 0.5 X 0.5) = 17.8 patients screened/patient entered into trial

  39. NNS Implications • Fraction with biomarker is fixed by biology • Maximize true positives (specificity) by optimized assay development • Minimize number of exclusion criteria • Make trial as user-friendly as possible for patients

  40. Problems With Biomarker Studies • Poor study design • Lack of assay reproducibility • Specimen availability issues • Issues with quantity, quality & preservation • Variability in assay results • Underpowered studies/overly optimistic reporting due to multiple testing, subset analyses & cut point optimization McShane, LM et al. J Clin Oncol 23: 9067-72, 2005

  41. Phase of Trial: Preclinical 0 I II III IV Discovery Clinical Practice Pharmacokinetic Pharmacodynamic Prognostic CLIA Predictive If Assay Used For Individual Patient Decision Making Pharmacogenomic Research Lab Clinical Lab Assay & Marker Space

  42. Clinical Assay Development Pipeline Assess assay performance in context: reproducibility, sensitivity, specificity, etc. Assess feasibility of detection/assay technology and marker prevalence Final late stage development, assay qualification Test cut-points in new retrospective specimen set Marker/technology discovery Set preliminary cut-points Test biomarker in retrospective set of specimens Trial activation

  43. NCI Clinical Assay Development Program Patient Characterization Center (PCC) Clinical Assay Development Network (CADN) Clinical Assay Development Center (CADC) CADP: overarching program to move assays from research to the clinic CADN: network of CLIA certified labs providing services, including assay optimization, assessment of analytical performance, clinical validity in context of clinical trials PCC: internal lab performing gene expression profiling and somatic mutation detection using semi-quantitative NextGen sequencing on newly diagnosed cancers CADC: internal lab, part of CADN, the assay development arm of PCC; develop “high risk” standardized assays that can be disseminated Specimen Retrieval System/caHUB

  44. Why Drugs Fail

  45. Failure Rates of Investigational Drugs in Clinical Trials 9 of 10 drugs entering Phase 1 clinical trials will fail Historical timing of drug development failures 10% discontinuation in Phase 1 50-60% discontinuation in Phase 2 20-35% discontinuation in Phase 3

  46. Why “Targeted” Agents Fail • The drug isn’t a drug • The drug isn’t used correctly • The drug is used in the wrong disease • Too much is asked of the drug • The drug is too toxic

  47. The Drug isn’t a Drug:SU5416

  48. SU5416 • Potent, selective inhibitor of VEGFR2 • Preclinical activity in animal models • Additivity/synergy with chemotherapeutics

  49. SU5416: not a drug, a rock • High lipophilicity (Log P= 4.4), an extremely low aqueous solubility (< 10 ng/ml at pH 2-13) and low solubility in common pharmaceutically acceptable organic solvents (i.e., ethanol, PEG 400, propylene glycol, etc.) • Rapid clearance (half-life < 1 hour) • Major metabolites are inactive

  50. 18FDG-PET of patient with GIST treated initially with SU5416 and later with imatinib mesylate. Pre- and post- treatment with SU5416 Pre- and post- treatment with imatinib Heymach et al, CCR, 2004