Molecularly Targeted Therapy in Lung Cancer: Hype, Hope, Myths and Reality Martin J. Edelman, MD University of Maryland Greenebaum Cancer Center Advanced NSCLC: The State of the Art 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 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. Six Essential Alterations in Cell Physiology in Malignancy Self-sufficiency in growth signals Evading apoptosis Hanahan & Weinberg, Cell 100:57 (2000) Insensitivity to anti-growth signals Targets for classical drugs? Targets for novel drugs? Sustained angiogenesis Tissue invasion & metastasis Limitless replicative potential 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. Survival by B-Tubulin III Phenotype In Taxane-treated NSCLC 1,0 0,9 p=0.02 0,8 0,7 0,6 0,5 0,4 0,3 0,2 0,1 0,0 0 2 4 6 8 10 Months after diagnosis 12 14 16 Dumontet, 2002 Better Identify and Utilize the Drugs We Already Have: GILT R A N D O M I Z E Standard Arm Docetaxel/Cisplatin Genomic Arm Beta tubulin ERCC1 Regimen Doc/CDDP + Doc/Gem + Gem/CDDP + + Gem/CPT-11 New Anti-tubulins: Epothilones Computer model of beta-tubulin mutations Taxane Epothilone Giannakakou et al. Proc. Natl. Acad. Sci. USA 2000, 97, 2904 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” Probability of Relapse 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 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 Myeloid (n=21) Lymphoid (n=14) 0 100 200 300 400 • 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 Targeted Therapy in the Common Solid Tumors: The Reality But what about Trastuzumab? • Degree of benefit is relatively modest. • Population is enriched by Herceptest. • Drug would have <10% RR if entire population treated The EGFR (ErbB) family and ligands EGF TGF Amphiregulin -cellulin HB-EGF Epiregulin Tyrosine kinase domain Heregulins NRG2 NRG3 Heregulins -cellulin 100 44 36 48 100 82 59 79 100 33 24 28 ErbB-1 Her1 EGFR ErbB-2 Her2 neu ErbB-3 Her3 Cysteine-rich domains C-terminus ErbB-4 Her4 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. Tumors Progressively Make More Angiogenesis Stimulators bFGF bFGF bFGF bFGF VEGF VEGF VEGF PDGF PDGF IL-8 Relf et al., Cancer Research, 57:953, 1997 How to hit the target • If you know the target, and there is only one target you can be very specific. • If you don’t really know or it’s a really big target, a larger weapon may be needed. 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 Leveraging your opponents weight, or how targeted therapy can work with other treatments and toss the opponent out of the ring Arachidonic Acid Metabolism Cell membrane phospholipids Sphingomyelin Neutral sphingomyelinase Arachidonic Acid COX 1,2 5-HPETE 12-HPETE 15-HPETE Celecoxib 5LO 12HETE 5HETE Zileuton LTA4 LTB4 LTC4 LTD4 LTE4 Ceramide 15HETE Prostaglandins CALGB 300203:Gemcitabine/ Carboplatin + Eicosanoid Modulators PD Stage IIIB (pleural effusion), IV NSCLC PS 0-1 Adequate organ fcn Carboplatin AUC =5.5 Gemcitabine 1000 mg/m2 Zileuton 600 mgpo qid 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 MJ Edelman, PI Off study Correlates: IHC, CYFRA VEGF levels 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. 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 Molecular Target Measurements • Enzyme activity measurements • e.g., DT-diaphorase, P450’s • 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 Clinical Trial Design With Biologic 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 Phase I of Targeted Agent: Use of Enzyme Inhibition to Determine Dose The Oncologist, 2002 7:401-409 Phase I Trial of a Targeted Agent: Use of Target Inhibition to Determine Dose 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 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. 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 Phase III Trials: The Problem of Molecular Heterogeneity Impact 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? Anaplastic Oligodendroglioma • Proportion of genetic subtypes differ in different cohorts of patients. – in recurrent disease: 90% 1p LOH – in newly dx’d disease: 60% 1p LOH • Genetic subtype is age dependent. – 1p LOH more common in young pts – older pts predominate in trials 0.8 0.6 0.2 0.4 1p LOH Neither 1p LOH nor TP53 0 Survival Probability 1.0 Molecular Subtypes of Anaplastic Oligodendrogliomas: Implication for Patient Management at Diagnosis Y. Ino et al. Clin Cancer Res 7:839,2001 0 50 100 Months 150 200 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. Identify Specific Subsets • The promise of genomic and proteomic technology. • This enriches the population. • We already do this: a b – PML – CML – Breast cancer Pharmacogenomics Drug metabolizing enzyme Frequency of variant poor Drug metabolism phenotype CYP 2D6 6.8% Sweden 1% China Codeine CYP 2 C9 3% England Warfarin CYP 2C19 2.7% white USA 14.6% China 18% Japan Omeprazole DPD 1% of the population 5FU 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. Targeted Therapy: The Future (cont’d) • 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.
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