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Targeted Therapies in Lung Cancer

Targeted Therapies in Lung Cancer. Martin J.Edelman, MD University of Maryland. Thoracic Oncology: Not Feeling Guilty Any More. Established first, second and third line therapies based upon solid evidence. Increasing cure rates in stage III disease.

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Targeted Therapies in Lung Cancer

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  1. Targeted Therapies in Lung Cancer Martin J.Edelman, MD University of Maryland

  2. Thoracic Oncology: Not Feeling Guilty Any More • Established first, second and third line therapies based upon solid evidence. • Increasing cure rates in stage III disease. • Dramatic benefit from platinum based chemotherapy in the adjuvant treatment of stage Ib-IIb disease.

  3. Current Challenges • Targeting therapies • Current drugs • “Current targeted drugs” • Moving forward: issues in future trials • Tumor heterogeneity • Populations heterogeneity

  4. Class Agents MMPI Batimistat, Marimistat Anti-angiogenesis Endostatin, Angiostatin, Thalidomide Anti-vascular Bevacuzimab CDK modulator Flavopiridol, UCN-01 EGFR inhibitor Iressa, C225 Novel Retinoid Bexarotene Eicosanoid Inhibition Celebrex, Zileuton BCL-2 inhibition Genasense Proteasome inhibition PS 341 Martha Stewart Investment Advice or New Agents in Development

  5. EGFR Family of Tyrosine Kinases Adapted with permission from Ritter CA, Arteaga CL. Semin Oncol. 2003;30(suppl 1):3-11.0

  6. Iressa: Not Exactly a Homerun INTACT-2

  7. rhuMAb VEGF (Recombinant Humanized Monoclonal Antibody to VEGF) • Humanized to avoid immunogenicity (93% human, 7% murine). • Recognizes all isoforms of vascular endothelial growth factor, Kd = 8 x 10-10 M • Terminal half life 17-21 days

  8. Randomized Phase II Trial of Rhumab VEGF PASCO 2000 #1896

  9. ECOG4599: Phase III Trial Stage IV NSCLC -Non-squamous histology - No CNS - No hemoptysis - PS 0-1 Carboplatin/Paclitaxel/anti-VEGF Carboplatin/Paclitaxel

  10. ECOG 4599

  11. VEGF as a target for the tratment of Lung Cancer: VEGF TUMOR Ineffective Vasculature High Interstitial Pressure Effective Vasculature

  12. VEGF as a target for the tratment of Lung Cancer: Anti-VEGF TUMOR Ineffective Vasculature Low Interstitial Pressure Effective Vasculature Jain et al, Nature Medicine, 2004

  13. Why the Disappointment: Problems with Trial Design • Unjustified approach: combination not really justified by Phase II data. • Phase I/II trials frequently utilize unrepresentative populations. • Unrecognized tumor heterogeneity • Unrecognized population heterogeneity

  14. Hype and Hope: The Problem of Single Center Studies Langer et al. J Clin Oncol. 1995;13:1860-1870. Langer et al. ECCO, 2001 Natale et al. Semin Oncol. 1996;23(6 suppl 16):51-54. Belani et al. PASCO, 1998 Schiller et al. PASCO 2000

  15. Referral Populations • Referral populations inherently do better. • Possible reasons: • Socioeconomics • Nutrition • Inherent biology JNCI 2001

  16. Molecular Heterogeneity and Trial Outcome • Cancer has two genetic subtypes; indistinguishable by histology. • What if there are subtypes with variable sensitivities to therapy? R.A. Betensky et al. J Clin Oncol 20:2495,2002

  17. Hypothetical TrialSample Size Required for 80% Power

  18. Identifying the Target Population • Refined classification of tumors based upon new methods of evaluating tumor DNA, RNA, protein. • Novel approaches with radiopharmaceuticals • Targeting specific patient populations.

  19. a b Identify Specific Subsets • The promise of genomic and proteomic technology. • We already do this: • PML • CML • Breast cancer • Need to limit the markers

  20. EGFR Mutations NEJM 2004

  21. CALGB 30406 Randomized Phase IIStudy: Trial Design Chemotherapy naive patients with stage III/IV adenocarcinoma or BAC who are never or “light” former smokers*ECOG PS 0-1 • Patients can continue therapy until evidence of disease progression or toxicity Daily oral erlotinib Daily oral erlotinib +6 cycles carboplatin/paclitaxel Daily oral erlotinib Daily oral erlotinib *never smoker:  100 cigarettes/lifetime; “light” former smoker: quit  1 year ago and  10 pack years

  22. The TARGET Trial: Trial to Assess Response to Gefitinib in EGFR-mutated Tumors S C R E E N I N G M U T A T I O N Enroll to Treatment (up to 35) Positive Eligible Patients Enter Negative Off-Protocol Patients eligible to be screened: adenocarcinoma, female, non-smoker, Japanese/Chinese Primary endpoint: RR (estimate 60%) Dana Farber/MGH P.Janne

  23. Molecular correlates of drug response • Beta-tubulin isoforms predict response to taxanes, vinca alkaloids. • ERCC1 predicts response to platinum agents.

  24. Isolation of Circulating Cancer Cells

  25. Target Identification in Circulating Cancer Cells ERCC1 Her2-neu

  26. Continual Reassessment Study Design R E GiSTER Marker A Marker B - - A/B - + A/C + - B/C + + C/D Marker A Marker B - - A/B - + A/C + - B/C + + C/D Resampling (every 21 days) Marker A- marker of resistance to drug A Marker B – marker of resistance to drug B Potential agents: Carboplatin, paclitaxel, gemcitabine, CPT-11, Premetrexed

  27. Rhenium Re 188 P2045 Re-188 P2045 Tc-99m 2045

  28. Scintigraphic images of prostate tumor bearing mice 70 min & 24 hrs post injection of 99mTc-HPMA copolymer-RGD4C/RGE4C conjugates. 70 min 70 min 24 hrs 24 hrs TUMOR TUMOR LIVER LIVER KIDNEY KIDNEY BLADDER BLADDER HPMA copolymer-RGE4C conjugate HPMA copolymer-RGD4C conjugate

  29. The fault may not be in the tumor , but in the patient • Boys are different from girls. • Political correctness aside, there are ethnic differences in toxicity and outcome. • Heterogeneity within specific populations may be considerable.

  30. Cancer Deaths: Women

  31. Gender Differences and Prognostic Markers ASCO 2004, #7008

  32. Treatment Outcomes: Female vs. Male

  33. Pharmacogenomics

  34. Japan-SWOG Common Arm Study ASCO 2004 #7007

  35. New Drug Development: Traditional Algorithm Phase I Pk, pd Preclinical Phase II Phase III

  36. New Drug Development: An Algorithm Phase I w. other agents XRT Clinic Phase I trial -pk, pd -assessment of targeting Phase III • Phase II: defined populations • required correlative studies • Dose ranging • Randomized Phase II Lab -preclinical w.other agents -XRT -development of assays -define and redefine mechanism Imaging Statistics Alternative schedules

  37. Conclusions • Current therapy of advanced NSCLC is beneficial but limited. • We still do not understand current, validated agents. • Trials of “targeted agents” will need to incorporate assessment of the target into the trial. Targeted agents may be less effective overall. • Successful future trials will need to be targeted and assessed for specific populations.

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