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Targeted therapy : Falso mito o reale innovazione?

Targeted therapy : Falso mito o reale innovazione? . Stefano Iacobelli Cancer Clinic & Laboratory of Molecular Oncology. Consorzio Interuniversitario Nazionale per la Bio -Oncologia (CINBO). What are Targeted Therapies ?.

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Targeted therapy : Falso mito o reale innovazione?

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  1. Targetedtherapy: Falso mito o reale innovazione? Stefano Iacobelli Cancer Clinic & Laboratory of MolecularOncology Consorzio Interuniversitario Nazionale per la Bio-Oncologia (CINBO)

  2. What are TargetedTherapies? • Targeted cancer therapies are drugs or other substances that block the growth and spread of cancer by interfering with specific molecules involved in tumor growth and progression. • Targeted cancer therapies that have been approved for use in specific cancers include drugs that interfere with cell growth signaling or tumor blood vessel development, promote the specific death of cancer cells, stimulate the immune system to destroy specific cancer cells, and deliver toxic drugs to cancer cells. NCI www.cancer.gov

  3. Mechanisms of common TargetedAnticancerTherapies: mAbs and TKIs Langer C & Soria JC, ClinLungCancer 11: 82-90, 2010

  4. FDA approvedTKIs and mAbs for cancertherapy aAgents with antiangiogenicmechanism Li J et al., TargOncol 2012

  5. Myth: ImatinibMesylate, “Proof of Principle” for Targeted Therapy • ImatinibMesylate targets the bcr-abl TK very specifically. • Bcr-abl is the root cause of CML, essentially a “monogenetic disease”

  6. Before Imatinib, only 30% of patients with CML survived for even five years after being diagnosed.  Results with Imatinibasinitialtherapy for newlydiagnosedchronic-phase CML 5-yr OS: 89% 5-yr CCR: 87% Druker BJ et al., N Engl J Med 2006

  7. The Reality: Targeted Therapy in the Common Solid Tumors

  8. CML and BreastCancer TargetedTherapiesVary in Effectiveness: The role of the “TARGET” AllBreastCancerPatients HER2 + BreastCancerPatients CML Patients Imatinib Trastuzumab Trastuzumab ~ 90% Response < 10 % Response ~ 35% Response

  9. The Ideal Target • Drivingmutation in a • “ Dumb ”tumorthatis • Easilydruggable • and the mutationisreally common

  10. Stupid and Smart Cancers StupidCancers Smart Cancers • Single dominatmutation • Small mutationalload • Monotherapyiseffective • Resistance rare, late, samepathway • Multiple mutational drivers • Large mutationalload • Multi-targetedtherapyrequired • Resistance common, early Sledge G, ASCO 2009

  11. CML: A StupidCancer NSCLC: A Smart Cancer Onemutation for every 3 cigarettes! A= Inter- and intra-chromosomalrearrangements B= LOH and allelicimbalance C= Copy numbervariations D= Single nucleotide variants • Driven by a single chromosomaltranslocation (BCR-ABL) • Success with the first drugthatcamealong • Thatdoesn’t work? • Use an "ib"targeting the samekinase domain Red = amplification Purple = LOH Black = mutation Lee et al., Nature 465: 473-7, 2010

  12. Somaticmutations of the EGFR gene werefound in 15 of 58 unselectedtumors from Japan and 1 of 61 from the US Somaticmutationswereidentified in the tyrosinekinase domain of the EGFR gene in 8 of 9 patients with gefitinib-responsive lungcancer, ascompared with none of the sevenpatients with no response (P<0.001)

  13. Erlotinib vs. standard chemotherapyas first-line treatment for Europeanpts with advanced EGFR-mutation positive NSCLC - EURTAC phase III study - 174 pts with EGFR mutations (exon 19 deletion or L858R mutation in exon 21) enrolled mPFS 9.7 vs. 5.2 months • Erlotinib150 mg daily • Standard chemotherapy: • cisplatin75 mg/m(2) d1 + docetaxel 75 mg/m(2) d1 or gemcitabine 1250 mg/m(2) d 1,8 q21 Rosell R et al., Lancet Oncol 2012; 13:239-46

  14. Gefitinib in Refractory Advanced NSCLC No Benefit Thatcher N et al., Lancet 366: 1527-37, 2005

  15. 40% K-Ras mutations in CRC

  16. No difference K-Ras mutations and Benefit from Cetuximab in Advanced CRC mOS 9.5 vs 4.8 months Karapetis CS, N Engl J Med 359:1757-65, 2008

  17. Clinicalevidence of oncogene addiction Oncogene addiction describes the phenomenon in which some cancers that contain multiple genetic, epigenetic, and chromosomal abnormalities remain dependent on (addicted to) one or a few genes for both maintenance of the malignant phenotype and cell survival. The need of a “COMPANION DIAGNOSTIC TEST” NagahiroSaijo, Cancer Res Treat. 2012; 44:1-10

  18. Recently, 2 targetedtherapieswereapproved by FDA with a companiondiagnostic to identifyenrichedsubpopulations of patientsthat are more likely to respond to the drug Parkinson DR et al., ClinCancer Res 2012

  19. Diagnosis of an EML4-ALK-Positive NSCLC in a single patient Adenocarcinoma (H&E) Kwak EL et al., N Engl J Med 2010 IHC analysis of ALK in tumorcells (brown) RT-PCR of EML4-ALK Panel A: The green probe hybridizes to the regionimmediately 5’ to ALK, and the red probe to the 3’ region. The separation of red and green probesindicates a chromosomalrearrangement of ALK. The probe usedwas the Vysis LSI ALK Dual Color, Break ApartRearrangement Probe (Abbott Molecular)

  20. Response to ALK Inhibition and PFS ORR 60.8% Crizotinib 250 mg bid in 28-day cycles mPFS 9.7 months CT before and afterCrizotinib Kwak EL et al., N Engl J Med 2010; Camidge DR et al., Lancet Oncol 2012

  21. Chapman PB et al., N Engl J Med 2011 ImprovedSurvival with Vemurafenib in Melanoma with BRAF V600E Mutation RR 48% vs. 5% Vemurafenibvs.Dacarbazine Vemurafenib 960 mg orallybid Dacarbazine 1000 mg/mq d1 q21

  22. BC – Using usual selection criteria(EBCTCG) (100 N0, pre-menopausal pts receiving CT, after 5 yrs follow-up) 100 83.5will be aliveevenw/o CT 13.5 will die despite CT 3 will be alive thanks to CT 75 Using the 70-gene signature 50 Only 27% of pts will be overtreated 25 0

  23. Conclusions • The outcome of CML wastransformed by targetedtherapy: mediansurvivalincreased from about4 yrsto 20-25 yrs • Solid tumors are more complexthan CML • Therefore the outcomes in CML are an aberration, and we are notlikely to seesuch a transformation in outcomes in solidtumors • Only a co-developmentstrategythatidentifiesbiomarkers of response and treatsonlyvulnerabletumorswill be defensiblegoingforward • Development strategiesthat administer therapies to populations • that are not selected or are selected with methodologies not validated, must become a strategy of the past.

  24. Molecular Diagnostics: The next step Stefano Iacobelli Cancer Clinic & Laboratory of MolecularOncology Consorzio Interuniversitario Nazionale per la Bio-Oncologia (CINBO)

  25. Targeted cancer drugs are expensive and often fail to yeld clinical benefit NSCLC Breast Pancreas Breast

  26. Provocative statement 1: Drug companies cannotafford NOT to have a moleculardiagnosticdivision • Tissue samples for MDx will become ever smaller as diagnosis improves, requiring concentration of MDx testing in single large central services laboratories • These MDx companies that offer the broadest range of diagnostic tests will receive the samples available for MDx • If co-development of drug and companion MDx test will become the norm and integral part of FDA/EMA regulatory process, any company that does not control the entire chain of events will be vulnerable.

  27. Provocative statement 2: Biomarkerdiscoveryshould start beforePhase 1 • Too often, companies start to think about biomarkers when the drug has falled in phase 3 (the Iniparib scenario) • Candidate biomarkers of response should be identified while a compound is in research phase, validated in phase 1 and 2 trials and used as an enrollment criterion in phase 3

  28. Provocative statement 3: No tissue, no trial! • Is it ethical to make biopsies mandatory for participation in trials or should we realize high consent to biopsies through patient education?

  29. Provocative statement 4: Heathcareinsurerswillnotpay for RxwithoutcompanionDx in the future • Future drugreimbursementwilldepend on quality of life yearsgained • How much are payerswilling to pay for a MDx test thatrules out half of the patientpopulation for a € 100,000 targetedtherapy?

  30. Grazie per la Vs attenzione!!

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