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Roma 22 Settembre 2012 La terapia medica del melanoma metastatico

Roma 22 Settembre 2012 La terapia medica del melanoma metastatico. Paola Queirolo Dept . Medical Oncology A National Institute for Cancer Research -Genova. Metastatic Melanoma: medical treatments. Chemotherapy Single agent or poly-Chemotherapy monochemotherapy best option of care

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Roma 22 Settembre 2012 La terapia medica del melanoma metastatico

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  1. Roma 22 Settembre 2012La terapia medica del melanoma metastatico Paola Queirolo Dept. MedicalOncology A National InstituteforCancerResearch-Genova

  2. Metastatic Melanoma: medical treatments • Chemotherapy Single agent or poly-Chemotherapy monochemotherapy best option of care • Immunotherapy : alpha IFNs, IL-2 Vaccinations • Bio-chemotherapy • Targeted therapies

  3. Overall Survival for Metastatic Melanoma Survivaldatafrom 42 Phase II trialswithover 2‘100 stage IV patients1: 12 month OS: 25.5 %, median OS: 6.2 months (stage IV melanomaincludingpatientswithbrainmetastases) Proportion alive Time (months) Adapted from Korn 2008 Due tothe lack ofefficacioustherapy, thepreferredtreatmentformetastaticmelanomaremainstheinclusion in a clinicaltrial 1Korn EL et al. J Clin Oncol 2008;26(4):527-34. 2Dummer R, Hauschild A, Jost L. Cutaneous malignant melanoma: ESMO clinical recommendations for diagnosis, treatment and follow-up. Ann Oncol 2008;19 Suppl 2:ii86-8.

  4. Metastatic Melanoma : Single Agent Options Overall responses with monotherapy Khayat, Educational Book, ASCO 2000

  5. CT/BioCT AND RRPhase II trials

  6. CT/BioCT AND RR

  7. Metastatic Melanoma: Phase III Biochemo vs Chemo No. of pts Author Regimen RR OS KeilholzCVDI-Il-2 23 9 (JCO ‘05) vs. 363 CVDI 21 9 AtkinsCVD-bio 17 9 (JCO ‘08) vs. 416 CVD 12 9

  8. NEW DRUGS. FDA and EMA approval in 2011 • Targeted immunotherapy: anti-CTLA-4 mAbs • Molecular targeted therapies: anti B raf V600 mut

  9. Melanoma isanimmunogeniccancer • Spontaneousremissions • TILsassociatedwithregression • Ab and CTL responsesto melanoma Antigens

  10. IMMUNOTHERAPY OF MELANOMA • BRMs: rIFN alfa, rIL-2, GM-CSF, IL-12,IL-18, IL-21 • Adoptiveimmunotherapy: TIL,NK,DC • Vaccines: autologous, allogeneic, peptides, anti idiotypes Abs, gene modifiedcacells, dendriticpulsed • DNA basedtherapy: allovectin 7 • Targeted therapies acting on immunologicalcells : antCTLA4

  11. Safety: Immune Breakthrough Events IBEs: Immune-mediated adverse events based on the action of Anti CTLA-4 mAbs • Correlation with clinical response • Usually linked to drug-exposure and reversible • Manageable with established therapies (e.g. corticosteroids)

  12. Novel targets for immunotherapy Potential Treatment Strategies - Antagonize receptors that suppress the immune response (e.g. CTLA-4 and PD-1) - Activate receptors that amplify the immune response (e.g. CD40 on APC; 4-1 BB and OX40 on T cells) - Inhibit or deplete immunosuppressive mechanisms (e.g. Tregs, IL-10, TGF-beta…) - Combinations of the above

  13. Anti-CTLA-4 mAbs:SAFETY • GI toxicity: Diarrhea: watery to frank blood Bx: inflammatory colitis • Skin toxicity: Rash, pruritus and vitiligo • Endocrine Toxicity: Hypophysitis; Thyroiditis

  14. Endocrinopathies Pituitary Insufficiency in a patient with metastaticmelanoma • Presumed Autoimmune Hypophysitis • Confusion, fatigue, impotence • Headache • Low ACTH/cortisol • ↓ T4, testosterone and/or prolactin • Increased pituitary size on MRI • Asymptomatic with replacement therapy • Slow return of some endocrine function Blansfield JA, Beck KE, Tran K, Yang JC, Hughes MS, Kammula US, et al. Cytotoxic T-lymphocyte-associated antigen-4 blockage can induce autoimmune hypophysitis in patients with metastatic melanoma and renal cancer. J Immunother 2005;28(6):593-8.

  15. Anti-CTLA-4 mAbs • Tumor responses are sufficient but not necessary for prolonged survival • Rationale for proceed with therapy after early progression • Increased volume of lesions may be due to lymphocytic infiltrate Bulanhagui et al. ASCO 2006

  16. 9 months 5.2 months “Conventional” response • Response in baseline lesions Response in baseline lesions 50 25 0 -25 -50 -75 -100 -125 2,894 2,556 2,218 1,881 1,543 1,206 868 530 193 -145 -482 PD SPD (mm2) PR Change from baseline SPD (%) CR -9 -3 3 9 15 21 27 33 39 45 51 Relative week from first dose date 'Stable disease' with slow, steady decline in total tumor volume 50 25 0 -25 -50 -75 -100 -125 2,810 2,482 2,154 1,826 1,498 1,171 843 515 187 -140 -468 • Stable disease Change from baseline SPD (%) -9 -3 3 9 15 21 27 33 39 45 51

  17. “Non conventional” response Response after initial increase in total tumor volume • Response in indexlesions and newlesionsafter the appearanceofnew • Response after initial increase in total tumour volume 150 125 100 75 50 25 0 -25 -50 -75 -100 -125 19,373 17,242 15,111 12,980 10,849 8,718 6,587 4,456 2,325 194 -1,937 Change from baseline SPD (%) SPD (mm2) 6 months -9 -3 3 9 15 21 27 33 39 45 51 Relative week from first dose date Response in index and new lesions At or after the appearance of new lesions 1,272 1,124 975 827 678 530 382 233 85 -64 -212 50 25 0 –25 –50 –75 –100 –125 9.4 months Change from baseline SPD (%) SPD (mm2) -9 -3 3 9 15 21 27 33 39 45 51

  18. Example of conventional pattern of response: response in baseline lesions Baseline Week 12

  19. Anti CTLA4 . Esempio di risposta Screening Week 72 Durable & ongoing response without signs of IRAEs Week 12 Initial increase in total tumour burden (mWHO PD) Week 16 Responding Courtesy of K. Harmankaya

  20. Kaplan-Meier Analysis of Survival lpi + Gp100 (A) lpi Alone (B) Gp100 Alone (C) 1.0 0.9 0.8 0.7 0.6 Proportion alive 0.5 0.4 0.3 0.2 0.1 0.0 1 2 3 4 Years Comparison HR p-value Arms A vs. C 0.68 0.0004 Arms B vs. C 0.66 0.0026 Hodi S et al. NEJM 2010;363(8):711-23

  21. Study 024: Design Screening INDUCTION MAINTENANCE * Ipilimumab 10 mg/kg Q3W X4 Ipilimumab 10 mg/kg Q12W Previously Untreated Metastatic Melanoma (N=502) Dacarbazine 850 mg/m2 Q3W x8 R Placebo Q3W X4 Placebo Q12W Dacarbazine 850 mg/m2 Q3W x8 = blinded randomization (1:1) R * in absence of progression or dose-limiting toxicity Week 1 Week 12 Week 24 Baseline Tumor Assessment First Scheduled Tumor Assessment Wolchok J, et al. Presented at ASCO 2011. Abstract LBA5.

  22. Study 024:Ipi in 1st line Overall Survival 1.0 0. 0.8 0.7 Alive 0.6 0.5 Proportion 0.4 0.3 0.2 0.1 0.0 0 1 3 4 Years *3-year survival was a post-hoc analysis Wolchok J, et al. Presented at ASCO 2011. Abstract LBA5.

  23. Ipilimumab. FDA Approval March 2011. EMA Approval August 2011 In USA in prima e secondalineaalla dose di 3 mg /kg In Europa in secondalinea 14 Gennaio 2012 si è interrottol’expanded access in attesadell’approvazione AIFA…………

  24. MELANOMA PATHWAY MOLECULAR TARGETS

  25. BRAF KinaseAn important mediator of cellular proliferation RAF RTK RG7204 selectively inhibits oncogenic BRAF Ras GTP Y-P Y-P MEK MEK P P Other Effectors ERK ERK P P ARRESTED Nuclear Translocation Gene Expression Growth Factors Normal signaling Oncogenic signaling BRAFV600E Membrane BRAF mutations are exclusive to tumors > 50% malignant melanomas ~10% of CRC ~8% all solid tumors Abnormal Cellular Proliferation

  26. The first-in-human trial of RO5185426 was a Phase I dose escalation study (PLX06-02) in patientswithsolidtumors.

  27. RG 7204Efficacydata in BRAF V600E-mutatedmelanoma - A total of 26 of the 32 patients had a response (81%), with a complete response in 2 patients and a partial response in 24 patients. - The estimated median progression-free survival among all patients was more than 7 months. Flaherty KT et al NEJM 2010: 363 (9):

  28. RG 7204Rapid and dramatic tumor shrinkage Pre-treatment Pre-treatment Pre-treatment Cycle 2 Week 8 Week 8 P Chapman , et al, ESMO 2009, Abstract 6BA

  29. Summary of adverse events in ≥ 10% of patients (n=55) includes 1120 mg cohort, not ongoing 960 mg cohort P Chapman , et al, ESMO 2009, Abstract 6BA

  30. Neoformazioni Verrucose Ipercheratotiche con iperplasia dello strato granuloso

  31. R A N D O M • Fattori di stratificazione • M1 e livelli di LDH • Trattamenti precedenti • Sesso DTIC 1000mg/mq g1 q21 RO5185426 bid 960mg

  32. Overall survival (Dec 30, 2010 cutoff) 100 90 80 70 60 50 40 30 20 10 0 0 1 2 3 4 5 6 7 8 9 10 11 12 Vemurafenib (N=336) Est 6 mo survival 84% Dacarbazine (N=336) Est 6 mo survival 64% Overall survival (%) Hazard ratio 0.37 (95% CI; 0.26 - 0.55) Log-rank P<0.0001 Months No. of patients in follow up Dacarbazine Vemurafenib 336 336 283 320 192 266 137 210 98 162 64 111 39 80 20 35 9 14 1 6 1 1 Chapman et al. ASCO 2011

  33. Progression-free survival (Dec 30, 2010 cutoff) 100 90 80 70 60 50 40 30 20 10 0 0 1 2 3 4 5 6 7 8 9 10 11 12 Hazard Ratio 0.26 (95% CI; 0.20 - 0.33) Log-rank P<0.0001 Vemurafenib (N=275) Dacarbazine (N=274) Progression-free survival (%) Median 5.3 mos Median 1.6 mos Months No. of patients in follow up Dacarbazine Vemurafenib 274 275 213 268 85 211 48 122 28 105 16 50 10 35 6 16 3 4 0 3 Chapmanet al. NEJM 2011

  34. Number of patients receiving anti-cancer therapies after initial treatment on BRIM-3 Chapman P. et al. abs 8502 ASCO Ann. Meeting Chicago 2012

  35. Summary of overall survival data Chapman P. et al. abs 8502 ASCO Ann. Meeting Chicago 2012 aCensored at crossover

  36. Patterns of disease progression and role for continuous dosing in a Phase 1 study of vemurafenib (PLX4032, RG7204) in patients with metastatic melanoma K Kim, K Flaherty, P. Chapman, J Sosman, A Ribas, G. McArthur, R Amaravadi, R Lee, K Nolop, I. Puzanov M. D. Anderson Cancer Center; Massachusetts General Hospital Cancer Center; Memorial Sloan-Kettering Cancer Center; Vanderbilt University; University of California, Los Angeles; Peter MacCallum Cancer Centre; Abramson Cancer Center; Roche Pharmaceuticals; Plexxikon Inc.

  37. Clinical outcome aCalculated from the start of vermurafenib therapy PFS, progression-free survival; OS, overall survival

  38. Vemurafenib (Zelboraf) expandedaccessstudy • Open-label, multicenterexpandedaccessstudyof RO5185426 in patientswithmetastatic melanoma harboring the BRAF V600 mutation • Approximately 3000 patientsrecruitedintothisstudy • 140 Centers in 30 Countries Roche MO25515

  39. FDA and EMA ApprovalAugust 2011 and February 2012 The FDA has approved Zelboraf™ (vemurafenib) for the treatment of BRAF V600 mutation-positive unresectable (inoperable) or metastatic melanoma. Zelboraf is not recommended for use in patients with wild-type BRAF melanoma The agency has also approved the Roche cobas® 4800 BRAFV600 Mutation Test, a diagnostic test developed to identify patients eligible for treatment

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  43. Efficacy and safety of oral MEK162 in patients with locally advanced and unresectable or metastatic cutaneous melanoma harboring BRAFV600 or NRAS mutations Paolo A. Ascierto,* CarolaBerking, Sanjiv S. Argawala, Dirk Schadendorf, Carla van Herpen, Paola Queirolo, Christian U. Blank, Axel Hauschild, J. Thaddeaus Beck, Angela Zubel, FaizNiazi, Simon Wandel, ReinhardDummer *National Cancer Institute, Naples Italy

  44. MEK inhibitors: targeting RAS and BRAF mutations in cancer 70-90% pancreatic cancer 30-40% colon cancer RAS ~30% lung cancer ~20% melanoma MEK162 50-60% melanoma 36% thyroid cancer BRAF 12% ovarian cancer 8- 12% colorectal cancer Frémin C, Meloche S. J Hematol Oncol. 2010;3:8; Pratilis CA, Solit DB. Clin Cancer Research, 2010;16:3329

  45. MEK inhibitors.Study Design Arm 1: BRAFV600E/(n = 28) MEK162 45 mg BID Patients with advanced or metastatic unresectablecutaneous malignant melanoma harboring BRAFV600E/NRAS mutation Arm 2: NRAS-mutant (n = 26) MEK162 45 mg BID Stratificationbased on metastatic stage (M1a, M1b and M1c), region, and baseline LDH (< 0.8 x ULN, 0.8–1.1 x ULN, >1.1-2 x ULN)

  46. Best percentage change from baseline and best overall response (NRAS) 45 mg NRAS N=28* Progressive Disease (PD) Stable Disease (SD) Partial Response (PR) Unconfirmed PR *Patients with missing best % change from baseline and unknown overall response are not included. Ongoing pts

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