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Roma 22 Settembre 2012 La terapia medica del melanoma metastatico Paola Queirolo Dept. Medical Oncology A National Institute for Cancer Research -Genova.

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Presentation on theme: "Roma 22 Settembre 2012 La terapia medica del melanoma metastatico Paola Queirolo Dept. Medical Oncology A National Institute for Cancer Research -Genova."— Presentation transcript:

1 Roma 22 Settembre 2012 La terapia medica del melanoma metastatico Paola Queirolo Dept. Medical Oncology A National Institute for Cancer Research -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 Survival data from 42 Phase II trials with over 2‘100 stage IV patients 1 : 12 month OS: 25.5 %, median OS: 6.2 months (stage IV melanoma including patients with brain metastases) 1 Korn EL et al. J Clin Oncol 2008;26(4):527-34. 2 Dummer 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. Time (months) Proportion alive Due to the lack of efficacious therapy, the preferred treatment for metastatic melanoma remains the inclusion in a clinical trial Adapted from Korn 2008

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

5 CT/BioCT AND RR Phase II trials AuthorsRegimenN. Pts RRSurvival (month) Legha Cancer J Sci Am ‘97 CVD+IL-2+IFN11560%12 Comella Eur J Cancer ‘97 FTM+DTIC+IFN4340%5.7 Legha JCO ‘98 CVD+IL-2+IFN5364%11.8 Atkins Clin Cancer Res ‘02 CV+TMZ+IL-2+IFN4847%7.5

6 CT/BioCT AND RR AuthorsRegimensN. Pts RRSurvival (month) Rosenberg JCO ‘99 CDDP+DTIC+Tam CD+IL-2+IFN+Tam 52 50 27% 44% 15 10 Eton JCO ‘02 CVD CVD+IL-2+IFN 92 91 25% 48% s 9 11 Avril JCO ‘04 DTIC Fotemustine 112 117 6.8% 15.2% s 5.6 7.3 Kaufmann JCO ‘05 Tmz Tmz+IFN 134 137 13% 24% s 8989 Bedikian JCO ‘06 DTIC DTIC+Oblimersen 385 386 7.5% 13.5% s 7.8 9

7 KeilholzCVDI-Il-2 239 (JCO ‘05) vs.363 CVDI 219 AtkinsCVD-bio 179 (JCO ‘08) vs.416 CVD129 AuthorRegimen No. of pts RROS Metastatic Melanoma: Phase III Biochemo vs Chemo

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 is an immunogenic cancer Spontaneous remissions TILs associated with regression Ab and CTL responses to melanoma Antigens

10 IMMUNOTHERAPY OF MELANOMA  BRMs: rIFN alfa, rIL-2, GM-CSF, IL-12,IL-18, IL-21  Adoptive immunotherapy: TIL,NK,DC  Vaccines: autologous, allogeneic, peptides, anti idiotypes Abs, gene modified ca cells, dendritic pulsed  DNA based therapy: allovectin 7  Targeted therapies acting on immunological cells : 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 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 Pituitary Insufficiency in a patient with metastatic melanoma Endocrinopathies 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 “Conventional” response Response in baseline lesions -9-33915212733394551 Relative week from first dose date Change from baseline SPD (%) SPD (mm 2 ) 2,894 2,556 2,218 1,881 1,543 1,206 868 530 193 -145 -482 50 25 0 -25 -50 -75 -100 -125 Response in baseline lesions PD PR CR 5.2 months 'Stable disease' with slow, steady decline in total tumor volume -9-33915212733394551 Stable disease Change from baseline SPD (%) 2,810 2,482 2,154 1,826 1,498 1,171 843 515 187 -140 -468 50 25 0 -25 -50 -75 -100 -125 9 months

17 150 125 100 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 SPD (mm 2 ) Relative week from first dose date 50 25 0 –25 –50 –75 –100 –125 Change from baseline SPD (%) 1,272 1,124 975 827 678 530 382 233 85 -64 -212 SPD (mm 2 ) Change from baseline SPD (%) -9-33915212733394551 Response after initial increase in total tumor volume 6 months 9.4 months Response in index and new lesions At or after the appearance of new lesions “Non conventional” response Response in index lesions and new lesions after the appearance of new Response after initial increase in total tumour volume

18 Example of conventional pattern of response: response in baseline lesions BaselineWeek 12

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

20 1234 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Proportion alive Years lpi + Gp100(A) lpi Alone(B) Gp100 Alone(C) Survival RateIpi + gp100 N=403Ipi + pbo N=137 gp100 + pbo N=136 1 year44%46%25% 2 year22%24%14% Kaplan-Meier Analysis of Survival Comparison HR p-value Comparison HR p-value Arms A vs. C 0.68 0.0004 Arms A vs. C 0.68 0.0004 Arms B vs. C 0.66 0.0026 Arms B vs. C 0.66 0.0026 Hodi S et al. NEJM 2010;363(8):711-23

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22 Baseline Tumor Assessment First Scheduled Tumor Assessment Screening Ipilimumab 10 mg/kg Q12W Ipilimumab 10 mg/kg Q3W X4 Week 12Week 24Week 1 INDUCTIONMAINTENANCE * * in absence of progression or dose- limiting toxicity Dacarbazine 850 mg/m 2 Q3W x8 Previously Untreated Metastatic Melanoma (N=502) Placebo Q3W X4 Placebo Q12W R R = blinded randomization (1:1) Dacarbazine 850 mg/m 2 Q3W x8 Study 024: Design Wolchok J, et al. Presented at ASCO 2011. Abstract LBA5.

23 Estimated Survival Rate1 Year2 Year3 Year* Ipilimumab + DTIC n=250 47.328.520.8 Placebo + DTIC n=252 36.317.912.2 *3-year survival was a post-hoc analysis Proportion Alive 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0. 1.0 Years 0134 Study 024:Ipi in 1 st line Overall Survival Wolchok J, et al. Presented at ASCO 2011. Abstract LBA5.

24 Ipilimumab. FDA Approval March 2011. EMA Approval August 2011 In USA in prima e seconda linea alla dose di 3 mg /kg In Europa in seconda linea 14 Gennaio 2012 si è interrotto l’expanded access in attesa dell’approvazione AIFA…………

25 MOLECULAR TARGETS MELANOMA PATHWAY

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27 Membrane RTK Y-P Ras GTP Other Effectors Growth Factors RAF MEK ERK P P Nuclear Translocation Gene Expression Normal signaling Oncogenic signaling BRAF V600E MEK P ERK P Abnormal Cellular Proliferation ARRESTED RG7204 selectively inhibits oncogenic BRAF BRAF Kinase An important mediator of cellular proliferation BRAF mutations are exclusive to tumors > 50% malignant melanomas ~10% of CRC ~8% all solid tumors

28 The first-in-human trial of RO5185426 was a Phase I dose escalation study (PLX06-02) in patients with solid tumors.

29 - 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): RG 7204 Efficacy data in BRAF V600E-mutated melanoma

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

31 Summary of adverse events in ≥ 10% of patients (n=55) includes 1120 mg cohort, not ongoing 960 mg cohort Adverse event All related adverse events Related Grade ≥ 3 Rash29 %2 % Fatigue24 %2 % Pruritus20 %2 % Photosensitivity reaction14 %0 % Nausea14 %0 % Anemia13 %0 % Cutaneous squamous cell carcinoma 11 % Alopecia11 %0 % P Chapman, et al, ESMO 2009, Abstract 6BA

32 Neoformazioni Verrucose Ipercheratotiche con iperplasia dello strato granuloso

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34 RANDOMRANDOM Fattori di stratificazione M1 e livelli di LDHM1 e livelli di LDH Trattamenti precedentiTrattamenti precedenti SessoSesso DTIC 1000mg/mq g1 q21 RO5185426 bid 960mg

35 100 90 80 70 60 50 40 30 20 10 0 Overall survival (%) No. of patients in follow up Dacarbazine Vemurafenib 0123456789101112 Vemurafenib (N=336) Est 6 mo survival 84% Months 336 283 320 192 266 137 210 98 162 64 111 39 80 20 35 1616 1111 Dacarbazine (N=336) Est 6 mo survival 64% 9 14 Hazard ratio 0.37 (95% CI; 0.26 - 0.55) Log-rank P<0.0001 Overall survival (Dec 30, 2010 cutoff) Chapman et al. ASCO 2011

36 100 90 80 70 60 50 40 30 20 10 0 Progression-free survival (%) No. of patients in follow up Dacarbazine Vemurafenib 0123456789101112 Hazard Ratio 0.26 (95% CI; 0.20 - 0.33) Log-rank P<0.0001 Months 274 275 213 268 85 211 48 122 28 105 16 50 10 35 6 16 3434 0303 Dacarbazine (N=274) Vemurafenib (N=275) Progression-free survival (Dec 30, 2010 cutoff) Median 1.6 mos Median 5.3 mos Chapman et al. NEJM 2011

37 Number of patients receiving anti-cancer therapies after initial treatment on BRIM-3 Subsequent anti-cancer therapy Dacarbazine (n=338) Vemurafenib (n=337) Any149 (44%)122 (36%) Ipilimumab73 (22%)60 (18%) Dabrafenib5 (1.5%)0 Crossover to vemurafenib 83 (25%)– Chapman P. et al. abs 8502 ASCO Ann. Meeting Chicago 2012

38 Summary of overall survival data ASCO 2011ASCO 2012 (post-hoc) DTICVemurafenibDTIC a Vemurafenib Median follow-up, months2.33.89.512.5 Median OS, monthsNot reliably estimated9.713.6 6-month survival, %64846684 12-month survival, %––4456 Hazard ratio, OS0.370.70 % reduction in risk of death 6330 a Censored at crossover Chapman P. et al. abs 8502 ASCO Ann. Meeting Chicago 2012

39 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.

40 Clinical outcome Outcome Duration of treatment post- progression All patients N=48) >30 days (N=20) <30 days (N=24) P-value Median PFS, months (range) a 6.6 (2.8–16.9) 6.3 (0.9–23.8) 0.7297.0 (0.9–26.0) Median treatment duration beyond initial PD, months (range) 3.8 (1.1–14.8) ––– Median survival beyond initial PD, months (range) >9.1 (1.9–24.3) 3.4 (0–19.6) 0.0086.0 (0–24.3) Median OS, months (range) a >25.2 (7.6–28.8) 11.2 (1.1–34.8) 0.05414.9 (1.1–34.8) a Calculated from the start of vermurafenib therapy PFS, progression-free survival; OS, overall survival

41 Open-label, multicenter expanded access study of RO5185426 in patients with metastatic melanoma harboring the BRAF V600 mutation Approximately 3000 patients recruited into this study 140 Centers in 30 Countries Vemurafenib (Zelboraf) expanded access study Roche MO25515

42 FDA and EMA Approval August 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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47 Efficacy and safety of oral MEK162 in patients with locally advanced and unresectable or metastatic cutaneous melanoma harboring BRAF V600 or NRAS mutations Paolo A. Ascierto,* Carola Berking, Sanjiv S. Argawala, Dirk Schadendorf, Carla van Herpen, Paola Queirolo, Christian U. Blank, Axel Hauschild, J. Thaddeaus Beck, Angela Zubel, Faiz Niazi, Simon Wandel, Reinhard Dummer *National Cancer Institute, Naples Italy

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

49 MEK inhibitors.Study Design Arm 1: BRAF V600E /(n = 28) MEK162 45 mg BID Arm 1: BRAF V600E /(n = 28) MEK162 45 mg BID Arm 2: NRAS-mutant (n = 26) MEK162 45 mg BID Arm 2: NRAS-mutant (n = 26) MEK162 45 mg BID Patients with advanced or metastatic unresectable cutaneous malignant melanoma harboring BRAF V600E /NRAS mutation Stratification based on metastatic stage (M1a, M1b and M1c), region, and baseline LDH ( 1.1-2 x ULN)

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

51 PFS – NRAS- /BRAF-mutant Number of patients at risk 100 PFS (%) Median (months) [95% CI]: 3.65 [2.53, 5.39] Median (days) [95% CI]: 111 [77, 164] Time (days) 002144371 45 mg 0 0 20 40 60 61 80 122 183274 365 Median (months) [95% CI]: 3.55 [2.00, 3.81] Median (days) [95% CI]: 108 [61, 116] NRASmt BRAFmt

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58 Rationale for Combination of BRAFi (GSK436) + MEKi (GSK212) in BRAF Mutant Tumors 1 Kefford et al., SMR 2010; 2 Lewis et al. Perspectives in Melanoma 2011 Tumor Type% BRAF Mutant Melanoma50% Thyroid50% Cholangioca15% NSCLC7-8% Colorectal5% Goals of Combination 1.Improve complete response rate 2.Suppress MAP kinase dependent resistance mechanisms and improve duration of response 3.Decrease incidence of BRAFi-induced proliferative skin lesions pERK BRAF MEK Proliferation Survival Invasion Metastasis BRAFi (GSK436) RR 77% 1 Mechanistic toxicity: Hyperproliferative skin AEs MEKi (GSK212) RR 35% 2 Mechanistic toxicity: rash RAS

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62 IPILIMUMAB VS VEMERAFENIB PFS IpilimumabVemurafenib

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64 Forty-three patients with metastatic melanoma harboring c-Kit aberrations were enrolled on this phase II trial. Each patient received a continuous dose of imatinib 400 mg/d unless intolerable toxicities or disease progression occurred. Fifteen patients who experienced progression of disease were allowed to escalate the dose to 800 mg/d.

65 PFS and OS Rates Median PFS 3.5 months1-year OS 51.0%.

66 Pre-screening for c-Kit mutation Screening Randomization 120 Patients1:1 Randomization 120 Patients1:1 DTIC 850 mg/m 2 IV q3weeks DTIC 850 mg/m 2 IV q3weeks Progression Tasigna 400 mg b.i.d. Tasigna 400 mg b.i.d. Progression Cross-over? Follow for survival No. Studio di fase III randomizzato. NILOTINIB vs DTIC in c-kit mutati

67 MELANOMA in 2012 SettingEMA approvalClinical trials evidence 1° lineB-Raf mutatedVemurafenibIpilimumab +/CT B-Raf WTCTIpilimumab +/-CT 2 lineB Raf mutatedIpilimumabIpilimumab ? BRAFi +MTT-CT B-Raf WTIpilimumab


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