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Roma 22 Settembre 2012 La terapia medica del melanoma metastatico

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Presentation on theme: "Roma 22 Settembre 2012 La terapia medica del melanoma metastatico"— 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 patients1: 12 month OS: 25.5 %, median OS: 6.2 months (stage IV melanoma including patients with brain metastases) Proportion alive Time (months) Adapted from Korn 2008 Due to the lack of efficacious therapy, the preferred treatment for metastatic melanoma remains the inclusion in a clinical trial 1Korn EL et al. J Clin Oncol 2008;26(4): 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 RR Phase II trials
Authors Regimen N. Pts RR Survival (month) Legha Cancer J Sci Am ‘97 CVD+IL-2+IFN 115 60% 12 Comella Eur J Cancer ‘97 FTM+DTIC+IFN 43 40% 5.7 JCO ‘98 53 64% 11.8 Atkins Clin Cancer Res ‘02 CV+TMZ+IL-2+IFN 48 47% 7.5

6 CT/BioCT AND RR Authors Regimens N. Pts RR Survival (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 8 Bedikian JCO ‘06 DTIC+Oblimersen 385 386 7.5% 13.5% s 7.8

7 Metastatic Melanoma: Phase III Biochemo vs Chemo
Author Regimen No. of pts RR OS Keilholz CVDI-Il (JCO ‘05) vs. 363 CVDI Atkins CVD-bio (JCO ‘08) vs. 416 CVD

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 Pituitary Insufficiency in a patient with metastatic melanoma
Endocrinopathies Pituitary Insufficiency in a patient with metastatic melanoma 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 Rationale for proceed with therapy after early progression
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 Response in baseline lesions 50 25 -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) 5.2 months PR Change from baseline SPD (%) CR 'Stable disease' with slow, steady decline in total tumor volume Relative week from first dose date 50 25 -25 -50 -75 -100 -125 2,810 2,482 2,154 1,826 1,498 1,171 843 515 187 -140 -468 9 months Stable disease Change from baseline SPD (%)

17 “Non conventional” response
Response after initial increase in total tumor volume Response after initial increase in total tumour volume 150 125 100 75 50 25 -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 (%) 6 months SPD (mm2) Relative week from first dose date Response in index and new lesions At or after the appearance of new lesions Response in index lesions and new lesions after the appearance of new 50 25 –25 –50 –75 –100 –125 1,272 1,124 975 827 678 530 382 233 85 -64 -212 9.4 months Change from baseline SPD (%) SPD (mm2)

18 Example of conventional pattern of response: response in baseline lesions
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
1 2 3 4 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) Comparison HR p-value  Arms A vs. C Arms B vs. C Survival Rate Ipi + gp100 N=403 Ipi + pbo N=137 gp100 + pbo N=136 1 year 44% 46% 25% 2 year 22% 24% 14% Hodi S et al. NEJM 2010;363(8):711-23

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22 First Scheduled Tumor Assessment
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 R = blinded randomization (1:1) Maint was offered but protocol doesn’t test necessity * 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 Abstract LBA5. 22

23 Study 024:Ipi in 1st line Overall Survival
1.0 0. 0.8 Alive 0.7 0.6 0.5 Proportion 0.4 0.3 0.2 0.1 0.0 1 3 4 Years Estimated Survival Rate 1 Year 2 Year 3 Year* Ipilimumab + DTIC n=250 47.3 28.5 20.8 Placebo + DTIC n=252 36.3 17.9 12.2 *3-year survival was a post-hoc analysis Wolchok J, et al. Presented at ASCO 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 BRAF Kinase An important mediator of cellular proliferation
Growth Factors Normal signaling Oncogenic signaling RTK Y-P Ras GTP Other Effectors RAF MEK ERK P Nuclear Translocation Gene Expression BRAFV600E Membrane ARRESTED RG7204 selectively inhibits oncogenic BRAF MEK P B-Raf Targeting Represents Rational Strategy Against Aberrant Signaling In Ras/Raf Pathway B-Raf is a direct downstream target of oncogenes signaling through the Ras pathway PLX4032 (R7204) is a selective drug that targets tumour cells that have the BRAFV600E mutation found in approximately 60% of all melanomas, and 8% of all solid tumours including approximately 10% of colorectal cancers and 35% of thyroid cancers. In preclinical studies in both melanoma and colorectal cancer models, PLX4032 (R7204) reduced tumour size and slowed tumour progression, without evidence of significant side effects. Because PLX4032 (R7204) is highly selective for the mutated BRAF kinase, it should work specifically on cancer cells carrying this mutation, leaving healthy cells untouched in contrast to many other anti-cancer agents. ERK P BRAF mutations are exclusive to tumors > 50% malignant melanomas ~10% of CRC ~8% all solid tumors Abnormal Cellular Proliferation 27 27

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

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

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

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 Rash 29 % 2 % Fatigue 24 % Pruritus 20 % Photosensitivity reaction 14 % 0 % Nausea Anemia 13 % Cutaneous squamous cell carcinoma 11 % Alopecia P Chapman , et al, ESMO 2009, Abstract 6BA

32 Neoformazioni Verrucose Ipercheratotiche con iperplasia dello strato granuloso

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34 Fattori di stratificazione
M Fattori di stratificazione M1 e livelli di LDH Trattamenti precedenti Sesso DTIC 1000mg/mq g1 q21 RO bid 960mg

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

36 Progression-free survival (Dec 30, 2010 cutoff)
Hazard Ratio 0.26 (95% CI; ) Log-rank P<0.0001 100 90 80 70 60 50 40 30 20 10 Vemurafenib (N=275) Dacarbazine (N=274) Progression-free survival (%) Median 1.6 mos Median 5.3 mos 1 2 3 4 5 6 7 8 9 10 11 12 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 3 Chapman et al. NEJM 2011

37 Chapman P. et al. abs 8502 ASCO Ann. Meeting Chicago 2012
Number of patients receiving anti-cancer therapies after initial treatment on BRIM-3 Subsequent anti-cancer therapy Dacarbazine (n=338) Vemurafenib (n=337) Any 149 (44%) 122 (36%) Ipilimumab 73 (22%) 60 (18%) Dabrafenib 5 (1.5%) Crossover to vemurafenib 83 (25%) Chapman P. et al. abs ASCO Ann. Meeting Chicago 2012

38 Summary of overall survival data
ASCO 2011 ASCO (post-hoc) DTIC Vemurafenib DTICa Median follow-up, months 2.3 3.8 9.5 12.5 Median OS, months Not reliably estimated 9.7 13.6 6-month survival, % 64 84 66 12-month survival, % 44 56 Hazard ratio, OS 0.37 0.70 % reduction in risk of death 63 30 aCensored at crossover Chapman P. et al. abs 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 Duration of treatment post-progression
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) 0.729 7.0 (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) 0.008 6.0 (0–24.3) Median OS, months (range)a >25.2 (7.6–28.8) 11.2 (1.1–34.8) 0.054 14.9 (1.1–34.8) aCalculated from the start of vermurafenib therapy PFS, progression-free survival; OS, overall survival

41 Vemurafenib (Zelboraf) expanded access study
Open-label, multicenter expanded access study of RO in patients with metastatic melanoma harboring the BRAF V600 mutation Approximately patients recruited into this study 140 Centers in 30 Countries Screening 2000, Braf+ 1000, SFs 100 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 BRAFV600 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 RAS MEK162 50-60% melanoma 8- 12% colorectal cancer 12% ovarian cancer 36% thyroid cancer BRAF 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
Patients with advanced or metastatic unresectable cutaneous malignant melanoma harboring BRAFV600E/NRAS mutation Arm 1: BRAFV600E/(n = 28) MEK mg BID Arm 2: NRAS-mutant (n = 26) MEK mg BID Stratification based 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)

50 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

51 PFS – NRAS- /BRAF-mutant
100 PFS (%) Median (months) [95% CI]: [2.53, 5.39] Median (days) [95% CI]: 111 [77, 164] Time (days) 2 14 43 71 45 mg 20 40 60 61 80 122 183 274 365 NRASmt Median (months) [95% CI]: 3.55 [2.00, 3.81] Median (days) [95% CI]: 108 [61, 116] BRAFmt Number of patients at risk

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58 Rationale for Combination of BRAFi (GSK436) + MEKi (GSK212) in BRAF Mutant Tumors
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 Tumor Type % BRAF Mutant Melanoma 50% Thyroid Cholangioca 15% NSCLC 7-8% Colorectal 5% Goals of Combination Improve complete response rate Suppress MAP kinase dependent resistance mechanisms and improve duration of response Decrease incidence of BRAFi-induced proliferative skin lesions Tona Gilmer: Constitutive activation of the RAS/RAF/MEK/ERK MAPK signaling pathway in melanoma can occur primarily through oncogenic mutations in BRAF or NRAS, or through autocrine growth factor stimulation. Activating mutations of BRAF at valine (V) 600 to glutamic acid (E) or lysine (K) occur in ~50% of melanoma cases, and promote downstream MEK–ERK signaling, resulting in cell proliferation, survival, invasion and metastasis. Both GSK and GSK are selective and potent kinase inhibitors. GSK436 targets RAF including the mutant forms of BRAF V600E (with IC50 value of 0.65 nM) and V600K with IC50 value of 0.5 nM. GSK212 inhibits both non-activated and the activated-MEK1/2 with IC50 values from nM. Recent clinical trials with both (GSK and GSK ) as monotherapy have shown activity in melanoma patients with tumors harboring BRAFV600E/K mutations. However, some tumors do not respond or develop resistance to these agents. Thus, an approach combining these two agents with different mechanisms of action to block the MAPK signaling pathway, may provide more effective treatment for this disease. In fact, GSK436 plus GSK212 has a synergistic effect on cell growth inhibition as exemplified in A375PF11 melanoma cells (shown at the right side of the slide), with combination index value ~ The combination demonstrated more effective blockade of the MAPK signaling measured by a reduction in phospho ERK (western blot). 1 Kefford et al., SMR 2010; 2 Lewis et al. Perspectives in Melanoma 2011 58

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62 IPILIMUMAB VS VEMERAFENIB PFS
Vemurafenib

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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 months 1-year OS 51.0%.

66 Pre-screening for c-Kit mutation
Studio di fase III randomizzato . NILOTINIB vs DTIC in c-kit mutati . Pre-screening for c-Kit mutation Screening Randomization 120 Patients1:1 DTIC 850 mg/m2 IV q3weeks Tasigna 400 mg b.i.d. Progression Progression Cross-over? Follow for survival No Follow for survival

67 MELANOMA in 2012 1° line B-Raf mutated Vemurafenib Ipilimumab +/CT
Setting EMA approval Clinical trials evidence 1° line B-Raf mutated Vemurafenib Ipilimumab +/CT B-Raf WT CT Ipilimumab +/-CT 2 line B Raf mutated Ipilimumab Ipilimumab ? BRAFi +MTT-CT


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