Presentation on theme: "Roma 22 Settembre 2012 La terapia medica del melanoma metastatico"— Presentation transcript:
1Roma 22 Settembre 2012 La terapia medica del melanoma metastatico Paola QueiroloDept. Medical Oncology ANational Institute for Cancer Research -Genova
2Metastatic Melanoma: medical treatments ChemotherapySingle agent or poly-Chemotherapymonochemotherapy best option of careImmunotherapy : alpha IFNs, IL-2VaccinationsBio-chemotherapyTargeted therapies
3Overall 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 aliveTime (months)Adapted from Korn 2008Due to the lack of efficacious therapy, the preferred treatment for metastatic melanoma remains the inclusion in a clinical trial1Korn 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.
4Metastatic Melanoma : Single Agent Options Overall responses with monotherapyKhayat, Educational Book, ASCO 2000
5CT/BioCT AND RR Phase II trials AuthorsRegimenN. PtsRRSurvival(month)LeghaCancer J Sci Am ‘97CVD+IL-2+IFN11560%12ComellaEur J Cancer ‘97FTM+DTIC+IFN4340%5.7JCO ‘985364%11.8AtkinsClin Cancer Res ‘02CV+TMZ+IL-2+IFN4847%7.5
7Metastatic Melanoma: Phase III Biochemo vs Chemo AuthorRegimenNo. of ptsRROSKeilholz CVDI-Il(JCO ‘05) vs. 363CVDIAtkins CVD-bio(JCO ‘08) vs. 416CVD
8NEW DRUGS. FDA and EMA approval in 2011 Targeted immunotherapy: anti-CTLA-4 mAbsMolecular targeted therapies: anti B raf V600 mut
9Melanoma is an immunogenic cancer Spontaneous remissionsTILs associated with regressionAb and CTL responses to melanoma Antigens
10IMMUNOTHERAPY OF MELANOMA BRMs: rIFN alfa, rIL-2, GM-CSF, IL-12,IL-18, IL-21Adoptive immunotherapy: TIL,NK,DCVaccines: autologous, allogeneic, peptides, anti idiotypes Abs, gene modified ca cells, dendritic pulsedDNA based therapy: allovectin 7Targeted therapies acting on immunological cells : antCTLA4
11Safety: Immune Breakthrough Events IBEs: Immune-mediated adverse events based on the action of Anti CTLA-4 mAbsCorrelation with clinical responseUsually linked to drug-exposure and reversibleManageable with established therapies (e.g. corticosteroids)
12Novel 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
13Anti-CTLA-4 mAbs: SAFETY GI toxicity:Diarrhea: watery to frank bloodBx: inflammatory colitisSkin toxicity:Rash, pruritus and vitiligoEndocrine Toxicity:Hypophysitis; Thyroiditis
14Pituitary Insufficiency in a patient with metastatic melanoma EndocrinopathiesPituitary Insufficiency in a patient with metastatic melanomaPresumed Autoimmune HypophysitisConfusion, fatigue, impotenceHeadacheLow ACTH/cortisol↓ T4, testosterone and/or prolactinIncreased pituitary size on MRIAsymptomatic with replacement therapySlow return of some endocrinefunctionBlansfield JA, Beck KE, Tran K, Yang JC, Hughes MS, Kammula US, et al. Cytotoxic T-lymphocyte-associated antigen-4 blockage caninduce autoimmune hypophysitis in patients with metastatic melanoma and renal cancer. J Immunother 2005;28(6):593-8.
15Rationale for proceed with therapy after early progression Anti-CTLA-4 mAbsTumor responses are sufficient but not necessary for prolonged survivalRationale for proceed with therapy after early progressionIncreased volume of lesions may be due to lymphocytic infiltrateBulanhagui et al. ASCO 2006
16“Conventional” response Response in baseline lesionsResponse in baseline lesions5025-25-50-75-100-1252,8942,5562,2181,8811,5431,206868530193-145-482PDSPD (mm2)5.2 monthsPRChange from baseline SPD (%)CR'Stable disease' with slow, steadydecline in total tumor volumeRelative week from first dose date5025-25-50-75-100-1252,8102,4822,1541,8261,4981,171843515187-140-4689 monthsStable diseaseChange from baseline SPD (%)
17“Non conventional” response Response after initial increase in total tumor volumeResponse after initial increase in total tumour volume150125100755025-25-50-75-100-12519,37317,24215,11112,98010,8498,7186,5874,4562,325194-1,937Change from baseline SPD (%)6 monthsSPD (mm2)Relative week from first dose dateResponse in index and new lesionsAt or after the appearance of new lesionsResponse in index lesions and new lesions after the appearance of new5025–25–50–75–100–1251,2721,12497582767853038223385-64-2129.4 monthsChange from baseline SPD (%)SPD (mm2)
18Example of conventional pattern of response: response in baseline lesions Week 12
19Anti CTLA4 . Esempio di risposta ScreeningWeek 72Durable & ongoing responsewithout signs of IRAEsWeek 12Initial increase intotal tumour burden (mWHO PD)Week 16RespondingCourtesy of K. Harmankaya
20Kaplan-Meier Analysis of Survival 12340.00.10.20.18.104.22.168.22.214.171.124Proportion aliveYearslpi + Gp100 (A)lpi Alone (B)Gp100 Alone (C)Comparison HR p-value Arms A vs. CArms B vs. CSurvival RateIpi + gp100 N=403Ipi + pbo N=137gp100 + pbo N=1361 year44%46%25%2 year22%24%14%Hodi S et al. NEJM 2010;363(8):711-23
22First Scheduled Tumor Assessment Study 024: DesignScreeningINDUCTIONMAINTENANCE *Ipilimumab 10 mg/kgQ3W X4Ipilimumab 10 mg/kgQ12WPreviouslyUntreatedMetastaticMelanoma(N=502)Dacarbazine 850 mg/m2Q3W x8RPlaceboQ3W X4PlaceboQ12WDacarbazine 850 mg/m2Q3W x8R= blindedrandomization(1:1)Maint was offered but protocol doesn’t test necessity* in absence of progression or dose-limiting toxicityWeek 1Week 12Week 24BaselineTumor AssessmentFirst Scheduled Tumor AssessmentWolchok J, et al. Presented at ASCO Abstract LBA5.22
23Study 024:Ipi in 1st line Overall Survival 1.00.0.8Alive0.70.60.5Proportion0.40.30.20.10.0134YearsEstimated Survival Rate1 Year2 Year3 Year*Ipilimumab + DTICn=25047.328.520.8Placebo + DTIC n=25236.317.912.2*3-year survival was a post-hoc analysisWolchok J, et al. Presented at ASCO Abstract LBA5.
24Ipilimumab. FDA Approval March 2011. EMA Approval August 2011 In USA in prima e seconda linea alla dose di 3 mg /kgIn Europa in seconda linea14 Gennaio 2012 si è interrotto l’expanded access in attesa dell’approvazione AIFA…………
27BRAF Kinase An important mediator of cellular proliferation Growth FactorsNormalsignalingOncogenicsignalingRTKY-PRasGTPOther EffectorsRAFMEKERKPNuclear TranslocationGene ExpressionBRAFV600EMembraneARRESTEDRG7204 selectively inhibits oncogenic BRAFMEKPB-Raf Targeting Represents Rational Strategy Against Aberrant Signaling In Ras/Raf PathwayB-Raf is a direct downstream target of oncogenes signaling through the Ras pathwayPLX4032 (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.ERKPBRAF mutations are exclusive to tumors> 50% malignant melanomas~10% of CRC~8% all solid tumorsAbnormal CellularProliferation2727
28The first-in-human trial of RO was a Phase I dose escalation study (PLX06-02) in patients with solid tumors.
29RG 7204 Efficacy data in BRAF V600E-mutated melanoma - A total of 26 of the 32 patients had a response (81%), with a completeresponse 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):
30RG 7204 Rapid and dramatic tumor shrinkage Pre-treatmentPre-treatmentPre-treatmentCycle 2Week 8Week 8P Chapman , et al, ESMO 2009, Abstract 6BA
31Summary of adverse events in ≥ 10% of patients (n=55) includes 1120 mg cohort, not ongoing 960 mg cohortAdverse eventAll relatedadverse eventsRelatedGrade ≥ 3Rash29 %2 %Fatigue24 %Pruritus20 %Photosensitivity reaction14 %0 %NauseaAnemia13 %Cutaneous squamous cell carcinoma11 %AlopeciaP Chapman , et al, ESMO 2009, Abstract 6BA
32Neoformazioni Verrucose Ipercheratotiche con iperplasia dello strato granuloso
34Fattori di stratificazione MFattori di stratificazioneM1 e livelli di LDHTrattamenti precedentiSessoDTIC 1000mg/mq g1 q21RO bid 960mg
35Overall survival (Dec 30, 2010 cutoff) 100908070605040302010Vemurafenib (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<0.0001123456789101112MonthsNo. of patients in follow upDacarbazineVemurafenib336283320192266137210981626411139802035914161Chapman et al. ASCO 2011
36Progression-free survival (Dec 30, 2010 cutoff) Hazard Ratio 0.26(95% CI; )Log-rank P<0.0001100908070605040302010Vemurafenib (N=275)Dacarbazine (N=274)Progression-free survival (%)Median 1.6 mosMedian 5.3 mos123456789101112MonthsNo. of patients in follow upDacarbazineVemurafenib27427521326885211481222810516501035616343Chapman et al. NEJM 2011
37Chapman P. et al. abs 8502 ASCO Ann. Meeting Chicago 2012 Number of patients receiving anti-cancer therapies after initial treatment on BRIM-3Subsequent anti-cancer therapyDacarbazine (n=338)Vemurafenib (n=337)Any149 (44%)122 (36%)Ipilimumab73 (22%)60 (18%)Dabrafenib5 (1.5%)Crossover to vemurafenib83 (25%)–Chapman P. et al. abs ASCO Ann. Meeting Chicago 2012
38Summary of overall survival data ASCO 2011ASCO (post-hoc)DTICVemurafenibDTICaMedian follow-up, months126.96.36.1992.5Median OS, monthsNot reliably estimated9.713.66-month survival, %64846612-month survival, %–4456Hazard ratio, OS0.370.70% reduction in risk of death6330aCensored at crossoverChapman P. et al. abs ASCO Ann. Meeting Chicago 2012
39Patterns of disease progression and role for continuous dosing in a Phase 1 study of vemurafenib (PLX4032, RG7204) in patients with metastatic melanomaK Kim, K Flaherty, P. Chapman, J Sosman, A Ribas, G. McArthur, R Amaravadi, R Lee, K Nolop, I. PuzanovM. 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.
40Duration of treatment post-progression Clinical outcomeOutcomeDuration of treatment post-progressionAll patients N=48)>30 days (N=20)<30 days (N=24)P-valueMedian PFS, months (range)a6.6 (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)aCalculated from the start of vermurafenib therapyPFS, progression-free survival; OS, overall survival
41Vemurafenib (Zelboraf) expanded access study Open-label, multicenter expanded access study of RO in patients with metastatic melanoma harboring the BRAF V600 mutationApproximately patients recruited into this study140 Centers in 30 CountriesScreening 2000, Braf+ 1000, SFs 100Roche MO25515
42FDA 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 melanomaThe agency has also approved the Roche cobas® 4800 BRAFV600 Mutation Test, a diagnostic test developed to identify patients eligible for treatment
47Efficacy and safety of oral MEK162 in patients with locally advanced and unresectable or metastatic cutaneous melanoma harboring BRAFV600 or NRAS mutationsPaolo 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, NaplesItaly
48MEK inhibitors: targeting RAS and BRAF mutations in cancer 70-90% pancreatic cancer30-40% colon cancer~30% lung cancer~20% melanomaRASMEK16250-60% melanoma8- 12% colorectal cancer12% ovarian cancer36% thyroid cancerBRAFFrémin C, Meloche S. J Hematol Oncol. 2010;3:8;Pratilis CA, Solit DB. Clin Cancer Research, 2010;16:3329
49MEK inhibitors.Study Design Patients with advanced or metastatic unresectable cutaneous malignant melanoma harboring BRAFV600E/NRAS mutationArm 1: BRAFV600E/(n = 28)MEK mg BIDArm 2: NRAS-mutant (n = 26)MEK mg BIDStratification 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)
50Best percentage change from baseline and best overall response (NRAS) 45 mg NRASN=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
58Rationale for Combination of BRAFi (GSK436) + MEKi (GSK212) in BRAF Mutant Tumors pERKBRAFMEKProliferationSurvivalInvasionMetastasisBRAFi (GSK436) RR 77%1Mechanistic toxicity: Hyperproliferative skin AEsMEKi (GSK212)RR 35%2Mechanistic toxicity: rashRASTumor Type% BRAF MutantMelanoma50%ThyroidCholangioca15%NSCLC7-8%Colorectal5%Goals of CombinationImprove complete response rateSuppress MAP kinase dependent resistance mechanisms and improve duration of responseDecrease incidence of BRAFi-induced proliferative skin lesionsTona 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 201158
64Forty-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.
65PFS and OS RatesMedian PFS 3.5 months1-year OS 51.0%.
66Pre-screening for c-Kit mutation Studio di fase III randomizzato . NILOTINIB vs DTIC in c-kit mutati.Pre-screening for c-Kit mutationScreeningRandomization120 Patients1:1DTIC 850 mg/m2IV q3weeksTasigna 400 mgb.i.d.ProgressionProgressionCross-over?Follow for survivalNoFollow for survival