La terapia medica: Microcitoma

Transcription

1 Microcitoma La terapia medica: Novità Sara Pilotto Oncologia Medica, Scuola di Specializzazione in Oncologia, Università di Verona Direttore: Prof. G.P. Tortora Policlinico G.B. Rossi, Azienda Ospedaliera Universitaria Integrata, Verona Lucca, 27 Novembre 2013

2 a Static Landscape Surgery Radiotherapy Nitrogen mustard Combination > single agent CAV or CEV 2 line CT PCI for LD SCLC TNM staging Novel agents SCLC vs NSCLC LD vs ED Cyclophosphamide EP CT + RT for LD SCLC IP PCI for ED SCLC Novel regimens Focus on targeted agents and news from WCLC 2013 Chan & Coward, J Thorac Dis 2013

3 Clinical Relevance of the Oncogene Addiction i In patients with solid malignancies in which a dominant mutation or gene amplification drives tumor growth, targeted therapies are highly hl effective but rarely curative ckit mutations in GIST HER2 amplification in breast cancer EGFR mutation in NSCLC ALK translocation in NSCLC GENETICS DEPENDENCY PHARMACOLOGIC VULNERABILITY Does that apply to SCLC? Modified By Bria and Puglisi

4 SCLC [vss NSCLC] Molecular Profile Biologic Behavior High cellular proliferation Short cell cycle time Rapid doubling time Central presentation Early metastasis Chemo radiation i sensitivity ii i Peifer et al, Nature Genetics 2012

5 Genomic Analysis of SCLC Hot spot mutations TP53, RB1, PIK3CA, CDKN2A, PTEN RAS family regulators (RAB37, RASGRF1, RASGRF2) Chromatin modifiers (EP300, DMBX1, MLL2, MED12, etc.) Hot spot mutationsplus q score RUNX1T1, CDYL, RIMS2 Gene families and pathways PI3K pathway, Notch and Hedgehog, g,glutamate receptor family, DNA repair/checkpoint, SOX family Focal amplifications MYC, SOX2, SOX4, KIT Circos plot whole genome SCLC 22 significantly mutated genes Recurrent translocations and fusion genes Recurrent: RLF MYCL1 Kinase fusions Peifer, M et al: Nature Genetics 44: , 2012 Rudin CM et al: Nature genetics 44: , 2012 Kelly, Oral Abstract Discussant IASLC 2013

6 the Old Glories Bevacizumab Sunitinib Pazopanib Ipilimumab b..and many others

7 the Old Glories Bevacizumab Sunitinib Pazopanib Ipilimumab b..and many others

8 Bevacizumab [phase II] Setting Exp arm * N RR(%) mpfs (ms) Control arm mos (ms) Control arm 1 line/m P60E120B x # # 1 line P30I65B x # # 1 line/m P65 vs C5 E100B x line/m C4I60B x # # 2 line T2.3B x S:6.2/R: # # 2 line TXL90B * Cisplatin 60 mg/mq d1/etoposide 120 mg/mq d1 3 + bevacizumab 15 mg/mq Cisplatin 30 mg/mq d1,8/irinotecan 65 mg/mq d1,8 + bevacizumab 15 mg/mq Cisplatin 65 mg/mq or carbo AUC5 d1/ d1/etoposide 100 mg/mq d1 3+ bevacizumab/p 15 mg/mq Carbo AUC4 d1,8,15/irinotecan 60 mg/mq d1,8,15 + bevacizumab 10 mg/mq d1,15 Oral topotecan 2.3 mg/mq d1 5 + bevacizumab 15 mg/mq d1 Pacllitaxel 90 mg/mq d1,8,15 + bevacizumab 10 mg/mq d1,15 Pacllitaxel 90 mg/mq d1815+ bevacizumab 10 mg/mq d1 15 Horn et al, JCO 2009 Spiegel et al, JCO 2009 Ready et al, JCO 2011 Schmittel et al, AO 2011 Hanna et al, JCO 2006 Spiegel CLC 2013 Spiegel et al, JCO 2011 Jalal et al, JCO 2010 # historical controls

9 Bevacizumab None of these trials reached the mos of 12.8 months obtained for IP in Noda, NEJM 2002 All regimes were feasible with few treatment related death end no evidence of serious haemoptysis The addition of bevacizumab to standard chemotherapy might implement the overall activity (in 1 st line) But phase IItrial il often overestimated the results Comparable of those observed in others malignancies a small clinical benefit Phase III randomized trial comparing 1 st chemotherapy +/ bevacizumab maybe appropriate Modified by Belani, IASLC 2013

10 Ongoing RCTs: DDP + VP 16 ± BEVACIZUMAB PI: A. Ardizzoni The objective of the study is voluntary pretentious (1 yr OS 40% 58%) = 206 pts Interim analysis (for futility) ongoing (140/206 pts)

11 the Old Glories Bevacizumab Sunitinib Pazopanib Ipilimumab b..and many others

12 Sunitinib Setting Exp arm * N RR(%) mpfs (ms) Control arm OS Control arm 2 line S ms M C4I60 S 34(17) 59(CT) 8.4(S) () 7.6(all) 85%(1y) 54%(1y) * Sunitinib 50 mg/d for 4/6 weeks Carbo AUC4 d1/irinotecan 60 mg/mq d1,8,15 sunitinib 25 mg/d Han et al, JCO 2011 Spigel et al, LC 2012 Ready, ASCO 2013

13 Modified by Ready, ASCO 2013

14 Modified by Ready, ASCO 2013

15 Modified by Ready, ASCO 2013

16 Modified by Ready, ASCO 2013

17 Sunitinib 2 nd line sunitinib (50 mg/d) does not seem to warrant further clinical evaluation Low PFS (1.4 ms) Sunitinib was discontinued in half of patients due to toxicity Interesting ti results deriving i from phase II trials with sunitinib ib in maintenance The ALLIANCE trial met its primary endpoint of PFS (although with a small difference with respect to the expected HR), with an OS trend (despite 40% crossover) Safety issues in the ALLIANCE trial 46% of grade 3/4 toxicities But carefully consider plans for a randomized phase III trial REMEMBER TOPOTECAN [Schiller JCO 2001], BEVACIZUMAB AND OTHER [Rossi LC 2010] Biomarker analysis of blood samples may be very challenging Modified by Wakelee, ASCO 2013

18 the Old Glories Bevacizumab Sunitinib Pazopanib Ipilimumab b..and many others

19 Kotsakis A. 1, Kentepozidis N. 2, Karavasilis V. 3, Varthalitis J. 4, Peroukidis S. 5, Ziras N. 6, Res H. 7, Mavroudis D. 1, Georgoulias V. 1, Agelaki S. 1 1 Department of Medical Oncology, University General Hospital of Heraklion, Crete, Greece, 2 Department of Medical Oncology, 251 Air Force General Hospital, Athens, Greece, 3 Department of Medical Oncology, "Papageorgiou" General Hospital, Thessaloniki, Greece, 4 Department of Medical Oncology, General Hospital of Chania, Crete, Greece, 5 Division of Oncology, Department of Medicine, University Hospital of Rio, Patras, Greece, 6 2 nd Department of Medical Oncology, Metaxa Anticancer Hospital, Piraeus, Greece, 7 Third Department of Medical Oncology, "Agioi Anargiri" Anticancer Hospital, Athens, Greece Kentepozidis, IASLC 2013

20 Study design: a two cohort, non randomized, two stage Phase II study Patients with sensitive (cohort A) and resistant/refractory (cohort B) are enrolled onto the study (sensitive: relapse in > 60 days; resistant: 60 days from the 1 st line chemo) Objectives: Primary endpoint: Progression free rate as determined by radiological assessment using standard RECIST 1.1 criteria at Week 8. Primary endpoints: Overall response rate, Overall survival (OS) and progression free survival (PFS), toxicity. Statistical consideration: Using the Simon's Minimax 2 Stage Design, in stage 1, 19 subjects will be enrolled into each cohort. If 7 or more subjects in cohort A or B have no PD at Week 8, further 20 subjects will be enrolled. The null hypothesis will be rejected in favor of the alternative hypothesis if 17 or more subjects out of the total of 39 subjects in cohort A or B have no PD at Week 8. Treatment plan: Pazopanib will be given at a dose of 800mg/day, orally Kentepozidis, IASLC 2013

21 Median follow up: 96months 9.6 ( ) Deaths: 7/19 patients 1 year OS (Kaplan Meier estimate): 57.3% Median PFS: 3.6 months ( ) Overall Response Rate Response n (%) CR PR 4 (21) SD 8 (42) Overall DCR (CR+PR+SD) 95% C.I. 12 (63) PD 7 (37) Kentepozidis, IASLC 2013

22 All Grades n % Leukopenia 8 42 Neutropenia 3 16 Anemia 7 37 Nausea 3 16 Vomiting 2 10 Diarrhoea 8 42 Mucositis 3 16 Epistaxis/ i Bleeding 6 32 Rash 4 21 Fatigue 8 42 Elevated 3 16 tranasaminases Proteinouria 6 32 Hypertension 7 37 Hair discoloration 8 42 GrIII n % Leukopenia 1 5 Neutropenia 1 5 Nausea 1 5 Diarrhoea 1 5 Epistaxis/ Bleeding 1 5 Fatigue 2 10 Hypertension 1 5 Kentepozidis, IASLC 2013

23 Pazopanib 2 nd line pazopanib in patients with sensitive relapse SCLC showed interesting activity (4/19 PR) Strengths: Multi site prospective phase II trial Pazopanib was well tolerated with manageable toxicity Biomarker analysis ongoing Weaknesses: The primary endpoint was 8 weeks PFS No data about resistant cohort Pazopanib 800 mg/d Another phase II trial [Gandi ASCO 2013] of pazopanib p in relapsed/refractory SCLC failed to demonstrate any activity No relevant results with others anti angiogenic agents [sunitinib, vandetanib, sorafenib,..] ]in this setting Modified by Millward, IASLC 2013

24 the Old Glories Bevacizumab Sunitinib Pazopanib Ipilimumab b..and many others

25 Design 130 untreated patients with ED SCLC randomized 1:1:1 to receive paclitaxel 175mg/mq/carboplatin AUC6 + placebo or ipilimumab 10 mg/kg in 2 regimens: CONCURRENT: I+TXL/C P+TXL/C PHASED: P + TXL/C I + TXL/C Every 3 ws for a maximum of 18 ws (induction) followed by maintenance ipilimumab or placebo every 12 ws Endpoint was PFS, irpfs, BORR, irborr, OS and safety IMMUNE RELATED [IR] response criteria Reck et al, AO 2013

26 Results Phased ipilimumabimproved irpfs vs control [HR0.64, p=0.03] No improvement in PFS [HR 0.93, p=0.37] or OS [HR 0.75, p=0.13] Median irpfs: 6.4 ms for phased I, 5.7 ms for concurrent I, 5.3 ms for control arm Median OS: 12,9 ms for phased I, 9,1 ms for concurrent I, 9,9 ms for control arm Grade 3/4 Aes was 17% for phased I, 21% for concurrent I, 9% for control Reck et al, AO 2013

27 Ipilimumab Reliable existence of an immune response against SCLC tumors [although often suppressed] LEMS and others paraneoplasticsyndromes Phased ipilimumab improved irpfs when added to standard 1 st line chemotherapy insclc A not significant trend towards OS prolongation [12.9 ms vs 9.9 ms, HR 0.75] PHASED somministration > concurrent 1. Reduction of tumor burden 2. Release of tumor antigens 3. Infiltration of cytolytic y T cells and diminishing of tumor associated immunosuppression Combination with chemotherapy/radiotherapy to achieve efficacy Immuneresponse requiretime irrc has not yet been validated only hypothesis generating results

28 the Old Glories Bevacizumab Sunitinib Pazopanib Ipilimumab b..and many others

29 ..the others AGENT SETTING TREATMENT RESULT NOTES Gfitiib Gefitinib relapse alone negative some results in EGFR mutant SCLC (3 4%, combined with adeno?) Imatinib 1 st line + IC relapse alone maintenance negative no correlation with c kit mutation Vandetanib chemosensitive alone negative gastrointestinal toxicity and rash Sorafenib relapse alone interesting comparable with historical 2 nd line major toxicity (18/89 discontinuation) Everolimus relapse alone negative limited activity in unselected SCLC Cediranib relapse alone negative limited activity in unselected SCLC Thalidomide chemosensitive alone negative trend towards longer OS in poor PS Lu et al, Oncology Letters 2013

30 EGFR, IG1 R, MET, KIT, RAS, PKC, MATRIX METALLOPROTEINASE INHIBITORS P53, Bcl 2, p16 VACCINES ONCOLYTIC VIRUS Modified by Adjei, IASLC 2013

31 the New Hopes ABT 263 OSI 906 Ganitumab/Rilotumumab t b Alisertib..and many others

32 the New Hopes ABT 263 OSI 906 Ganitumab/Rilotumumab t b Alisertib..and many others

33 ABT 263 Modified by Adjei, IASLC 2013

34 Modified by Adjei, IASLC 2013

35 Modified by Adjei, IASLC 2013

36 ABT 263 Limited efficacy in heavy pre treated SCLC DCR 27%, PFS 1.6 ms, OS 3.2 ms Relevant toxicity Serious AEs 11/39, dose reduction 6/39 Diarrhoea [43%], back pain [43%], thrombocytopenia [29%] Might potentially implement CT cytotoxic effect First line study comparing ABT 263 with CE is in progress Modified by Adjei, IASLC 2013

37 the New Hopes ABT 263 OSI 906 Ganitumab/Rilotumumab t b Alisertib..and many others

38 Modified by Kelly, IASLC 2013

39 Modified by Kelly, IASLC 2013

40 Modified by Kelly, IASLC 2013

41 Modified by Kelly, IASLC 2013

42 OSI 906 Response rate and efficacy outcome suggest drug inactivity DCR1%,PFS1.4ms,OS3.6ms No Relevant toxicity A Data Safety Monitoring Board is evaluating about the pursuance or not of this study Modified by Kelly, IASLC 2013

43 the New Hopes ABT 263 OSI 906 Ganitumab/Rilotumumab t b Alisertib..and many others

44 Glisson et al, IASLC 2013 Modified by Kelly, IASLC 2013

45 Glisson et al, IASLC 2013

46 Glisson et al, IASLC 2013 Modified by Kelly, IASLC 2013

47 Ganitumab/Rilotumumab Phase II multi site study of two experimental agents in frontline SCLC The study did not met its primary OS endpoint Not significant signal of activity/efficacy with the addiction of ganitumab or rilotumumab to PE Norelevant ttoxicity it Open questions: Isthe target oncologically relevant for SCLCsurvival? Preclinical data Are the experimental drugs really inactive? Are the experimental agents only active in a selected population? Biomarker analysis [low IGFBP 2 levels associated with increased response to ganitumab] Modified by Kelly, IASLC 2013

48 the New Hopes ABT 263 OSI 906 Ganitumab/Rilotumumab t b Alisertib..and many others

49 Havel et al, IASLC 2013 Modified by Kelly, IASLC 2013

50 Havel et al, IASLC 2013 Modified by Kelly, IASLC 2013

51 Havel et al, IASLC 2013 Modified by Kelly, IASLC 2013

52 Alisertib The study met its primary ORR endpoint Antitumor activity was seen in bothsensitive andrefractory disease Modest response rate when compared to others 2 nd line agents Particularly in chemosensitive patients [19% vs 44% amrubicin and 15% topotecan] Hematological toxicity was modest grade 3 neutropenia 30% with alisertib [41% with amrubicin and 53% with topotecan] Convenient oral dosing and schedule Interesting candidate predictive biomarker profile identified Continued evaluation of alisertib is warranted Modified by Kelly, IASLC 2013

53 the New Hopes ABT 263 OSI 906 Ganitumab/Rilotumumab t b Alisertib..and many others

54 ..the others AGENT TARGET SETTING RESULT NOTES Bec2/BCG GD3 ganglioside phase III adj responding LD SCLC negative trend towards longer OS for those developing a humoral response Marimastat MMP responding SCLC negative limited activity in unselected SCLC BY MMP responding SCLC Negative limited activity in unselected SCLC Obatoclax Bcl 2 1 st line + CT Interesting trend towards longer OS Panobinostat HDI relapse Negative limited activity in unselected SCLC Cixutumab Vismodegib IGF1 R Hedgehog 1 st line/m + CT Negative limited activity in unselected SCLC Modified by Murray, IASLC 2013

55 something completely different Pravastatin Picornavirus

56 Rationale Anti tumor effects of statins Inhibition of tumor cell growth [stabilization cell cycle kinase, inhibition RAS] Inhibition of angiogenesis [inhibition capillary formation, decreased VEGF] Induction of apoptosis p [decrease in Bcl 2, caspase activation] Repression of tumor metastasis [decrease MMP and EGF] Results No advantage in the primary endpoint OS Negative study expending considerable resources Seckl et al, IASLC Modified by Murray, IASLC 2013

57 Rationale The replication competent virus might replicate in cancer cells resulting in cell death Results The maintenance therapy with NTX 010 did not improve PFS OS was adversely affected in patients with viral titers at 7 and 14 d Molina et al, IASLC Modified by Murray, IASLC 2013

58 Conclusions No clinical practice changing data A growing attention towards the deeper characterization for refining the SCLC molecular background To better drive target therapy strategy Strengthen the preclinical rationale of new agents in SCLC models Redesigning early phase clinical trials Availability of biological material [biobanking of tumor tissue, blood samples, re biopsies at progression, biomarker analysis]

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