Microcitoma La terapia medica: Novità

Sara Pilotto Oncologpgia 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 ‘a Static Landscape’

Surgery Combination > single agent 2° line CT TNM staging Radiotherapy CAV or CEV PCI for LD‐SCLC Novel agents Nitrogen mustard 1940 1970 1990

1960 1980 2000

SCLC vs NSCLC EP IP LD vs ED CT + RT for LD‐ PCI for ED‐SCLC Cyclophosphamide SCLC Novel regimens

Focus on targeted agents and news from WCLC 2013

Chan & Coward, J Thorac Dis 2013 Clinical Relevance of the ‘Oncogene Addicti on’

• In patients with solid malignancies in which a dominant mutation or gene amplification drives tumor growth, targeted therapies are hhhlighly effective but rarely curative… – cKit mutations in GIST – HER2 amplification in breast cancer – EGFR mutation in NSCLC – ALK translocation in NSCLC

PHARMACOLOGIC GENETICS DEPENDENCY VULNERABILITY …Does that apply to SCLC? Modified By Bria and Puglisi SCLC [vs NSCLC]

Molecular Profile Biologic Behavior

• High cellular proliferation • Short cell cycle time • Rapid doubling time • Central presentation • Early metastasis • Chemo‐radiati on sensiiiitivity

Peifer et al, Nature Genetics 2012 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 mutations PLUS q‐score – RUNX1T1, CDYL, RIMS2 • Gene families and pathways – PI3K ppy,athway, Notch and Hedggg,ehog, 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 44:1104‐1110, 2012 Rudin CM et al: Nature genetics 44:1111‐1116, 2012 Kelly, Oral Abstract Discussant IASLC 2013 ‘the Old Glories’

Ipili mumab

 ..and many others ‘the Old Glories’

Bevacizumab

Sunitinib

Pazopanib

Ipili mumab

 ..and many others Bevacizumab [phase II]

Setting Exp arm* N RR(%) mPFS (ms) ‘Control arm’ mOS (ms) ‘Control arm’ 1° line/M P60E120B x 4 63 63.5 4.7 4.6# 10.9 10.2# 1° line P30I65B x 6 72 75 7 414.1# 11.6 939.3# P65 vs C5 1° line/M 52 58 5.5 4.4 9.4 10.9 E100B x 4 1° line/M C4I60B x 65184 9.1 6# 12.1 10# 2° line T2.3B x 8 5016S:6.2/R:2.94.1# 7.4 6.5# 2° line TXL90B 34 18 3.7 ‐ 7.5 ‐

* 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 d1d1815,8,15 + bevacizumab 10 mg/mq d1,15 Horn et al, JCO 2009 Spgpiegel et al, JCO 2009 Ready et al, JCO 2011 Schmittel et al, AO 2011 # historical controls Hanna et al, JCO 2006 Spiegel CLC 2013 Spiegel et al, JCO 2011 Jalal et al, JCO 2010 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 might implement the overall activity (in 1st line) . But phase II trilial often overestidimated theresults . Comparable of those observed in others malignancies  a small clinical benefit . Phase III randomized trial comparing 1st chemotherapy +/‐ bevacizumab may be appropriate

Modified by Belani, IASLC 2013 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) ‘the Old Glories’

Bevacizumab

Sunitinib

Pazopanib

Ipili mumab

 ..and many others Sunitinib

Setting Exp arm* N RR(%) mPFS (ms) ‘Control arm’ OS ‘Control arm’ 2° line S 25 9 1.4 ‐ 5.6ms ‐ 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 Modified by Ready, ASCO 2013 Modified by Ready, ASCO 2013 Modified by Ready, ASCO 2013 Modified by Ready, ASCO 2013 Sunitinib

. 2nd 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 . ItInteresti ng results diideriving from phase II titria lswith sunitinib 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 ‘the Old Glories’

Bevacizumab

Sunitinib

Pazopanib

Ipili mumab

 ..and many others Kotsakis A.1, Kentepozidis N.2, Karavasilis V.3, Var thaliti s J.4, PkidiPeroukidis 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 2nd Department of Medldical Oncology, Metaxa Anticancer Hospital, Piraeus, Greece, 7 Thdhird Department of Medldical Oncology, "Agioi Anargiri" Anticancer Hospital, Athens, Greece

Kentepozidis, IASLC 2013 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 1st 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 • Median follow up: 969.6 months (1. 0 – 22.6) • Deaths: 7/19 patients • 1‐year OS (Kaplan‐Meier estimate): 57.3% • Median PFS: 3.6 months (0.8‐ 17.7)

OllOverall Response Rate Response n (%) CR ‐ PR 4 (21) SD 8 (42) Overall DCR (CR+PR+SD) 12 (63) 95% C.I. 41.5 ‐ 84.85 PD 7 (37) Kentepozidis, IASLC 2013 All Grades ≥ GrIII n % n % Leukopenia 8 42 Leukopenia 1 5 Neutropenia 3 16 Neutropenia 1 5 Anemia 7 37 Nausea 1 5 Nausea 3 16 Diarrhoea 1 5 Vomiting 2 10 Epistaxis/ Bleeding 1 5 Diarrhoea 8 42 Fatigue 2 10 Mucositis 3 16 Hypertension 1 5 EitEpistax is/ Blee ding 6 32 Rash 4 21 Fatigue 8 42 Elevated 316 tranasaminases Proteinouria 6 32 Hypertension 7 37 Hair discoloration 8 42 Kentepozidis, IASLC 2013 Pazopanib

. 2nd 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 pppazopanib in relapp/sed/refractor ySCLC failed to demonstrate any activity . No relevant results with others anti‐angiogenic agents [sunitinib, vandibdetanib,sorafibfenib,..] in this setting

Modified by Millward, IASLC 2013 ‘the Old Glories’

Bevacizumab

Sunitinib

Pazopanib

Ipili mumab

 ..and many others . Design . 130 untreated patients with ED‐SCLC randomized 1:1:1 to receive paclitaxel 175mg/mq/carboplatin AUC6 + placebo or 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 . Results . Phased ipilimumab improved irPFS vs control [HR 0.64, 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 Ipilimumab

. Reliable existence of an immune response against SCLC tumors [although often suppressed] . LEMS and others paraneopltilasticsyndromes . Phased ipilimumab improved irPFS when added to standard 1st line chemotherapy in SCLC . 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 cyyytolytic T cells and diminishing of tumor‐associated immunosuppression . Combination with chemotherapy/radiotherapy to achieve efficacy . Immune response require time . irRC has not yet been validated  only hypothesis generating results ‘the Old Glories’

Bevacizumab

Sunitinib

Pazopanib

Ipili mumab

 ..and many others ……..the others

AGENT SETTING TREATMENT RESULT NOTES some results in EGFR mutant SCLC GfitiibGefitinib relapse alone negative (3‐4%, combined with adeno?) 1st line + IC relapse negative no correlation with c‐ mutation alone maintenance chemosensitive alone negative gastrointestinal toxicity and rash comparable with historical 2nd line relapse alone interesting major toxicity (18/89 discontinuation) Everolimus relapse alone negative limited activity in unselected SCLC 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 EGFR, IG1‐R, MET, KIT, RAS, PKC, … MATRIX METALLOPROTEINASE INHIBITORS

P53, Bcl‐2, p16 VACCINES ONCOLYTIC VIRUS

Modified by Adjei, IASLC 2013 ‘the New Hopes’

ABT‐263

OSI‐906

GitbGanitumab/Rilot umumab

Alisertib

 ..and many others ‘the New Hopes’

ABT‐263

OSI‐906

GitbGanitumab/Rilot umumab

Alisertib

 ..and many others ABT‐263

Modified by Adjei, IASLC 2013 Modified by Adjei, IASLC 2013 Modified by Adjei, IASLC 2013 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 ‘the New Hopes’

ABT‐263

OSI‐906

GitbGanitumab/Rilot umumab

Alisertib

 ..and many others Modified by Kelly, IASLC 2013 Modified by Kelly, IASLC 2013 Modified by Kelly, IASLC 2013 Modified by Kelly, IASLC 2013 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 ‘the New Hopes’

ABT‐263

OSI‐906

GitbGanitumab/Rilot umumab

Alisertib

 ..and many others Glisson et al, IASLC 2013 Modified by Kelly, IASLC 2013 Glisson et al, IASLC 2013 Glisson et al, IASLC 2013 Modified by Kelly, IASLC 2013 Ganitumab/

. 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 . Noreltlevant tiittoxicity . Open questions: . Is the target ‘oncologically relevant’ for SCLC survival? . 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 ‘the New Hopes’

ABT‐263

OSI‐906

GitbGanitumab/Rilot umumab

Alisertib

 ..and many others Havel et al, IASLC 2013 Modified by Kelly, IASLC 2013 Havel et al, IASLC 2013 Modified by Kelly, IASLC 2013 Havel et al, IASLC 2013 Modified by Kelly, IASLC 2013 Alisertib

. The study met its primary ORR endpoint . Antitumor activity was seen in both sensitive and refractory disease . Modest response rate when compared to others 2nd 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 ‘the New Hopes’

ABT‐263

OSI‐906

GitbGanitumab/Rilot umumab

Alisertib

 ..and many others ……..the others

AGENT TARGET SETTING RESULT NOTES phase III adj trend towards longer OS for those Bec2/BCG GD3 ganglioside negative responding LD‐SCLC developing a humoral response Marimastat MMP responding SCLC negative limited activity in unselected SCLC BY‐129566 MMP responding SCLC Negative limited activity in unselected SCLC Obatoclax Bcl‐21st line + CT Interesting trend towards longer OS Panobinostat HDI relapse Negative limited activity in unselected SCLC Cixutumab IGF1‐R 1st line/M + CT Negative limited activity in unselected SCLC Vismodegib Hedgehog

Modified by Murray, IASLC 2013 ‘something completely different’

Pravastatin

Picornavirus . 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 apppoptosis [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 . Rationale . The replication‐competent virus might replicate in cancer cells resulting in cell death . RlResults . 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 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]