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Minelli M. Le nuove Terapie in Oncologia. ASMaD 2016

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Gianfranco Tammaro

The document discusses recent advancements in targeted therapies for breast cancer, focusing on HER2-positive tumors. It highlights the efficacy of trastuzumab and lapatinib, along with combination treatments such as trastuzumab plus pertuzumab, demonstrating significant improvements in patient outcomes. Additionally, it mentions the genetic aspects of breast cancer, particularly the BRCA mutations and their role in cancer therapy.

Health & Medicine
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LUNCH MEETING AL PASTEUR QUICK UPDATE LE NUOVE TERAPIE IN ONCOLOGIA Dott. MAURO MINELLI Direttore f.f. U.O.C. di Oncologia Medica Az. Ospedaliera S. Giovanni – Addolorata, Roma
CARCINOMA MAMMARIO UN MODELLO DIUN MODELLO DI SVILUPPOSVILUPPO DELLA RICERCADELLA RICERCA CLINICACLINICA
RIVOLUZIONE DEI CONCETTI NEGLI ULTIMI 30 ANNI DADA TRATTAMENTOTRATTAMENTO MASSIMOMASSIMO TOLLERABILETOLLERABILE CONCEZIONECONCEZIONE ANATOMICAANATOMICA MEDICINAMEDICINA TRADIZIONALETRADIZIONALE AA TRATTAMENTOTRATTAMENTO MINIMOMINIMO EFFICACEEFFICACE CONCEZIONECONCEZIONE BIOLOGICABIOLOGICA NEDICINA BASATANEDICINA BASATA SULL’EVIDENZASULL’EVIDENZA
EVOLUZIONE ESTREMAMENTE RAPIDA DELLE NUOVE ACQUISIZIONI SULLE TERAPIE BIOMOLECOLARI TARGET THERAPY NUOVA ATTITUDINE MEDICA E DI RICERCA UTILIZZO DI FARMACI CHE AGISCONO SU RECETTORI CELLULARI SPECIFICI
IDENTIFICAZIONE DI MARKERS MOLECOLARI DELLE CELLULE NEOPLASTICHE UN DETERMINAT O DIFETTO GENICO C O L P I R E LA VIA METABOLICA ALTERATA
TARGET THERAPY A metà degli anni ’80 fu scoperto il GENE HER-2 posto sul cromosoma 17 HER-2 è presente in piccolissima quantità sulla membrana delle cellule normali, circa 20.000 recettori per cellula.
TARGET THERAPY Nel 20-30% dei carcinomi della mammella: HER-2 di 100 volte per Amplificazione genica Sovraespressione recettoriale
IPER ESPRESSIONE HER -2 SVILUPPO E MANTENIMENTO DEL TUMORE MAMMARIO MAGGIORE AGGRESSIVITA’ INTERESSAMENTO LINFONODALE ELEVATA FRAZIONE DI CRESCITA E GRADING NEGATIVITA’ DEI RECETTORI ORMONALI
TRASTUZUMAB ANTICORPO MONOCLONALE UMANIZZATO ANTI HER- 2 (95% umano – 5% murino) Approvato dalla FDA nel 1998 per il trattamento del CARCINOMA della MAMMELLA METASTATICO (13 anni dopo la clonazione del Gene HER-2)
AZIONE DEL TRASTUZUMAB Arresto dell’attività proliferativa Induzione di apoptosi Inibizione di angiogenesi POTENTE INDUTTORE DI RISPOSTA IMMUNITARIA CITOTOSSICA CELLULO- MEDIATA ANTICORPO-DIPENDENTE (ADCC) E COMPLEMENTO DIPENDENTE •Occupazione del sito di legameOccupazione del sito di legame •Blocco della dimerizzazione del recettoreBlocco della dimerizzazione del recettore •Alterazione del segnale di fosforilazione del recettoreAlterazione del segnale di fosforilazione del recettore •Accelerata internalizzazione e degradazione del recettoreAccelerata internalizzazione e degradazione del recettore
Herceptin ® plus a taxane Two large randomised trials show efficacy and tolerability of Herceptin ® plus a taxane:  Slamon et al. Herceptin ® plus paclitaxel  Marty et al. Herceptin ® plus docetaxel Marty M, et al. J Clin Oncol in press. Slamon DJ, et al. N Engl J Med 2001;344:783–92
Herceptin ® plus paclitaxel: efficacy (IHC 3+) Herceptin® + paclitaxel (n=68) Paclitaxel alone (n=77) ORR (%) 49.0 17.0 Median TTP (months) 7.1 3.0 Median OS (months) 24.8 17.9 Median DR (months) 10.9 4.6 Baselga J. Oncology 2001;61(Suppl. 2):14–21
Herceptin ® plus paclitaxel: 39% increase in survival (IHC 3+) Smith IE. Anticancer Drugs 2001;12:S3–10 1.0 0.8 0.6 0.4 0.2 0 Time (months) 0 5 10 15 20 25 30 35 40 45 50 17.9 24.8 Probabilityofsurvival ↑ 39% Herceptin ® + paclitaxel Paclitaxel
Herceptin® plus docetaxel: efficacy Herceptin® + docetaxel (n=68) Docetaxel alone (n=77) p-value ORR (%) 61.0 34.0 0.0002 Median TTP (months) 10.6 5.7 0.0001 Median OS (months) 30.5 22.1 0.0062 Median DR (months) 11.4 5.1 0.0011 12-month cut-off Marty M, et al. J Clin Oncol in press.
Herceptin® plus docetaxel: 38% increase in survival 1.0 0.8 0.6 0.4 0.2 0 Probabilityofsurvival 0 3 6 9 12 15 18 21 24 27 30 33 36 Time (months) Intent-to-treat population, 12-month cut-off Documented crossover = 48% p=0.0062 22.1 30.5 Herceptin® + docetaxel Docetaxel alone Marty M, et al. J Clin Oncol in press. ↑ 38%
TRASTUZUMAB ADIUVANTE MEDIAN FOLLOW UP(HR) 1 HERA 1 ANNO (0.54) 2 HERA 2 ANNI (0.64) 3 N9831 AC-T-H 1,5 ANNI (0.87) 4 COMBINED ANALYSIS 2 ANNI (0.48) 5 BCIRG 006 AC DH→ 2 ANNI (0,61) 6 BCIRG 006 DCarboH 2 ANNI (0,67) 7 FinHER VH/DH 3 ANNI (0,42) 8 PACS 04 4 ANNI (0,86) 0 1 2FAVOUR TRASTUZUMAB FAVOUR NO TRASTUZUMAB
E SE FALLISCE HERCEPTIN…?
LAPATINIB farmaco orale  INIBITORE DELLE TIROSINOCHINASI e HER 2  STUDI PRECLINICI HANNO DIMOSTRATO CHE LAPATINIB INDUCE APOPTOSI E INIBISCE IL SEGNALE MEDIATO DALL’INSULIN GROWTH FACTOR I RECEPTOR IN LINEE CELLULARI RESISTENTI AL TRASTUZUMAB
LAPATINIB Segnali extracellulari  O O O O Membrana cellulare RECETTORI ErbB2 FOSFORILAZIONE O O O O Pl3k fosforilato Akt fosforilata PTEN FOSFORILAZIONE AngiogenesiProliferazioneSopravvivenza delle CELLULE TUMORALI CELLULA TUMORALE Inibizione Serin/treonin chinasi Akt Fosfatidilinositol-3,4,5- trifosfato
TERAPIA ORALE Patients with ErbB2-positive locally advanced or metastatic breast cancer who progressed after prior anthracycline, taxane and trastuzumab (N=399) R A N D O M I S A T I O N Capecitabine 2500 mg/m2 /day po Days 1–14 q 3 wk Lapatinib 1250 mg po qd continuously + capecitabine 2000 mg/m2 /day po Days 1–14 q 3 wk EGF100151 (Cameron1 ) 1. Cameron D, et al. Breast Can Res Treat 2008;DOI 10.1007/s10549-007-9885-0; 23.
LAPATINIB Lapatinib e Capecitabina nel trattamento del carcinoma mammario avanzato HER-2 positivo Lapatinib+capecitibinaLapatinib+capecitibina ( n=198)( n=198) CapecitabinaCapecitabina (n=201)(n=201) Hazard ratioHazard ratio ( 95% IC)( 95% IC) PP Tempo allaTempo alla progressioneprogressione (mesi)(mesi) 6,26,2 4,34,3 0,57 (0,43-0,77)0,57 (0,43-0,77) 0,00010,0001 Risposta (%)Risposta (%) 23,723,7 13,913,9 0,010,01 SopravvivenzaSopravvivenza 15,615,6 15,315,3 0,78 (0,55-1,12)0,78 (0,55-1,12) 0,170,17 Percentuale diPercentuale di metastasimetastasi encefaliche comeencefaliche come primo eventoprimo evento 2%2% 6%6% -- 0,040,04 Cameron D, et al. Breast Cancer Res Treat 2008
Pertuzumab meccanismo d’azionePertuzumab meccanismo d’azionePertuzumab meccanismo d’azionePertuzumab meccanismo d’azione 2013 LA NUOVA ERA IL PERTUZUMAB PREVIENE LA DIMERIZZAZIONE DI HER2/HER3 INDOTTA DAL LIGANDO
DOPPIO BLOCCO ?? 2013 LA NUOVA ERA I TUMORI DELLA MAMMELLA HER2+ SONO GUIDATI DA ENTRAMBI I COMPLESSI HER2- HER3 LIGANDO DIPENDENTI O INDIPENDENTI I TUMORI DELLA MAMMELLA HER2+ SONO GUIDATI DA ENTRAMBI I COMPLESSI HER2- HER3 LIGANDO DIPENDENTI O INDIPENDENTI Il DOPPIO BLOCCO DI QUESTI COMPLESSI CON TRASTUZUMAB+ PERTUZUMAB E’ CLINICAMENTE MOLTO ATTIVO VS IL TRATTAMENTO CON SOLO TRASTUZUMAB Il DOPPIO BLOCCO DI QUESTI COMPLESSI CON TRASTUZUMAB+ PERTUZUMAB E’ CLINICAMENTE MOLTO ATTIVO VS IL TRATTAMENTO CON SOLO TRASTUZUMAB
2013 LA NUOVA ERA PERTUZUMAB 1a LINEA METASTATICA: studio CLEOPATRA Docetaxel – Trastuzumab – Placebo vs Docetaxel – Trastuzumab – Pertuzumab PFS 12,4 vs 18,7 con HR < 0,62 ORR 69,3% vs 80,2% OS mediana 37,6 vs Non raggiunto ESMO 2014 Dr. Sandra Swain: We’ re never seen anything like this before OS  4,5 aa
Caso clinico : uso del doppio blocco
ANTICORPO FARMACO CONIUGATO Meccanismo d’azione Il T-DM1 tramite il trastuzumab si lega al recettore dell’ HER2 sulla superficie della cellula tumorale 2013 LA NUOVA ERA the "magic bullet"
T-DM1 meccanismo d’azione all’interno della cellula il DM1 si lega ai microtubuli e inibisce la loro polimerizzazione L’inibizione della polimerizzazione dei microtubuli arresta l’evoluzione del ciclo con la conseguente morte cellulare Il legame HER2 +TDM1-1 per endocitosi entra all’interno della cellula tumorale Terminata l’endocitosi il trastuzumab e il recettore HER2 sono degradati e viene rilasciato un metabolita citotossico 2013 LA NUOVA ERA
2013 LA NUOVA ERA TDM -1 2 linea: studio EMILIA TDM -1 vs LAPATINIB + CAPECITABINA PFS 9,6 vs 6,4 OS mediana 30,2 vs 25,1
La maggior parte dei carcinomi mammari sono forme sporadiche SOLO il 5-7% sono legati a fattori ereditari ¼ di questi sono determinati dalla mutazione di due geni: BRCA-1  LOCALIZZATO SUL BRACCIO LUNGO DEL CROMOSOMA 17 (24 ESONI) BRCA-2  LOCALIZZATO SUL BRACCIO LUNGO DEL CROMOSOMA 13 (27 ESONI BRCA -1 e 2 (BReast CAncer)
BRCA -1 e 2 (BReast CAncer) IDENTIFICATI NEL 1994 E NEL 1995 COME GENI ONCOSOPPRESSORI IN FAMIGLIE CON ALTA PREVALENZA DI TUMORI DELLA MAMMELLA E DELL’OVAIO SONO COSTITUENTI CENTRALI DI COMPLESSI MULTIPROTEICI COINVOLTI NEL RIPARO DEI DANNI DEL DNA Angelina Jolie
BRCA -1 e 2 (BReast CAncer) MASCHIO CON CARCINOMA MAMMARIO DONNA CON CARCINOMA MAMMARIO E CARCINOMA OVARICO DONNA CON CARCINOMA MAMMARIO < 36 ANNI < 50 ANNI < 50 ANNI E STORIA FAMILIARE DI ≥ PARENTE DI 1° GRADO CON: Carcinoma mammario < 50 anni Carcinoma ovarico a qualsiasi età Carcinoma mammario bilaterale Carcinoma mammario maschile > 50 ANNI SOLO SE STORIA FAMILIARE DI CA.MAMMARIO O OVARICO IN ≥ 2 PARENTI DI 1° GRADO (di cui 1 in 1° grado con lei) < 60 ANNI con carcinoma mammario « triplo negativo » Ad ogni età con storia familiare di carcinoma mammario esocrino del pancreas in ≥ 2 parenti di 1° grado ( di cui 1 in 1° grado con lei) DONNA CON CARCINOMA OVARICO/TUBA/PRIMITIVO DEL PERITONEO A QUALSIASI ETA’ SOGGETTO CON CA. MAMMARIO ESOCRINO DEL PANCREAS E STORIA FAMILIARE DI CA. MAMMARIO O DELL’OVAIO O ESOCRINO DEL PANCREAS IN ≥ 2 PARENTI DI 1° GRADO (di cui 1 in 1° grado con lei) CONDIZIONI DI STORIA ONCOLOGICA ASSOCIATE A UNA PROBABILITA’ DI MUTAZIONE BRCA ≥ 10%
BRCA -1 e 2 (BReast CAncer) RISCHIO CUMULATIVO DI CARCINOMA MAMMARIO E OVARICO (FINO AI 70 ANNI DI ETA’) NELLE DONNE PORTATRICI DI MUTAZIONE BRCA BRCA 1 (Rischio cumulativo a 70 anni) BRCA 2 (Rischio cumulativo a 70 anni) Metanalisi Chen S, J Clin Oncol 2007 Carcinoma mammario 57% (IC al 95% 47-66%) 49% (IC al 95% 40-57%) Carcinoma ovarico 40% (IC al 95% 35-46%) 18% (IC al 95% 13-23%) Metanalisi Nelson HD, USPSTF 2014 Carcinoma mammario 46-70% 50-71% Carcinoma ovarico 41-46% 17-23% Analisi prospettica di EMBRACE Mavaddat N, J Natl Cancer Inst 2013 Carcinoma mammario 60% (IC al 95% 44-75%) 55% (IC al 95% 41-70%) Carcinoma ovarico 59% (IC al 95% 43-76%) 16% (IC al 95% 7,5-34%) Carcinoma mammario controlaterale 83% (IC al 95% 69-94%) 62% (IC al 95% 44-79,5%)
LE CELLULE NORMALI MA ANCHE QUELLE DEL TUMORE RIPARANO I DANNI ATTRAVERSO DIVERSI MECCANISMI MOLECOLARI. ALCUNI DI QUESTI MECCANISMI COINVOLGONO LE PARP-POLI (ADP RIBOSIO) POLIMERASI, ENZIMI RESPONSABILI DELLA APOPTOSI (MORTE CELLULARE PROGRAMMATA).
IL MECCANISMO ATTRAVERSO CUI, IN UN SISTEMA «BRCA- DEFICENT», PARP VIENE INIBITO E SI INDUCONO DANNI AL DNA MEDIANTE AGENTI ALCHILANTI O ATTRAVERSO LA RADIOTERAPIA E’ DETTA «LETALITA’ SINTETICA» Esistono farmaci PARP inibitori (OLAPARIB)
Minelli M. Le nuove Terapie in Oncologia. ASMaD 2016
L’uso di anti-EGFR (Cetuximab/Panitumumab) in prima linea nei pazienti mCRC RAS WT consente di raggiungere una OS mediana di oltre 30 mesi Dati di Efficacia
Bisogna riconoscere un merito scientifico… La storia del RAS (a partire da KRAS) nasce con gli studi su Panitumumab
Follow-up Supportive Care (BSC) vs. BSC Alone After Failure of Standard Chemotherapy in mCRC Randomization stratification • ECOG score: 0-1 vs 2 • Geographic region: Western EU vs Central and Eastern EU vs rest of world 1:1 panitumumab 6.0 mg/kg Q2W + BSC (n = 231) Best Supportive Care (BSC) (n = 232) R A N D O M I Z E Optional panitumumab Crossover Study (n = 176) 76% of BSC alone patients entered crossover study PDPD PD Follow-up Van Cutsem E, et al. J Clin Oncol 2007;25:1658-64.
Wild-type KRAS Subgroup: PFS by Treatment 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 Weeks 36 38 40 42 44 46 48 50 52 7 7 6 5 5 10 9 9 6 6 6 5 4 3 3 2 2 2 2 1 124 115/124 (93) 12.3 19.0 114/119 (96) 7.3 9.3 Pmab + BSC BSC Alone Events/N (%) Median In Weeks Mean In Weeks HR = 0.45 (95% CI: 0.34–0.59) Stratified log-rank test, p < 0.0001 Pmab + BSC BSC Alone Patients at Risk 119 112106 80 69 63 58 50 45 44 44 33 25 21 20 17 13 13 13 10 119 109 91 81 38 20 15 15 14 11 6 ProportionwithPFS Amado RG, et al. J Clin Oncol 2008;26:1626-34
Mutant KRAS Subgroup: PFS by Treatment 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 ProportionwithPFS Pmab + BSC BSC Alone 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 Weeks 36 38 40 42 44 46 48 50 52 Patients at Risk 78 76 72 26 10 8 6 5 5 5 5 4 4 4 4 2 2 2 2 2 2 2 1 1 1 91 77 61 37 22 19 10 9 8 6 5 5 4 4 4 4 4 4 3 3 3 2 2 2 2 84 100 76/84 (90) 7.4 9.9 95/100 (95) 7.3 10.2 Pmab + BSC BSC Alone Events/N (%) Median In Weeks Mean In Weeks HR = 0.99 (95% CI: 0.73–1.36) Amado RG, et al. J Clin Oncol 2008;26:1626-34
Cetuximab e Panitumumab sono Ab monoclonali con STRUTTURA DIVERSA • Diversa incidenza di possibili reazioni allergiche • Diversa gestione della premedicazione
The Development of Human Monoclonal Antibodies 100% Mouse Protein Mouse ~34% Mouse Protein Chimeric cetuximab ~10% Mouse Protein Humanized bevacizumab Fully Human 100% Human Protein panitumumab Yang XD, et al. Crit Rev Oncol Hematol 2001;38:17-23. 1. Erbitux® , MabThera® , Avastin® , Vectibix® European Public Assessment Reports as of Dec 2008. 2. Erbitux® US Package Insert as of Dec 2008, http://packageinserts.bms.com/pi/pi_erbitux.pdf. 3. Avastin® US Prescribing Information as of Dec 2008. 4. Kang and Saif. J Support Oncol 2007; 5:451-7.* Non-Hodgkins’s lymphoma. † Monotherapy in mCRC. Data are not from comparative studies. Infusion reactions All grades Severe panitumumab† bevacizumabcetuximab† 2% <1% (grade 3)1 <3% <1%3,4 20% 5%2 nonenone antihistamine + corticosteroid (mandatory for first, recommended for subsequent infusions) Premedication1
TOSSICITA’ CUTANEA • Cetuximab e Panitumumab hanno un profilo di tossicità cutanea simile. • Tuttavia, nella pratica clinica notiamo che le reazioni cutanee da Panitumumab tendono ad essere più imponenti
SCHEDULA DI SOMMINISTRAZIONE • Cetuximab: settimanale • Panitumumab: bisettimanale
SCHEDULA DI CHEMIOTERAPIA IN PRIMA LINEA • Cetuximab + FOLFIRI/FOLFOX (lo studio registrativo in prima linea - Crystal- è con FOLFIRI; dati contrastanti sull’associazione con regimi a base di oxaliplatino, specie con XELOX) • Panitumumab + FOLFOX (al momento secondo scheda AIFA è l’unico schema consentito in prima linea)
I nuovi farmaci Inibitori delle Cicline
Slide 2 Presented By Nicholas Turner at 2015 ASCO Annual Meeting
Palbociclib Presented By Nicholas Turner at 2015 ASCO Annual Meeting
Abstract LBA502 <br /><br /> A Double Blind Phase 3 Trial of Fulvestrant With or Without Palbociclib in Pre- and Post-menopausal Women With Hormone Receptor-positive, HER2- negative Advanced Breast Cancer That Progressed on Prior Endocrine Therapy<br />(PALOMA3 Study) Presented By Nicholas Turner at 2015 ASCO Annual Meeting
PALOMA3 Study Design Presented By Nicholas Turner at 2015 ASCO Annual Meeting
Study Endpoints Presented By Nicholas Turner at 2015 ASCO Annual Meeting
Statistical Design Presented By Nicholas Turner at 2015 ASCO Annual Meeting
Tumor Characteristics and Prior Treatment Presented By Nicholas Turner at 2015 ASCO Annual Meeting
Treatment Summary Presented By Nicholas Turner at 2015 ASCO Annual Meeting
Adverse Events—All Cause Presented By Nicholas Turner at 2015 ASCO Annual Meeting
Summary of Adverse Events Presented By Nicholas Turner at 2015 ASCO Annual Meeting
Primary Endpoint: PFS (ITT Population) Presented By Nicholas Turner at 2015 ASCO Annual Meeting
PFS: Central Blinded Review Audit (n=211) Presented By Nicholas Turner at 2015 ASCO Annual Meeting
I nuovi farmaci Immunoterapia
 5-year survival rates are poor for many patients with advanced cancera New Therapies are Needed to Improve the Survival of Patients With Advanced Disease Tumor Type 5-Year Survival Rate Overall Advanced Disease Prostate 99.2% 27.9% Melanoma 91.3% 16.0% Breast 89.2% 24.3% Kidney/renal pelvis 71.8% 12.3% Colorectal 64.9% 12.5% Ovarian 44.2% 27.3% Stomach 27.7% 3.9% Lung 16.6% 3.9% Pancreatic 6.0% 2.0% a Based on patients diagnosed in the United States between 2003 and 2009. Surveillance, Epidemiology and End Results (SEER) Program. http://seer.cancer.gov.
Emerging Hallmarks of Cancer: Avoiding Immune Destruction Adapted from Hanahan, et al. Cell. 2011;144:646–674. Mercury No: ONCHQ14NP02639-01-IT
Immuno-Oncology is Being Studied for its Potential to Become a New Treatment Modality for Cancer 1. DeVita VT Jr, et al. Cancer Res. 2008;68:8643–8653; 2. American Cancer Society. http://www.cancer.org/cancer/cancerbasics/thehistoryofcancer/; 3. Hodi FS, et al. N Engl J Med. 2010;363:711–723; 4. Sznol M, et al. Presented at ASCO 2013: oral presentation; 5. Kantoff PW, et al. N Engl J Med. 2010;363:411–422; 6. Finn OJ. Ann Oncol. 2012;23(suppl 8):viii6–viii9. Surgery 1846 Radiation Therapy 1901 Chemotherapy 1946 Targeted Therapy 1997 Immuno-Oncology 2011 Mercury No: ONCHQ14NP02639-01-IT
 Innate immune system: involving proteins (chemokines and cytokines) and cells, is considered to be the first line of immune defense and does not generate an antigen- specific response1,2 Cells of the Immune System DC = dendritic cell; NK = natural killer. 1. Dranoff G. Nat Rev Cancer. 2004;4:11–22; 2. Janeway CA, et al. Immunobiology: The Immune System in Health and Disease. 6th ed. New York, NY: Garland Science; 2004. • Adaptive immune system: mediated by B and T cells is highly specific and capable of generating an antigen-specific response1,2 – Induction requires presentation of antigens by cells of the innate immune system Innate Immunity (rapid response) Adaptive Immunity (slow response, memory) Macrophage DC Mast cell γδ T cell NKT cell NK cell Basophil Complement protein Eosinophil Granulocytes Neutrophil B cell Antibodies T cell CD4+ cell CD8+ cell Adapted from Dranoff G.1
Normal Immune Response Adapted from Abbas and Lichtman, 2005 Abbas et al. Cellular and Molecular Immunology 5th ed. 2005, Elsevier Saunders
 T cells require multiple signals to become fully activated1  In addition to antigen stimulation in the context of MHC molecules, positive co- stimulation is required1  Co-stimulatory or activating receptors include CD28, CD137, CD40, and OX-402 Activation of Naïve T Cells a Anergy describes a state of functional inactivation. 1. Janeway CA, et al. Immunobiology. 2008; 2. Pardoll DM. Nat Rev Cancer. 2012;12:252–264. T cell APC Activates T cell Co-stimulatory signal and specific signal MHC class II TCR Co-stimulator 1 2 T cell APC T cell becomes anergica Specific signal alone 1 T cell APC No effect on T cell Co-stimulatory signal alone 2 CD4 Mercury No: ONCHQ14NP02639-01-IT
 Immune checkpoints limit, or “check,” an ongoing immune response  Prevents damage to the body’s healthy tissues  Negative co-stimulation, also called “co-inhibition,” helps shut down immune responses  PD-1, CTLA-4, and LAG-3 are examples of co-inhibitory “checkpoint” molecules  Amplitude and quality of a T-cell response is regulated by a balance of activating and inhibitory signals Regulation of T-Cell Activation: Balancing Activating and Inhibitory Signals CTLA-4 = cytotoxic T-lymphocyte antigen-4; LAG-3 = lymphocyte activation gene-3; PD-1 = programmed death-1; PD-L1 = programmed death-ligand 1. Pardoll DM. Nat Rev Cancer. 2012;12:252–264. APC/ Tumor T cell PD-1 B7-1 (CD80) PD-L1 PD-L2 CD40 CD40L CD137 OX40 CD137L OX40L LAG-3 MHC CD28 ActivationB7-2 (CD86) B7-1 (CD80) CTLA-4 Inhibition TCR Inhibition Inhibition Activation Activation Activation Inhibition
The Immune System Recognizes and Eliminates Cancer Via Multiple, Complex Mechanisms 1. Janeway CA, et al. Immunobiology: The Immune System in Health and Disease. 6th ed. New York, NY: Garland Science; 2004; 2. Padmanabhan RR, et al. J Leuk Biol. 1988;43:509–519; 3. Kim R, et al. Immunology. 2007;121:1–14; 4. Vivier E, et al. Science. 2011;331:44–49; 5. Dunn GP, et al. Nat Immunol. 2002;3:991–998.
 The three E’s of cancer immunoediting describe the immune system’s roles in protecting against tumor development and promoting tumor growth Immunoediting: The Role of the Immune System in Cancer Development and Progression Elimination • Effective antigen processing/presentation • Effective activation and function of effector cells – eg, T-cell activation without co-inhibitory signals Cancer Immunosurveillance Equilibrium • Genetic instability • Tumor heterogeneity • Immune selection Cancer Dormancy Escape • Tumors may avoid elimination by the immune system through outgrowth tumor cells that can suppress, disrupt, or “escape” the immune system Cancer Progression Vesely MD, et al. Ann Rev Immunol. 2011;29:235–271. Tumor Cell CD8+ T cell CD4+ T cell NK cell Normal Cells Treg
Tumors Use Complex, Overlapping Mechanisms to Evade and Suppress the Immune System 1. Drake CG, et al. Adv Immunol. 2006;90:51–81; 2. Vesely MD, et al. Annu Rev Immunol. 2011;29:235–271. (eg, Tregs) (eg, TGF-B) (eg, down regulation of MHC I) (eg, disruption of T-cell checkpoint pathways) Inhibition of tumor antigen presentation 1 Secretion of immunosuppressive factors 2 Inhibition of attack by immune cells 3 Recruitment of immunosuppressive cell types 4 APCAPC Tumor Cell T-regActivatedActivated T-cellT-cell
In the presence of cancer, there is evidence that the immune system has responded to the tumor:1,2 Antibodies against tumor antigens3 Tumor-specific T cells4 TILs5 In some tumors, the infiltration of CD8+ effector T cells correlates with improved prognosis and therapy outcome6,7 Occasional reports of spontaneous regression of metastatic tumors proposed to be at least partly immune mediated5,8 Evidence of an Antitumor Immune Response in Many Types of Cancer TILs = tumor-infiltrating lymphocytes. 1. Vesely MD, et al. Annu Rev Immunol. 2011;29:235–271; 2. Finn OJ. Ann Oncol. 2012;23(suppl 8):viii6–viii9; 3. Reuschenback M, et al. Cancer Immunol Immunother. 2009;58:1535–1544; 4. Godet Y, et al. Clin Can Res. 2012;18:2943–2953; 5. Mlecnik B, et al. Cancer Metastasis Rev. 2011;30:5–12; 6. Jochems C, et al. Exp Biol Med (Maywood). 2011;236:567–579; 7. Galon J, et al. Science. 2006;313:1960– 1964; 8. Kalialis LV, et al. Melanoma Res. 2009;19:275–282.
Data Suggesting Tumor Infiltration of Cytotoxic (CD8+ ) T Cells is Associated With Favorable Prognosis a Analysis conducted using surgical specimens. 1. Erdag G, et al. Cancer Res. 2012;72:1070–1080; 2. Ruffini E, et al. Ann Thorac Surg. 2009;87:356–372. Survival in Metastatic Melanoma1,a L = Low (lower than the median) numbers of CD8+ cells H = High (greater than the median) numbers of CD8+ cells Years 4 62 8 100 P = 0.03 TILs were almost exclusively CD8+ in this study 0.0 0.2 0.4 0.6 0.8 1.0 TIL (–): n = 415 TIL (+): n = 134 Survival in Squamous Cell Lung Cancer2,a P = 0.0001 HR = 2.09 TILs were CD8+ in this study 1.0 0.8 0.6 0.4 0.2 0.0 0 1 2 24 36 48 60 Time (mo) TIL Low TIL High Patients at Risk 72 73 53 39 43 25 32 14 23 11 20 8 Patients at Risk 415 134 228 81 150 51 77 23 49 17 31 12 TIL (-) TIL (+) TIL (L) TIL (H)
Data Suggesting Tumor Infiltration of Regulatory T Cells is Associated With Unfavorable Prognosis Survival in Early-Stage Non- Small Cell Lung Cancer1,a Months After Surgery SurvivalProbability 0 20 40 60 80 100 0.0 0.2 0.4 0.6 0.8 1.0 Log rank P = 0.021 Treg count <5 Tregsb 5–25 Tregsb >25 Tregsb a Analysis conducted using surgical specimens. b FOXP3+ cells. Tregs = regulatory T cells. 1. Tao H, et al. Lung Cancer. 2012;75:95–101; 2. Siddiqui SA, et al. Clin Cancer Res. 2007;13:2075–2081. Survival in Renal Cell Carcinoma2,a P = 0.004 Tregs<10% 0 20 40 60 80 100 Tregs≥10% 0 321 Years From Nephrectomy to Last Follow-up
Selected T-Cell Checkpoints: Targets for Active Immunotherapy1,2,a  T-cell responses are regulated though a complex balance of inhibitory (“checkpoint”) and activating signals  Tumors can dysregulate checkpoint and activating pathways, and consequently, the immune response  Targeting checkpoint and activating pathways is an evolving approach to active immunotherapy, designed to promote an immune response a The image shows only a selection of the receptors/pathways involved. 1. Adapted from Mellman I, et al. Nature. 2011:480;481–489; 2. Pardoll DM. Nat Rev Cancer. 2012;12:252– 264. CTLA-4 PD-1 TIM-3 BTLA VISTA LAG-3 HVEM CD27 CD137 GITR OX40 CD28 T-cell stimulation Blocking antibodies Agonistic antibodies Inhibitory receptors Activating receptors T cell B7-1 T cell
Il legame del recettore PD-1 presente sui linfociti T attivati infiltranti il tumore con i ligandi PD-L1 e PD-L2, espressi nel microambiente tumorale, induce l’inibizione delle cellule T e lainibizione delle cellule T e la perdita della loro funzione effettriceperdita della loro funzione effettrice, proteggendo in definitiva il tumore dall’attacco delle cellule T. Il blocco del segnale di PD-1 può ripristinare la sorveglianza immunologica, permettendo al sistema immunitario di riconoscere e uccidere le cellule tumorali. La via PD-1 costituisce un importante checkpoint del normale funzionamento del sistema immunitario. Tuttavia, i tumori possono eludere il riconoscimento da parte del sistema immunitario attraverso l’espressione di molecole regolatrici che sopprimono le risposte immunitarie contro i tumori. Una di queste molecole regolatrici è PD-1.Una di queste molecole regolatrici è PD-1. IMMUNOTERAPIAIMMUNOTERAPIAIMMUNOTERAPIAIMMUNOTERAPIA Il coinvolgimento di normali vie di checkpoint immunitariovie di checkpoint immunitario nel microambiente tumorale, come la via PD-1/PD-L1/2via PD-1/PD-L1/2, rappresenta uno dei meccanismi attraverso cui i tumori possono sopprimere le risposte immunitarie.
ANTICORPOANTICORPO ANTI-PD-1/PD-L1ANTI-PD-1/PD-L1ANTICORPOANTICORPO ANTI-PD-1/PD-L1ANTI-PD-1/PD-L1
This is a simplified rendering of immune system activity TUMOR-INDUCED IMMUNE SUPPRESSION Cancers may evade the body’s protective immune response by exploiting key immune checkpoint pathways that are regulators of T-cell activity and can be used by the tumor as defense mechanisms against the immune system.1-4 Antigen- presenting cell Inactive T cell Inactive T cell Inactive T cell Inactive T cell Inactive T cell Inactive T cell Inactive T cell Inactive T cell Tumor Tumors exploit checkpoint pathways and turn off the immune response in different ways1,2,4,5 Single cancer cell Single inhibited T cell The PD-1 Pathway Inactivating T cells1-4 Tumors exploit the PD-1 checkpoint pathway to turn off the immune response by inactivating T cells at the tumor site. Initial T-cell attack may result in the tumor expressing PD-1 ligands. Both PD-L1 and PD-L2 can bind to the PD-1 receptor on T cells to suppress T-cell attack. PD-1 receptor PD-L2 PD-1 receptor PD-L1 ‘ Single antigen-presenting cell Single inhibited T cell The CTLA-4 Pathway Decreasing T-cell proliferation2,6,7 Tumors exploit the CTLA-4 checkpoint pathway to turn off the immune response by decreasing T-cell proliferation. Interaction of the CTLA-4 receptor on the T cell with ligands on the antigen-presenting cell (APC) leads to T-cell suppression. CD80/CD86 CD28CTLA-4
Ipilimumab mechanism of action T cell inhibition T cell activation T cell potentiation T cell TCR CTLA-4 APC MHC B7 T cell TCR CTLA-4 APC MHC B7 T cell TCR CTLA-4 APC MHC B7 IPILIMUMA B blocks CTLA-4 CD28CD28 Adapted from Weber J. Cancer Immunol Immunother. 2009;58:823.
MHC PD-L1 PD-1 PD-1 PD-1 PD-1 Nivolumab PD-1 receptor-blocking Ab Recognition of tumour by T cell through MHC/antigen interaction mediates IFNγ release and PD-L1/2 upregulation on tumour Recognition of tumour by T cell through MHC/antigen interaction mediates IFNγ release and PD-L1/2 upregulation on tumour Priming and activation of T cells through MHC/antigen and CD28/B7 interactions with antigen-presenting cells Priming and activation of T cells through MHC/antigen and CD28/B7 interactions with antigen-presenting cells T cell receptor T cell receptor PD-L1 PD-L2 PD-L2 MHC CD28 B7 T cell NFκB Other PI3K IFNγ IFNγR Shp-2 Shp-2 Nivolumab mechanism of action
Targeting the Immune System for Cancer Therapy Advantages Disadvantages • Acts throughout the body1,2 • Adapts to changing tumor characteristics3,4 • Potential to provide long- term memory and durable tumor control1,2,4,5 • Potential for activity in multiple tumor types3 • Selective pressure from the immune system can result in tumors capable of evading the immune system1 • Tumors may use multiple mechanisms to evade the immune system6 • Potential for inflammatory reactions in normal tissue7 1. Vesely MD, et al. Annu Rev Immunol. 2011;29:235–271; 2. Janeway CA, et al. Immunobiology: The Immune System in Health and Disease. 5th ed. New York, NY: Garland Science; 2004; 3. Eggermont AM. Ann Oncol. 2012;23(suppl 8):viii53–viii57; 4. Finn OJ. Ann Oncol. 2012;23(suppl 8):viii6–viii9; 5. Pardoll DM. Nat Rev Cancer. 2012;12:252–264; 6. Drake CG, et al. Adv Immunol. 2006;90:51–81; 7. Corsello SM, et al. J Clin Endocrinol Metab. 2013;98:1361–1375. Harnessing the body’s own natural defense/surveillance mechanisms may enable tumor control4
Treatment strategies in advanced NSCLC in 2016 Patient with driver mutation Patients w/o driver mutation Chemotherapy chemoterapy + biological Targeted therapy Immunotherapy
CLINICAL DEVELOPMENT of PD-1 and PD-L1 INHIBITORS PD-1 Nivolumab Fully human IgG4 mAb BMS ph III Pidilizumab Humanized IgG1 mAb Cure Tech ph II Pembrolizumab Humanized IgG4 mAb Merck ph III AMP -224 Recombinant PD-L2 Fc fusion protein GSK ph I PD- L1 BM2-936559 Fully human IgG4 mAb BMS ph I MEDI4736 (Durvalumab) Engineered human IgG1 mAb MedImmune ph III MPDL3280A (Atezolizumab) Engineered human IgG1 mAb Genentech ph III MSB0010718C (Avelumab) Engineered human IgG1 mAb EMD Serono ph II
CheckMate 017 (NCT01642004) study design • Stage IIIb/IV non-SQ NHSCLC • Pre-treatment (archival or recent) tumor samples required for PD-L1 • ECOG PS 0-1 • Failed 1 prior platinum doublet • Prior maintenance therapy alloweda • Prior TKl ttherapy allowed for known ALK translocation or EGFR mutation N= 582 Nivolumab 3mg/kg IV Q2W until PD or unacceptable toxicity n= 292 Docetaxel 75 mg/m2 IV Q3W until PD or unacceptable toxicity n= 290 • Primary Endpoint: - OS • Additional Endpoints - ORRb - PFS b - Safety - Efficay by tumor PD-L1 expression - Quality of life(LCSS) Patients stratified by prior manintenance therapy and line of therapy (second- vs third line)  PD-L1 expession measured using the Dako/BMS automated IHC assay 14,15  Fully validated with analitycal performance having met all pre-determined acceptance criteria for sensitivity, specificity, precision and robustness a Maintenance terapy included pemetrexed, bevacizumab, or erlotinib (non considered a separate line of therapy; b Per RECIST v1.1 criteria determined by the investigator Paz-Ares L, ASCO 2015
Minelli M. Le nuove Terapie in Oncologia. ASMaD 2016
CheckMate 057 (NCT01673867) study design • Stage IIIb/IV SQ NHSCLC • 1 prior platinum doublet- based chemotherapy • ECOG PS 0-1 • Pre-treatment (archival or fresh) tumor samples required for PD-L1 analysis N= 272 Nivolumab 3mg/kg IV Q2W until PD or unacceptable toxicity n= 135 Docetaxel 75 mg/m2 IV Q2W until PD or unacceptable toxicity n= 137 • Primary Endpoint: - OS • Additional Endpoints - Investigator –assessed ORR - Investigator - assessed PFS - Correlation between PD-L1 exprssion and efficacy - Safety - Quality of life(LCSS) Patients stratified by region and prior paclitaxel use • One pre-planned interim analysis for OS • At time of DBL (Decembre 15,201) 199 deaths were reported (86& of deaths required for final analysis) • The boundary for declaring superiority for OS at the pre-planned analysis was P <0,03 Spigel DR, ASCO 2015
Minelli M. Le nuove Terapie in Oncologia. ASMaD 2016
ClinicalTrials.gov: NCT01905657 (a) priot yherapy must have included ≥ 2 cycles of platinum-doublet chtemotherapy. An appropriate tyrosine Kinase inhibition was required for patients whose tumors had an EGFR sensitizing mutation or an ALK translocation (b) Added after 441 patients enrolled based on results from Keynote001 (Garan EB et al. N.Engl.J.Med 2015; 372:2018-28 (c) patients received the maximum number of cycles permitted by the local regulatory authority Herbst RS, Lancet 2015 Key note-010: study design R 1:1:1 Stratification factors: -ECOG PS (0 vs1) -Region (East Asia vs non-East Asia) - PD-L1 status (b) TPS > 50% vs 1%-49% End points in the TPS > 50 stratum and TPS > 1% population •Primary: PFS and OS •Secondary: ORR, duration of response, safety
Minelli M. Le nuove Terapie in Oncologia. ASMaD 2016
Minelli M. Le nuove Terapie in Oncologia. ASMaD 2016
Minelli M. Le nuove Terapie in Oncologia. ASMaD 2016
Examples of ongoing combination trials CHEMOTHERAPY RADIOTHERAPY TARGETED IMMUNOTHERAPY NIVOLUMAB (ANTI PD-1) + CICPLATIN/GEMCITABINE, CISPLATIN/PEMETREXED OR CARBOPLATIN / PACLITAXEL (NCT 01454102) NR + BEVACIZUMAB OR ERLOTINIB (NCT 01454102) + IPILIMUMAB (NCT 01454102) + anti-KIR (NCT 01714739) + nati- LAG3 (NCT 01968109) PEMBROLIZUMAB (ANTI PD-1) CISPLATIN /PEMETREXED OR CARBOPLATIN / PACLITAXEL (NCT 01840579) +PACLITAXEL / CARBOPLATIN ±BEVACIZUMAB (NCT 02039674) NR + GEFITINIB OR ERLOTINIB (NCT 02039674) + IPILIMUMAB (NCT 02039674) + INCB024360 (NCT 02178722) MEDI-4736 (ANTI PD –L1) NR NR + GEFINITIB ( NCT 02088112) + AZD929 (NCT 02143466) + TREMELIMUMAB (NCT 02000947, NCT 02141347) MPDL3280A (ANTI PD –L1) NR NR + ERLOTINIB (NCT 02013219) + COBIMETINIB (NCT 019988896) + IPILIMUMAB (NCT 002174172) IPILIMUMAB (ANTI-CTLA-4) VARIOUS (NCT00527735; NCT01165216; NCT01285609; NCT 01331525; NCT 01450761; NCT 01454102) STEREOTACTIC RADIOSURGERY* (NCT 02107755 , NCT 02239900) + IONIZING RADIATION (NCT 02221739) + ERLOTINIB OR CRIZOTINIB ( NCT 01998126) + NIVOLUMAB (NCT 01454102) + PEMBROLIZUMAB (NCT 02039674) TREMELIMUMAB (ANTI-CTLA-4) NR NR + GEFITINB (NCT 020400464) + MEDI-4736 (NCT 02000947) * Trials in patients with melanoma with metastatic disease to a visceral organ (lung, liver,, adreanal, nodal station outsider the drenal limph-drainage of the primary, vertebral bodies, NR: no trials reported
CheckMate 012: overall study design STAGE IIIB/IV NSCLS; no prior chemoterapy for advanced disease; ECOG PS 0 or 1 NIVOLUMAB monotherapy NIVOLUMAB + PT-DC NIVOLUMAB + ERLOTINIB NIVOLUMAB + BEVACIZUMAB NIVOLUMAB + IPILIMUMAB Rizvi N, WCLC 2015
Minelli M. Le nuove Terapie in Oncologia. ASMaD 2016
Take home messages  NIVOLUMAB and PEMBROLIZUMAB (in PD-L1 positive) are the new standard of treatment for andvanced NSCLC progressed on platinum-based chemotherapy  Due to the cost of these new agents, the patients selection will be very important for the treatment decision. Today, PD-L1 expression is the only biomarker available predictive of anti PD1- PDL1 benefit.  New response evaluation criteria are important for the clinical practice.  Combination with chemotherapy, targeted agents or other immunoterapeutic agents could be the future for anti-PD1- PDL1 inhibitors.

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Minelli M. Le nuove Terapie in Oncologia. ASMaD 2016

  • 1. LUNCH MEETING AL PASTEUR QUICK UPDATE LE NUOVE TERAPIE IN ONCOLOGIA Dott. MAURO MINELLI Direttore f.f. U.O.C. di Oncologia Medica Az. Ospedaliera S. Giovanni – Addolorata, Roma
  • 2. CARCINOMA MAMMARIO UN MODELLO DIUN MODELLO DI SVILUPPOSVILUPPO DELLA RICERCADELLA RICERCA CLINICACLINICA
  • 3. RIVOLUZIONE DEI CONCETTI NEGLI ULTIMI 30 ANNI DADA TRATTAMENTOTRATTAMENTO MASSIMOMASSIMO TOLLERABILETOLLERABILE CONCEZIONECONCEZIONE ANATOMICAANATOMICA MEDICINAMEDICINA TRADIZIONALETRADIZIONALE AA TRATTAMENTOTRATTAMENTO MINIMOMINIMO EFFICACEEFFICACE CONCEZIONECONCEZIONE BIOLOGICABIOLOGICA NEDICINA BASATANEDICINA BASATA SULL’EVIDENZASULL’EVIDENZA
  • 4. EVOLUZIONE ESTREMAMENTE RAPIDA DELLE NUOVE ACQUISIZIONI SULLE TERAPIE BIOMOLECOLARI TARGET THERAPY NUOVA ATTITUDINE MEDICA E DI RICERCA UTILIZZO DI FARMACI CHE AGISCONO SU RECETTORI CELLULARI SPECIFICI
  • 5. IDENTIFICAZIONE DI MARKERS MOLECOLARI DELLE CELLULE NEOPLASTICHE UN DETERMINAT O DIFETTO GENICO C O L P I R E LA VIA METABOLICA ALTERATA
  • 6. TARGET THERAPY A metà degli anni ’80 fu scoperto il GENE HER-2 posto sul cromosoma 17 HER-2 è presente in piccolissima quantità sulla membrana delle cellule normali, circa 20.000 recettori per cellula.
  • 7. TARGET THERAPY Nel 20-30% dei carcinomi della mammella: HER-2 di 100 volte per Amplificazione genica Sovraespressione recettoriale
  • 8. IPER ESPRESSIONE HER -2 SVILUPPO E MANTENIMENTO DEL TUMORE MAMMARIO MAGGIORE AGGRESSIVITA’ INTERESSAMENTO LINFONODALE ELEVATA FRAZIONE DI CRESCITA E GRADING NEGATIVITA’ DEI RECETTORI ORMONALI
  • 9. TRASTUZUMAB ANTICORPO MONOCLONALE UMANIZZATO ANTI HER- 2 (95% umano – 5% murino) Approvato dalla FDA nel 1998 per il trattamento del CARCINOMA della MAMMELLA METASTATICO (13 anni dopo la clonazione del Gene HER-2)
  • 10. AZIONE DEL TRASTUZUMAB Arresto dell’attività proliferativa Induzione di apoptosi Inibizione di angiogenesi POTENTE INDUTTORE DI RISPOSTA IMMUNITARIA CITOTOSSICA CELLULO- MEDIATA ANTICORPO-DIPENDENTE (ADCC) E COMPLEMENTO DIPENDENTE •Occupazione del sito di legameOccupazione del sito di legame •Blocco della dimerizzazione del recettoreBlocco della dimerizzazione del recettore •Alterazione del segnale di fosforilazione del recettoreAlterazione del segnale di fosforilazione del recettore •Accelerata internalizzazione e degradazione del recettoreAccelerata internalizzazione e degradazione del recettore
  • 11. Herceptin ® plus a taxane Two large randomised trials show efficacy and tolerability of Herceptin ® plus a taxane:  Slamon et al. Herceptin ® plus paclitaxel  Marty et al. Herceptin ® plus docetaxel Marty M, et al. J Clin Oncol in press. Slamon DJ, et al. N Engl J Med 2001;344:783–92
  • 12. Herceptin ® plus paclitaxel: efficacy (IHC 3+) Herceptin® + paclitaxel (n=68) Paclitaxel alone (n=77) ORR (%) 49.0 17.0 Median TTP (months) 7.1 3.0 Median OS (months) 24.8 17.9 Median DR (months) 10.9 4.6 Baselga J. Oncology 2001;61(Suppl. 2):14–21
  • 13. Herceptin ® plus paclitaxel: 39% increase in survival (IHC 3+) Smith IE. Anticancer Drugs 2001;12:S3–10 1.0 0.8 0.6 0.4 0.2 0 Time (months) 0 5 10 15 20 25 30 35 40 45 50 17.9 24.8 Probabilityofsurvival ↑ 39% Herceptin ® + paclitaxel Paclitaxel
  • 14. Herceptin® plus docetaxel: efficacy Herceptin® + docetaxel (n=68) Docetaxel alone (n=77) p-value ORR (%) 61.0 34.0 0.0002 Median TTP (months) 10.6 5.7 0.0001 Median OS (months) 30.5 22.1 0.0062 Median DR (months) 11.4 5.1 0.0011 12-month cut-off Marty M, et al. J Clin Oncol in press.
  • 15. Herceptin® plus docetaxel: 38% increase in survival 1.0 0.8 0.6 0.4 0.2 0 Probabilityofsurvival 0 3 6 9 12 15 18 21 24 27 30 33 36 Time (months) Intent-to-treat population, 12-month cut-off Documented crossover = 48% p=0.0062 22.1 30.5 Herceptin® + docetaxel Docetaxel alone Marty M, et al. J Clin Oncol in press. ↑ 38%
  • 16. TRASTUZUMAB ADIUVANTE MEDIAN FOLLOW UP(HR) 1 HERA 1 ANNO (0.54) 2 HERA 2 ANNI (0.64) 3 N9831 AC-T-H 1,5 ANNI (0.87) 4 COMBINED ANALYSIS 2 ANNI (0.48) 5 BCIRG 006 AC DH→ 2 ANNI (0,61) 6 BCIRG 006 DCarboH 2 ANNI (0,67) 7 FinHER VH/DH 3 ANNI (0,42) 8 PACS 04 4 ANNI (0,86) 0 1 2FAVOUR TRASTUZUMAB FAVOUR NO TRASTUZUMAB
  • 18. LAPATINIB farmaco orale  INIBITORE DELLE TIROSINOCHINASI e HER 2  STUDI PRECLINICI HANNO DIMOSTRATO CHE LAPATINIB INDUCE APOPTOSI E INIBISCE IL SEGNALE MEDIATO DALL’INSULIN GROWTH FACTOR I RECEPTOR IN LINEE CELLULARI RESISTENTI AL TRASTUZUMAB
  • 19. LAPATINIB Segnali extracellulari  O O O O Membrana cellulare RECETTORI ErbB2 FOSFORILAZIONE O O O O Pl3k fosforilato Akt fosforilata PTEN FOSFORILAZIONE AngiogenesiProliferazioneSopravvivenza delle CELLULE TUMORALI CELLULA TUMORALE Inibizione Serin/treonin chinasi Akt Fosfatidilinositol-3,4,5- trifosfato
  • 20. TERAPIA ORALE Patients with ErbB2-positive locally advanced or metastatic breast cancer who progressed after prior anthracycline, taxane and trastuzumab (N=399) R A N D O M I S A T I O N Capecitabine 2500 mg/m2 /day po Days 1–14 q 3 wk Lapatinib 1250 mg po qd continuously + capecitabine 2000 mg/m2 /day po Days 1–14 q 3 wk EGF100151 (Cameron1 ) 1. Cameron D, et al. Breast Can Res Treat 2008;DOI 10.1007/s10549-007-9885-0; 23.
  • 21. LAPATINIB Lapatinib e Capecitabina nel trattamento del carcinoma mammario avanzato HER-2 positivo Lapatinib+capecitibinaLapatinib+capecitibina ( n=198)( n=198) CapecitabinaCapecitabina (n=201)(n=201) Hazard ratioHazard ratio ( 95% IC)( 95% IC) PP Tempo allaTempo alla progressioneprogressione (mesi)(mesi) 6,26,2 4,34,3 0,57 (0,43-0,77)0,57 (0,43-0,77) 0,00010,0001 Risposta (%)Risposta (%) 23,723,7 13,913,9 0,010,01 SopravvivenzaSopravvivenza 15,615,6 15,315,3 0,78 (0,55-1,12)0,78 (0,55-1,12) 0,170,17 Percentuale diPercentuale di metastasimetastasi encefaliche comeencefaliche come primo eventoprimo evento 2%2% 6%6% -- 0,040,04 Cameron D, et al. Breast Cancer Res Treat 2008
  • 22. Pertuzumab meccanismo d’azionePertuzumab meccanismo d’azionePertuzumab meccanismo d’azionePertuzumab meccanismo d’azione 2013 LA NUOVA ERA IL PERTUZUMAB PREVIENE LA DIMERIZZAZIONE DI HER2/HER3 INDOTTA DAL LIGANDO
  • 23. DOPPIO BLOCCO ?? 2013 LA NUOVA ERA I TUMORI DELLA MAMMELLA HER2+ SONO GUIDATI DA ENTRAMBI I COMPLESSI HER2- HER3 LIGANDO DIPENDENTI O INDIPENDENTI I TUMORI DELLA MAMMELLA HER2+ SONO GUIDATI DA ENTRAMBI I COMPLESSI HER2- HER3 LIGANDO DIPENDENTI O INDIPENDENTI Il DOPPIO BLOCCO DI QUESTI COMPLESSI CON TRASTUZUMAB+ PERTUZUMAB E’ CLINICAMENTE MOLTO ATTIVO VS IL TRATTAMENTO CON SOLO TRASTUZUMAB Il DOPPIO BLOCCO DI QUESTI COMPLESSI CON TRASTUZUMAB+ PERTUZUMAB E’ CLINICAMENTE MOLTO ATTIVO VS IL TRATTAMENTO CON SOLO TRASTUZUMAB
  • 24. 2013 LA NUOVA ERA PERTUZUMAB 1a LINEA METASTATICA: studio CLEOPATRA Docetaxel – Trastuzumab – Placebo vs Docetaxel – Trastuzumab – Pertuzumab PFS 12,4 vs 18,7 con HR < 0,62 ORR 69,3% vs 80,2% OS mediana 37,6 vs Non raggiunto ESMO 2014 Dr. Sandra Swain: We’ re never seen anything like this before OS  4,5 aa
  • 25. Caso clinico : uso del doppio blocco
  • 26. ANTICORPO FARMACO CONIUGATO Meccanismo d’azione Il T-DM1 tramite il trastuzumab si lega al recettore dell’ HER2 sulla superficie della cellula tumorale 2013 LA NUOVA ERA the "magic bullet"
  • 27. T-DM1 meccanismo d’azione all’interno della cellula il DM1 si lega ai microtubuli e inibisce la loro polimerizzazione L’inibizione della polimerizzazione dei microtubuli arresta l’evoluzione del ciclo con la conseguente morte cellulare Il legame HER2 +TDM1-1 per endocitosi entra all’interno della cellula tumorale Terminata l’endocitosi il trastuzumab e il recettore HER2 sono degradati e viene rilasciato un metabolita citotossico 2013 LA NUOVA ERA
  • 28. 2013 LA NUOVA ERA TDM -1 2 linea: studio EMILIA TDM -1 vs LAPATINIB + CAPECITABINA PFS 9,6 vs 6,4 OS mediana 30,2 vs 25,1
  • 29. La maggior parte dei carcinomi mammari sono forme sporadiche SOLO il 5-7% sono legati a fattori ereditari ¼ di questi sono determinati dalla mutazione di due geni: BRCA-1  LOCALIZZATO SUL BRACCIO LUNGO DEL CROMOSOMA 17 (24 ESONI) BRCA-2  LOCALIZZATO SUL BRACCIO LUNGO DEL CROMOSOMA 13 (27 ESONI BRCA -1 e 2 (BReast CAncer)
  • 30. BRCA -1 e 2 (BReast CAncer) IDENTIFICATI NEL 1994 E NEL 1995 COME GENI ONCOSOPPRESSORI IN FAMIGLIE CON ALTA PREVALENZA DI TUMORI DELLA MAMMELLA E DELL’OVAIO SONO COSTITUENTI CENTRALI DI COMPLESSI MULTIPROTEICI COINVOLTI NEL RIPARO DEI DANNI DEL DNA Angelina Jolie
  • 31. BRCA -1 e 2 (BReast CAncer) MASCHIO CON CARCINOMA MAMMARIO DONNA CON CARCINOMA MAMMARIO E CARCINOMA OVARICO DONNA CON CARCINOMA MAMMARIO < 36 ANNI < 50 ANNI < 50 ANNI E STORIA FAMILIARE DI ≥ PARENTE DI 1° GRADO CON: Carcinoma mammario < 50 anni Carcinoma ovarico a qualsiasi età Carcinoma mammario bilaterale Carcinoma mammario maschile > 50 ANNI SOLO SE STORIA FAMILIARE DI CA.MAMMARIO O OVARICO IN ≥ 2 PARENTI DI 1° GRADO (di cui 1 in 1° grado con lei) < 60 ANNI con carcinoma mammario « triplo negativo » Ad ogni età con storia familiare di carcinoma mammario esocrino del pancreas in ≥ 2 parenti di 1° grado ( di cui 1 in 1° grado con lei) DONNA CON CARCINOMA OVARICO/TUBA/PRIMITIVO DEL PERITONEO A QUALSIASI ETA’ SOGGETTO CON CA. MAMMARIO ESOCRINO DEL PANCREAS E STORIA FAMILIARE DI CA. MAMMARIO O DELL’OVAIO O ESOCRINO DEL PANCREAS IN ≥ 2 PARENTI DI 1° GRADO (di cui 1 in 1° grado con lei) CONDIZIONI DI STORIA ONCOLOGICA ASSOCIATE A UNA PROBABILITA’ DI MUTAZIONE BRCA ≥ 10%
  • 32. BRCA -1 e 2 (BReast CAncer) RISCHIO CUMULATIVO DI CARCINOMA MAMMARIO E OVARICO (FINO AI 70 ANNI DI ETA’) NELLE DONNE PORTATRICI DI MUTAZIONE BRCA BRCA 1 (Rischio cumulativo a 70 anni) BRCA 2 (Rischio cumulativo a 70 anni) Metanalisi Chen S, J Clin Oncol 2007 Carcinoma mammario 57% (IC al 95% 47-66%) 49% (IC al 95% 40-57%) Carcinoma ovarico 40% (IC al 95% 35-46%) 18% (IC al 95% 13-23%) Metanalisi Nelson HD, USPSTF 2014 Carcinoma mammario 46-70% 50-71% Carcinoma ovarico 41-46% 17-23% Analisi prospettica di EMBRACE Mavaddat N, J Natl Cancer Inst 2013 Carcinoma mammario 60% (IC al 95% 44-75%) 55% (IC al 95% 41-70%) Carcinoma ovarico 59% (IC al 95% 43-76%) 16% (IC al 95% 7,5-34%) Carcinoma mammario controlaterale 83% (IC al 95% 69-94%) 62% (IC al 95% 44-79,5%)
  • 33. LE CELLULE NORMALI MA ANCHE QUELLE DEL TUMORE RIPARANO I DANNI ATTRAVERSO DIVERSI MECCANISMI MOLECOLARI. ALCUNI DI QUESTI MECCANISMI COINVOLGONO LE PARP-POLI (ADP RIBOSIO) POLIMERASI, ENZIMI RESPONSABILI DELLA APOPTOSI (MORTE CELLULARE PROGRAMMATA).
  • 34. IL MECCANISMO ATTRAVERSO CUI, IN UN SISTEMA «BRCA- DEFICENT», PARP VIENE INIBITO E SI INDUCONO DANNI AL DNA MEDIANTE AGENTI ALCHILANTI O ATTRAVERSO LA RADIOTERAPIA E’ DETTA «LETALITA’ SINTETICA» Esistono farmaci PARP inibitori (OLAPARIB)
  • 36. L’uso di anti-EGFR (Cetuximab/Panitumumab) in prima linea nei pazienti mCRC RAS WT consente di raggiungere una OS mediana di oltre 30 mesi Dati di Efficacia
  • 37. Bisogna riconoscere un merito scientifico… La storia del RAS (a partire da KRAS) nasce con gli studi su Panitumumab
  • 38. Follow-up Supportive Care (BSC) vs. BSC Alone After Failure of Standard Chemotherapy in mCRC Randomization stratification • ECOG score: 0-1 vs 2 • Geographic region: Western EU vs Central and Eastern EU vs rest of world 1:1 panitumumab 6.0 mg/kg Q2W + BSC (n = 231) Best Supportive Care (BSC) (n = 232) R A N D O M I Z E Optional panitumumab Crossover Study (n = 176) 76% of BSC alone patients entered crossover study PDPD PD Follow-up Van Cutsem E, et al. J Clin Oncol 2007;25:1658-64.
  • 39. Wild-type KRAS Subgroup: PFS by Treatment 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 Weeks 36 38 40 42 44 46 48 50 52 7 7 6 5 5 10 9 9 6 6 6 5 4 3 3 2 2 2 2 1 124 115/124 (93) 12.3 19.0 114/119 (96) 7.3 9.3 Pmab + BSC BSC Alone Events/N (%) Median In Weeks Mean In Weeks HR = 0.45 (95% CI: 0.34–0.59) Stratified log-rank test, p < 0.0001 Pmab + BSC BSC Alone Patients at Risk 119 112106 80 69 63 58 50 45 44 44 33 25 21 20 17 13 13 13 10 119 109 91 81 38 20 15 15 14 11 6 ProportionwithPFS Amado RG, et al. J Clin Oncol 2008;26:1626-34
  • 40. Mutant KRAS Subgroup: PFS by Treatment 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 ProportionwithPFS Pmab + BSC BSC Alone 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 Weeks 36 38 40 42 44 46 48 50 52 Patients at Risk 78 76 72 26 10 8 6 5 5 5 5 4 4 4 4 2 2 2 2 2 2 2 1 1 1 91 77 61 37 22 19 10 9 8 6 5 5 4 4 4 4 4 4 3 3 3 2 2 2 2 84 100 76/84 (90) 7.4 9.9 95/100 (95) 7.3 10.2 Pmab + BSC BSC Alone Events/N (%) Median In Weeks Mean In Weeks HR = 0.99 (95% CI: 0.73–1.36) Amado RG, et al. J Clin Oncol 2008;26:1626-34
  • 41. Cetuximab e Panitumumab sono Ab monoclonali con STRUTTURA DIVERSA • Diversa incidenza di possibili reazioni allergiche • Diversa gestione della premedicazione
  • 42. The Development of Human Monoclonal Antibodies 100% Mouse Protein Mouse ~34% Mouse Protein Chimeric cetuximab ~10% Mouse Protein Humanized bevacizumab Fully Human 100% Human Protein panitumumab Yang XD, et al. Crit Rev Oncol Hematol 2001;38:17-23. 1. Erbitux® , MabThera® , Avastin® , Vectibix® European Public Assessment Reports as of Dec 2008. 2. Erbitux® US Package Insert as of Dec 2008, http://packageinserts.bms.com/pi/pi_erbitux.pdf. 3. Avastin® US Prescribing Information as of Dec 2008. 4. Kang and Saif. J Support Oncol 2007; 5:451-7.* Non-Hodgkins’s lymphoma. † Monotherapy in mCRC. Data are not from comparative studies. Infusion reactions All grades Severe panitumumab† bevacizumabcetuximab† 2% <1% (grade 3)1 <3% <1%3,4 20% 5%2 nonenone antihistamine + corticosteroid (mandatory for first, recommended for subsequent infusions) Premedication1
  • 43. TOSSICITA’ CUTANEA • Cetuximab e Panitumumab hanno un profilo di tossicità cutanea simile. • Tuttavia, nella pratica clinica notiamo che le reazioni cutanee da Panitumumab tendono ad essere più imponenti
  • 44. SCHEDULA DI SOMMINISTRAZIONE • Cetuximab: settimanale • Panitumumab: bisettimanale
  • 45. SCHEDULA DI CHEMIOTERAPIA IN PRIMA LINEA • Cetuximab + FOLFIRI/FOLFOX (lo studio registrativo in prima linea - Crystal- è con FOLFIRI; dati contrastanti sull’associazione con regimi a base di oxaliplatino, specie con XELOX) • Panitumumab + FOLFOX (al momento secondo scheda AIFA è l’unico schema consentito in prima linea)
  • 47. Slide 2 Presented By Nicholas Turner at 2015 ASCO Annual Meeting
  • 48. Palbociclib Presented By Nicholas Turner at 2015 ASCO Annual Meeting
  • 49. Abstract LBA502 <br /><br /> A Double Blind Phase 3 Trial of Fulvestrant With or Without Palbociclib in Pre- and Post-menopausal Women With Hormone Receptor-positive, HER2- negative Advanced Breast Cancer That Progressed on Prior Endocrine Therapy<br />(PALOMA3 Study) Presented By Nicholas Turner at 2015 ASCO Annual Meeting
  • 50. PALOMA3 Study Design Presented By Nicholas Turner at 2015 ASCO Annual Meeting
  • 51. Study Endpoints Presented By Nicholas Turner at 2015 ASCO Annual Meeting
  • 52. Statistical Design Presented By Nicholas Turner at 2015 ASCO Annual Meeting
  • 53. Tumor Characteristics and Prior Treatment Presented By Nicholas Turner at 2015 ASCO Annual Meeting
  • 54. Treatment Summary Presented By Nicholas Turner at 2015 ASCO Annual Meeting
  • 55. Adverse Events—All Cause Presented By Nicholas Turner at 2015 ASCO Annual Meeting
  • 56. Summary of Adverse Events Presented By Nicholas Turner at 2015 ASCO Annual Meeting
  • 57. Primary Endpoint: PFS (ITT Population) Presented By Nicholas Turner at 2015 ASCO Annual Meeting
  • 58. PFS: Central Blinded Review Audit (n=211) Presented By Nicholas Turner at 2015 ASCO Annual Meeting
  • 60.  5-year survival rates are poor for many patients with advanced cancera New Therapies are Needed to Improve the Survival of Patients With Advanced Disease Tumor Type 5-Year Survival Rate Overall Advanced Disease Prostate 99.2% 27.9% Melanoma 91.3% 16.0% Breast 89.2% 24.3% Kidney/renal pelvis 71.8% 12.3% Colorectal 64.9% 12.5% Ovarian 44.2% 27.3% Stomach 27.7% 3.9% Lung 16.6% 3.9% Pancreatic 6.0% 2.0% a Based on patients diagnosed in the United States between 2003 and 2009. Surveillance, Epidemiology and End Results (SEER) Program. http://seer.cancer.gov.
  • 61. Emerging Hallmarks of Cancer: Avoiding Immune Destruction Adapted from Hanahan, et al. Cell. 2011;144:646–674. Mercury No: ONCHQ14NP02639-01-IT
  • 62. Immuno-Oncology is Being Studied for its Potential to Become a New Treatment Modality for Cancer 1. DeVita VT Jr, et al. Cancer Res. 2008;68:8643–8653; 2. American Cancer Society. http://www.cancer.org/cancer/cancerbasics/thehistoryofcancer/; 3. Hodi FS, et al. N Engl J Med. 2010;363:711–723; 4. Sznol M, et al. Presented at ASCO 2013: oral presentation; 5. Kantoff PW, et al. N Engl J Med. 2010;363:411–422; 6. Finn OJ. Ann Oncol. 2012;23(suppl 8):viii6–viii9. Surgery 1846 Radiation Therapy 1901 Chemotherapy 1946 Targeted Therapy 1997 Immuno-Oncology 2011 Mercury No: ONCHQ14NP02639-01-IT
  • 63.  Innate immune system: involving proteins (chemokines and cytokines) and cells, is considered to be the first line of immune defense and does not generate an antigen- specific response1,2 Cells of the Immune System DC = dendritic cell; NK = natural killer. 1. Dranoff G. Nat Rev Cancer. 2004;4:11–22; 2. Janeway CA, et al. Immunobiology: The Immune System in Health and Disease. 6th ed. New York, NY: Garland Science; 2004. • Adaptive immune system: mediated by B and T cells is highly specific and capable of generating an antigen-specific response1,2 – Induction requires presentation of antigens by cells of the innate immune system Innate Immunity (rapid response) Adaptive Immunity (slow response, memory) Macrophage DC Mast cell γδ T cell NKT cell NK cell Basophil Complement protein Eosinophil Granulocytes Neutrophil B cell Antibodies T cell CD4+ cell CD8+ cell Adapted from Dranoff G.1
  • 64. Normal Immune Response Adapted from Abbas and Lichtman, 2005 Abbas et al. Cellular and Molecular Immunology 5th ed. 2005, Elsevier Saunders
  • 65.  T cells require multiple signals to become fully activated1  In addition to antigen stimulation in the context of MHC molecules, positive co- stimulation is required1  Co-stimulatory or activating receptors include CD28, CD137, CD40, and OX-402 Activation of Naïve T Cells a Anergy describes a state of functional inactivation. 1. Janeway CA, et al. Immunobiology. 2008; 2. Pardoll DM. Nat Rev Cancer. 2012;12:252–264. T cell APC Activates T cell Co-stimulatory signal and specific signal MHC class II TCR Co-stimulator 1 2 T cell APC T cell becomes anergica Specific signal alone 1 T cell APC No effect on T cell Co-stimulatory signal alone 2 CD4 Mercury No: ONCHQ14NP02639-01-IT
  • 66.  Immune checkpoints limit, or “check,” an ongoing immune response  Prevents damage to the body’s healthy tissues  Negative co-stimulation, also called “co-inhibition,” helps shut down immune responses  PD-1, CTLA-4, and LAG-3 are examples of co-inhibitory “checkpoint” molecules  Amplitude and quality of a T-cell response is regulated by a balance of activating and inhibitory signals Regulation of T-Cell Activation: Balancing Activating and Inhibitory Signals CTLA-4 = cytotoxic T-lymphocyte antigen-4; LAG-3 = lymphocyte activation gene-3; PD-1 = programmed death-1; PD-L1 = programmed death-ligand 1. Pardoll DM. Nat Rev Cancer. 2012;12:252–264. APC/ Tumor T cell PD-1 B7-1 (CD80) PD-L1 PD-L2 CD40 CD40L CD137 OX40 CD137L OX40L LAG-3 MHC CD28 ActivationB7-2 (CD86) B7-1 (CD80) CTLA-4 Inhibition TCR Inhibition Inhibition Activation Activation Activation Inhibition
  • 67. The Immune System Recognizes and Eliminates Cancer Via Multiple, Complex Mechanisms 1. Janeway CA, et al. Immunobiology: The Immune System in Health and Disease. 6th ed. New York, NY: Garland Science; 2004; 2. Padmanabhan RR, et al. J Leuk Biol. 1988;43:509–519; 3. Kim R, et al. Immunology. 2007;121:1–14; 4. Vivier E, et al. Science. 2011;331:44–49; 5. Dunn GP, et al. Nat Immunol. 2002;3:991–998.
  • 68.  The three E’s of cancer immunoediting describe the immune system’s roles in protecting against tumor development and promoting tumor growth Immunoediting: The Role of the Immune System in Cancer Development and Progression Elimination • Effective antigen processing/presentation • Effective activation and function of effector cells – eg, T-cell activation without co-inhibitory signals Cancer Immunosurveillance Equilibrium • Genetic instability • Tumor heterogeneity • Immune selection Cancer Dormancy Escape • Tumors may avoid elimination by the immune system through outgrowth tumor cells that can suppress, disrupt, or “escape” the immune system Cancer Progression Vesely MD, et al. Ann Rev Immunol. 2011;29:235–271. Tumor Cell CD8+ T cell CD4+ T cell NK cell Normal Cells Treg
  • 69. Tumors Use Complex, Overlapping Mechanisms to Evade and Suppress the Immune System 1. Drake CG, et al. Adv Immunol. 2006;90:51–81; 2. Vesely MD, et al. Annu Rev Immunol. 2011;29:235–271. (eg, Tregs) (eg, TGF-B) (eg, down regulation of MHC I) (eg, disruption of T-cell checkpoint pathways) Inhibition of tumor antigen presentation 1 Secretion of immunosuppressive factors 2 Inhibition of attack by immune cells 3 Recruitment of immunosuppressive cell types 4 APCAPC Tumor Cell T-regActivatedActivated T-cellT-cell
  • 70. In the presence of cancer, there is evidence that the immune system has responded to the tumor:1,2 Antibodies against tumor antigens3 Tumor-specific T cells4 TILs5 In some tumors, the infiltration of CD8+ effector T cells correlates with improved prognosis and therapy outcome6,7 Occasional reports of spontaneous regression of metastatic tumors proposed to be at least partly immune mediated5,8 Evidence of an Antitumor Immune Response in Many Types of Cancer TILs = tumor-infiltrating lymphocytes. 1. Vesely MD, et al. Annu Rev Immunol. 2011;29:235–271; 2. Finn OJ. Ann Oncol. 2012;23(suppl 8):viii6–viii9; 3. Reuschenback M, et al. Cancer Immunol Immunother. 2009;58:1535–1544; 4. Godet Y, et al. Clin Can Res. 2012;18:2943–2953; 5. Mlecnik B, et al. Cancer Metastasis Rev. 2011;30:5–12; 6. Jochems C, et al. Exp Biol Med (Maywood). 2011;236:567–579; 7. Galon J, et al. Science. 2006;313:1960– 1964; 8. Kalialis LV, et al. Melanoma Res. 2009;19:275–282.
  • 71. Data Suggesting Tumor Infiltration of Cytotoxic (CD8+ ) T Cells is Associated With Favorable Prognosis a Analysis conducted using surgical specimens. 1. Erdag G, et al. Cancer Res. 2012;72:1070–1080; 2. Ruffini E, et al. Ann Thorac Surg. 2009;87:356–372. Survival in Metastatic Melanoma1,a L = Low (lower than the median) numbers of CD8+ cells H = High (greater than the median) numbers of CD8+ cells Years 4 62 8 100 P = 0.03 TILs were almost exclusively CD8+ in this study 0.0 0.2 0.4 0.6 0.8 1.0 TIL (–): n = 415 TIL (+): n = 134 Survival in Squamous Cell Lung Cancer2,a P = 0.0001 HR = 2.09 TILs were CD8+ in this study 1.0 0.8 0.6 0.4 0.2 0.0 0 1 2 24 36 48 60 Time (mo) TIL Low TIL High Patients at Risk 72 73 53 39 43 25 32 14 23 11 20 8 Patients at Risk 415 134 228 81 150 51 77 23 49 17 31 12 TIL (-) TIL (+) TIL (L) TIL (H)
  • 72. Data Suggesting Tumor Infiltration of Regulatory T Cells is Associated With Unfavorable Prognosis Survival in Early-Stage Non- Small Cell Lung Cancer1,a Months After Surgery SurvivalProbability 0 20 40 60 80 100 0.0 0.2 0.4 0.6 0.8 1.0 Log rank P = 0.021 Treg count <5 Tregsb 5–25 Tregsb >25 Tregsb a Analysis conducted using surgical specimens. b FOXP3+ cells. Tregs = regulatory T cells. 1. Tao H, et al. Lung Cancer. 2012;75:95–101; 2. Siddiqui SA, et al. Clin Cancer Res. 2007;13:2075–2081. Survival in Renal Cell Carcinoma2,a P = 0.004 Tregs<10% 0 20 40 60 80 100 Tregs≥10% 0 321 Years From Nephrectomy to Last Follow-up
  • 73. Selected T-Cell Checkpoints: Targets for Active Immunotherapy1,2,a  T-cell responses are regulated though a complex balance of inhibitory (“checkpoint”) and activating signals  Tumors can dysregulate checkpoint and activating pathways, and consequently, the immune response  Targeting checkpoint and activating pathways is an evolving approach to active immunotherapy, designed to promote an immune response a The image shows only a selection of the receptors/pathways involved. 1. Adapted from Mellman I, et al. Nature. 2011:480;481–489; 2. Pardoll DM. Nat Rev Cancer. 2012;12:252– 264. CTLA-4 PD-1 TIM-3 BTLA VISTA LAG-3 HVEM CD27 CD137 GITR OX40 CD28 T-cell stimulation Blocking antibodies Agonistic antibodies Inhibitory receptors Activating receptors T cell B7-1 T cell
  • 74. Il legame del recettore PD-1 presente sui linfociti T attivati infiltranti il tumore con i ligandi PD-L1 e PD-L2, espressi nel microambiente tumorale, induce l’inibizione delle cellule T e lainibizione delle cellule T e la perdita della loro funzione effettriceperdita della loro funzione effettrice, proteggendo in definitiva il tumore dall’attacco delle cellule T. Il blocco del segnale di PD-1 può ripristinare la sorveglianza immunologica, permettendo al sistema immunitario di riconoscere e uccidere le cellule tumorali. La via PD-1 costituisce un importante checkpoint del normale funzionamento del sistema immunitario. Tuttavia, i tumori possono eludere il riconoscimento da parte del sistema immunitario attraverso l’espressione di molecole regolatrici che sopprimono le risposte immunitarie contro i tumori. Una di queste molecole regolatrici è PD-1.Una di queste molecole regolatrici è PD-1. IMMUNOTERAPIAIMMUNOTERAPIAIMMUNOTERAPIAIMMUNOTERAPIA Il coinvolgimento di normali vie di checkpoint immunitariovie di checkpoint immunitario nel microambiente tumorale, come la via PD-1/PD-L1/2via PD-1/PD-L1/2, rappresenta uno dei meccanismi attraverso cui i tumori possono sopprimere le risposte immunitarie.
  • 76. This is a simplified rendering of immune system activity TUMOR-INDUCED IMMUNE SUPPRESSION Cancers may evade the body’s protective immune response by exploiting key immune checkpoint pathways that are regulators of T-cell activity and can be used by the tumor as defense mechanisms against the immune system.1-4 Antigen- presenting cell Inactive T cell Inactive T cell Inactive T cell Inactive T cell Inactive T cell Inactive T cell Inactive T cell Inactive T cell Tumor Tumors exploit checkpoint pathways and turn off the immune response in different ways1,2,4,5 Single cancer cell Single inhibited T cell The PD-1 Pathway Inactivating T cells1-4 Tumors exploit the PD-1 checkpoint pathway to turn off the immune response by inactivating T cells at the tumor site. Initial T-cell attack may result in the tumor expressing PD-1 ligands. Both PD-L1 and PD-L2 can bind to the PD-1 receptor on T cells to suppress T-cell attack. PD-1 receptor PD-L2 PD-1 receptor PD-L1 ‘ Single antigen-presenting cell Single inhibited T cell The CTLA-4 Pathway Decreasing T-cell proliferation2,6,7 Tumors exploit the CTLA-4 checkpoint pathway to turn off the immune response by decreasing T-cell proliferation. Interaction of the CTLA-4 receptor on the T cell with ligands on the antigen-presenting cell (APC) leads to T-cell suppression. CD80/CD86 CD28CTLA-4
  • 77. Ipilimumab mechanism of action T cell inhibition T cell activation T cell potentiation T cell TCR CTLA-4 APC MHC B7 T cell TCR CTLA-4 APC MHC B7 T cell TCR CTLA-4 APC MHC B7 IPILIMUMA B blocks CTLA-4 CD28CD28 Adapted from Weber J. Cancer Immunol Immunother. 2009;58:823.
  • 78. MHC PD-L1 PD-1 PD-1 PD-1 PD-1 Nivolumab PD-1 receptor-blocking Ab Recognition of tumour by T cell through MHC/antigen interaction mediates IFNγ release and PD-L1/2 upregulation on tumour Recognition of tumour by T cell through MHC/antigen interaction mediates IFNγ release and PD-L1/2 upregulation on tumour Priming and activation of T cells through MHC/antigen and CD28/B7 interactions with antigen-presenting cells Priming and activation of T cells through MHC/antigen and CD28/B7 interactions with antigen-presenting cells T cell receptor T cell receptor PD-L1 PD-L2 PD-L2 MHC CD28 B7 T cell NFκB Other PI3K IFNγ IFNγR Shp-2 Shp-2 Nivolumab mechanism of action
  • 79. Targeting the Immune System for Cancer Therapy Advantages Disadvantages • Acts throughout the body1,2 • Adapts to changing tumor characteristics3,4 • Potential to provide long- term memory and durable tumor control1,2,4,5 • Potential for activity in multiple tumor types3 • Selective pressure from the immune system can result in tumors capable of evading the immune system1 • Tumors may use multiple mechanisms to evade the immune system6 • Potential for inflammatory reactions in normal tissue7 1. Vesely MD, et al. Annu Rev Immunol. 2011;29:235–271; 2. Janeway CA, et al. Immunobiology: The Immune System in Health and Disease. 5th ed. New York, NY: Garland Science; 2004; 3. Eggermont AM. Ann Oncol. 2012;23(suppl 8):viii53–viii57; 4. Finn OJ. Ann Oncol. 2012;23(suppl 8):viii6–viii9; 5. Pardoll DM. Nat Rev Cancer. 2012;12:252–264; 6. Drake CG, et al. Adv Immunol. 2006;90:51–81; 7. Corsello SM, et al. J Clin Endocrinol Metab. 2013;98:1361–1375. Harnessing the body’s own natural defense/surveillance mechanisms may enable tumor control4
  • 80. Treatment strategies in advanced NSCLC in 2016 Patient with driver mutation Patients w/o driver mutation Chemotherapy chemoterapy + biological Targeted therapy Immunotherapy
  • 81. CLINICAL DEVELOPMENT of PD-1 and PD-L1 INHIBITORS PD-1 Nivolumab Fully human IgG4 mAb BMS ph III Pidilizumab Humanized IgG1 mAb Cure Tech ph II Pembrolizumab Humanized IgG4 mAb Merck ph III AMP -224 Recombinant PD-L2 Fc fusion protein GSK ph I PD- L1 BM2-936559 Fully human IgG4 mAb BMS ph I MEDI4736 (Durvalumab) Engineered human IgG1 mAb MedImmune ph III MPDL3280A (Atezolizumab) Engineered human IgG1 mAb Genentech ph III MSB0010718C (Avelumab) Engineered human IgG1 mAb EMD Serono ph II
  • 82. CheckMate 017 (NCT01642004) study design • Stage IIIb/IV non-SQ NHSCLC • Pre-treatment (archival or recent) tumor samples required for PD-L1 • ECOG PS 0-1 • Failed 1 prior platinum doublet • Prior maintenance therapy alloweda • Prior TKl ttherapy allowed for known ALK translocation or EGFR mutation N= 582 Nivolumab 3mg/kg IV Q2W until PD or unacceptable toxicity n= 292 Docetaxel 75 mg/m2 IV Q3W until PD or unacceptable toxicity n= 290 • Primary Endpoint: - OS • Additional Endpoints - ORRb - PFS b - Safety - Efficay by tumor PD-L1 expression - Quality of life(LCSS) Patients stratified by prior manintenance therapy and line of therapy (second- vs third line)  PD-L1 expession measured using the Dako/BMS automated IHC assay 14,15  Fully validated with analitycal performance having met all pre-determined acceptance criteria for sensitivity, specificity, precision and robustness a Maintenance terapy included pemetrexed, bevacizumab, or erlotinib (non considered a separate line of therapy; b Per RECIST v1.1 criteria determined by the investigator Paz-Ares L, ASCO 2015
  • 84. CheckMate 057 (NCT01673867) study design • Stage IIIb/IV SQ NHSCLC • 1 prior platinum doublet- based chemotherapy • ECOG PS 0-1 • Pre-treatment (archival or fresh) tumor samples required for PD-L1 analysis N= 272 Nivolumab 3mg/kg IV Q2W until PD or unacceptable toxicity n= 135 Docetaxel 75 mg/m2 IV Q2W until PD or unacceptable toxicity n= 137 • Primary Endpoint: - OS • Additional Endpoints - Investigator –assessed ORR - Investigator - assessed PFS - Correlation between PD-L1 exprssion and efficacy - Safety - Quality of life(LCSS) Patients stratified by region and prior paclitaxel use • One pre-planned interim analysis for OS • At time of DBL (Decembre 15,201) 199 deaths were reported (86& of deaths required for final analysis) • The boundary for declaring superiority for OS at the pre-planned analysis was P <0,03 Spigel DR, ASCO 2015
  • 86. ClinicalTrials.gov: NCT01905657 (a) priot yherapy must have included ≥ 2 cycles of platinum-doublet chtemotherapy. An appropriate tyrosine Kinase inhibition was required for patients whose tumors had an EGFR sensitizing mutation or an ALK translocation (b) Added after 441 patients enrolled based on results from Keynote001 (Garan EB et al. N.Engl.J.Med 2015; 372:2018-28 (c) patients received the maximum number of cycles permitted by the local regulatory authority Herbst RS, Lancet 2015 Key note-010: study design R 1:1:1 Stratification factors: -ECOG PS (0 vs1) -Region (East Asia vs non-East Asia) - PD-L1 status (b) TPS > 50% vs 1%-49% End points in the TPS > 50 stratum and TPS > 1% population •Primary: PFS and OS •Secondary: ORR, duration of response, safety
  • 90. Examples of ongoing combination trials CHEMOTHERAPY RADIOTHERAPY TARGETED IMMUNOTHERAPY NIVOLUMAB (ANTI PD-1) + CICPLATIN/GEMCITABINE, CISPLATIN/PEMETREXED OR CARBOPLATIN / PACLITAXEL (NCT 01454102) NR + BEVACIZUMAB OR ERLOTINIB (NCT 01454102) + IPILIMUMAB (NCT 01454102) + anti-KIR (NCT 01714739) + nati- LAG3 (NCT 01968109) PEMBROLIZUMAB (ANTI PD-1) CISPLATIN /PEMETREXED OR CARBOPLATIN / PACLITAXEL (NCT 01840579) +PACLITAXEL / CARBOPLATIN ±BEVACIZUMAB (NCT 02039674) NR + GEFITINIB OR ERLOTINIB (NCT 02039674) + IPILIMUMAB (NCT 02039674) + INCB024360 (NCT 02178722) MEDI-4736 (ANTI PD –L1) NR NR + GEFINITIB ( NCT 02088112) + AZD929 (NCT 02143466) + TREMELIMUMAB (NCT 02000947, NCT 02141347) MPDL3280A (ANTI PD –L1) NR NR + ERLOTINIB (NCT 02013219) + COBIMETINIB (NCT 019988896) + IPILIMUMAB (NCT 002174172) IPILIMUMAB (ANTI-CTLA-4) VARIOUS (NCT00527735; NCT01165216; NCT01285609; NCT 01331525; NCT 01450761; NCT 01454102) STEREOTACTIC RADIOSURGERY* (NCT 02107755 , NCT 02239900) + IONIZING RADIATION (NCT 02221739) + ERLOTINIB OR CRIZOTINIB ( NCT 01998126) + NIVOLUMAB (NCT 01454102) + PEMBROLIZUMAB (NCT 02039674) TREMELIMUMAB (ANTI-CTLA-4) NR NR + GEFITINB (NCT 020400464) + MEDI-4736 (NCT 02000947) * Trials in patients with melanoma with metastatic disease to a visceral organ (lung, liver,, adreanal, nodal station outsider the drenal limph-drainage of the primary, vertebral bodies, NR: no trials reported
  • 91. CheckMate 012: overall study design STAGE IIIB/IV NSCLS; no prior chemoterapy for advanced disease; ECOG PS 0 or 1 NIVOLUMAB monotherapy NIVOLUMAB + PT-DC NIVOLUMAB + ERLOTINIB NIVOLUMAB + BEVACIZUMAB NIVOLUMAB + IPILIMUMAB Rizvi N, WCLC 2015
  • 93. Take home messages  NIVOLUMAB and PEMBROLIZUMAB (in PD-L1 positive) are the new standard of treatment for andvanced NSCLC progressed on platinum-based chemotherapy  Due to the cost of these new agents, the patients selection will be very important for the treatment decision. Today, PD-L1 expression is the only biomarker available predictive of anti PD1- PDL1 benefit.  New response evaluation criteria are important for the clinical practice.  Combination with chemotherapy, targeted agents or other immunoterapeutic agents could be the future for anti-PD1- PDL1 inhibitors.

Editor's Notes

  • #15: To summarise the efficacy data, the combination of first-line Herceptin® plus docetaxel improved overall response rate, time to disease progression and median overall survival with statistical significance compared with docetaxel alone. Additionally, duration of response more than doubled from 5.1 to 11.4 months when Herceptin® was added to docetaxel.
  • #16: Median overall survival increased from 22.1 months in the docetaxel-alone arm to 30.5 months (p=0.0062) in the combination arm. This is a statistically significant difference and means that patients in the Herceptin® plus docetaxel arm survived on average 8.4 months longer than those in the docetaxel-alone arm. This difference is seen despite the fact that approximately 48% of patients in the docetaxel arm crossed over to receive Herceptin® at disease progression, which reduces the difference in survival seen between the two arms.
  • #39: This large, randomized, phase 3 trial included patients with EGFR-expressing metastatic colorectal tumours with documented evidence of disease progression after failure of fluoropyrimidines and prespecified exposure to oxaliplatin and irinotecan. An open-label design was used in this study, as blinding was not feasible because of expected skin-related toxicities in patients receiving panitumumab. Patients were randomized between panitumumab 6 mg/kg every 2 weeks plus best supportive care (BSC) and BSC alone. Panitumumab was administered by intravenous (IV) infusion at a dose of 6 mg/kg given once every 2 weeks until disease progression, inability to tolerate the investigational product or other reason for discontinuation. Patients who progressed in the BSC alone group had the option of receiving panitumumab 6 mg/kg once every 2 weeks in a separate open-label crossover study. Stratification was done for performance status and geographical region; this study was conducted in Europe, Australia, Canada and New Zealand. Patients determined to have progressive disease by the investigator were discontinued from the treatment phase of the study. Patients were evaluated for tumour response according to the modified Response Evaluation Criteria in Solid Tumors (RECIST) at 1- to 2-month intervals during the first year (i.e. at weeks 8, 12, 16, 24, 32, 40, and 48) and every 3 months thereafter until disease progression. All patients were followed for survival approximately every 3 months for up to 2 years after their randomization into the study. Best supportive care could include psychotherapy, counselling, antibiotics, analgesics, growth factors, palliative surgery or nutritional support. References Peeters M, et al. A phase 3, multicenter, randomized controlled trial of panitumumab plus best supportive care (BSC) vs. BSC alone in patients with metastatic colorectal cancer. Proc Am Assoc Cancer Res. 2006;47:A CP-1. Peeters M. presented at: 97th Annual Meeting of the American Association for Cancer Research (AACR) meeting; 4/3/2006; Washington DC. Presentation available at http://www.aacr.org/page6026.aspx#. Accessed 7/25/06 Van Cutsem E, Peeters M, Siena S, et al. Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer. J Clin Oncol. 2007;25(13):1658-1664.
  • #65: This illustration depicts the key events in a normal immune response to a protein antigen in a lymph node. In step 1, antigens are captured from their site of entry by dendritic cells. In step 2, antigens are transported via lymphatics into regional lymph nodes where, in step 3, they activate naïve lymphocytes, causing them to differentiate into effector and memory lymphocytes that enter the circulation, in step 4. From there, effector T cells and antibodies enter tissue and eliminate the antigen, in step 5A; and memory lymphocytes take up residence in normal tissues in preparation of the next infection, in step 5B.
  • #77: References Azuma T, Yao S, Zhu G, et al. B7-H1 is a ubiquitous antiapoptotic receptor on cancer cells. Blood. 2008;111(7):3635-3643. Pardoll D, Drake C. Immunotherapy earns its spot in the ranks of cancer therapy. J Exp Med. 2012;209(2):201-209. Latchman Y, Wood CR, Chernova T, et al. PD-L2 is a second ligand for PD-1 and inhibits T cell activation. Nat Immunol. 2001;2(3):261-268. Dong H, Strome SE, Salomao DR, et al. Tumor-associated B7-H1 promotes T-cell apoptosis: A potential mechanism of immune evasion. Nat Med. 2002;8(8):793-800. Freeman GJ, Long AJ, Iwai Y, et al. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med. 2000;192(7):1027-1034. Ribas A. Tumor immunotherapy directed at PD-1. N Engl J Med. 2012;366(26):2517-2519. Lipson EJ, Drake CG. Ipilimumab: an anti-CTLA-4 antibody for metastatic melanoma. Clin Cancer Res. 2011;17(22):6958-6962.
  • #78: Mercury number: 1506HQ14NP06940-01 Approved August 2014; expires August 2016 Original Mercury number: 1506HQ13NP08597 APC = antigen-presenting cell; CTLA-4 = cytotoxic T-lymphocyte-associated antigen-4; MHC = major histocompatibility complex; TCR = T cell receptor.
  • #79: Mercury number: 1506HQ14NP06940-01 Approved August 2014; expires August 2016 Original Mercury number: 1506HQ13NP08597 Use this slide to describe role of anti-PD1 as cancer therapy The PD1 pathway delivers inhibitory signals that regulate the balance between T cell activation and peripheral tolerance Tumours may exploit immune suppression mediated through the PD-1 pathway to escape the immune system PD-L1 is expressed on many solid tumours, including NSCLC Blocking the interactions between PD-1 and PD-L1 can disrupt suppressive mechanisms NSCLC tumours use to escape the immune system Nivolumab (anti-PD-1) is thought to disrupt tumour-induced immune suppression and restore anti-tumour T cell activity in NSCLC patients IFN = interferon gamma; IFNR = interferon-gamma receptor; MHC = major histocompatibility complex; NF-ϰB = nuclear factor-Kappa B; PD-1 = programmed cell death protein 1; PD-L1 = programmed death ligand-1; PD-L2 = programmed death ligand-2.