Gli inibitori dell’angiogenesi in associazione alla chemioterapia: perché e quando Dott. Marcello Tiseo Oncologia Medica Coordinatore PDTA Oncologia Toracica Azienda Ospedaliero-Universitaria Parma Chemo-immuno-target therapies: tre strategie di trattamento nel NSCLC in stadio avanzato Camogli Aprile 2016

Agenda u Introduzione u Bevacizumab nel NSCLC u Anti-angiogenici in II linea nel NSCLC: Nintedanib e Ramucirumab u Fattori predittivi u Prospettive future

Agenda u Introduzione u Bevacizumab nel NSCLC u Anti-angiogenici in II linea nel NSCLC: Nintedanib e Ramucirumab u Fattori predittivi u Prospettive future

Hanahan and Weinberg, Cell 2011

Kowanetz and Ferrara, Clin Cancer Res 2006

Angiogenesis and Lung cancer u VEGF expression demonstrated in 42-75% NSCLC u Many studies demonstrated association between tumoral VEGF expression, more advanced disease and a worse prognosis u Microvessel density is also predictive of metastases and poor prognosis in NSCLC u VEGF expression and high microvessel density are also predictive of poor outcomes in SCLC u Elevated pretreatment serum VEFG levels are also associated with a poor response and worse survival Wheatley-Price and Shepherd, J Thoracic Oncol 2008

Bevacizumab Vatalanib Sorafenib Vandetanib Cediranib Motesanib Aflibercept Sunitinib Ramucirumab Nintedanib Anti-Angiogenic agents in NSCLC Pazopanib Axitinib Vadimezan

u Redundancy of the angiogenic pathway that leads to primary and secondary resistance to an agent targeting a specific pathway u Combination with CT might not be the best setting for the use of multitargeted anti-angiogenesis inhib u Increased risk of toxicity (squamous hystology) u The absence of validated biomarkers u Intrinsic resistence to anti-angiogenic agents Anti-Angiogenic agents in NSCLC: reasons of failure

Agenda u Introduzione u Bevacizumab nel NSCLC u Anti-angiogenici in II linea nel NSCLC: Nintedanib e Ramucirumab u Fattori predittivi u Prospettive future

ECOG 4599: Overall survival in adenocarcinoma Sandler et al, J Thorac Oncol 2010 Randomized patients adenocarcinoma CP (n=302) BV/CP (n=300) Median survival time (mos) Unstratified HR (rel. to CP) (%95 CI) 0.69 (0.58 – 0.83)

Bevacizumab in NSCLC: meta-analysis of first-line trials Soria et al, Ann Oncol 2013

Bevacizumab in NSCLC: Real Life Lynch et al, J Thoracic Oncol 2014

Bevacizumab in NSCLC vs Pemetrexed Zinner et al, J Thoracic Oncol 2015 PRONOUNCE trial POINT BREAK trial Patel et al, J Clin Oncol 2013

Carbo-Taxolo-Beva vs CDDP + PEM

Bevacizumab in NSCLC: Phase III trials StudyLineDesignEnd- point I OS ECOG4599ICT +/- BevaOS + AVAILIPG +/- BevaPFS (+)- ATLASMaintenanceBeva +/- Erlotinib PFS (+)- AVAPERLMaintenanceBeva +/- Pemetrexed PFS (+)- BeTaIIErlotinib +/- Beva OS- ECOG1505AdjuvantCT +/- BevaOS?

Wakelee et al. J Thorac Oncol 2015; 10 (suppl 2): PLEN04.03 Only 37% of patients completed treatment per protocol in Bevacizumab arm Bevacizumab in adjuvant? ECOG1505

Bevacizumab ongoing studies

Agenda u Introduzione u Bevacizumab nel NSCLC u Anti-angiogenici in II linea nel NSCLC: Nintedanib e Ramucirumab u Fattori predittivi u Prospettive future

Nintedanib and Ramucirumab Ramucirumab Nintedanib

Docetaxel +/- anti-angiogenic: Phase III second-line trials Garon EB et al, Lancet 2014 Ramucirumab: REVEL trial Nintedanib LUME-Lung 1 Trial Reck M et al, Lancet Oncol 2014

Garon EB et al, Lancet 2014 Ramucirumab: REVEL trial Nintedanib LUME-Lung 1 Trial Reck M et al, Lancet Oncol 2014 Docetaxel +/- anti-angiogenic: Phase III second-line trials

Garon EB et al, Lancet 2014 Ramucirumab: REVEL trial Nintedanib LUME-Lung 1 Trial Reck M et al, Lancet Oncol 2014 u + 1 mese in OS overall –HR 0.94, p u mesi in ADK –HR 0.83, p u + 3 mesi in ADK-PD < 9 ms –HR 0.75, p u Non sign in SCC u mesi in OS overall –HR 0.86, p u mesi in ADK –HR 0.83 (0.71–0.97) u mesi in SCC –HR 0.88 (0.69–1.13) Docetaxel +/- anti-angiogenic: Phase III second-line trials

Docetaxel +/- anti-angiogenico: OS Sottogruppi in LUME-Lung 1 Reck M et al, Lancet Oncol 2014

Docetaxel +/- anti-angiogenico: OS Sottogruppi in REVEL trial Garon EB et al, Lancet 2014

LUME-Lung1 trial NINTEDANIB REVEL trial RAMUCIRUMAB RR (exper. vs plac) 4.4% vs 3.3% 23% vs 14%  PFS (exper. vs plac) 3.4 vs 2.7 months HR 0.79 ( ) 4.5 vs 3 months HR 0.76 ( ) Toxicity G3-4  Diarrea, AST-ALT  NF, Hypertension QolNo detrimental Garon EB et al, Lancet 2014Reck M et al, Lancet Oncol 2014 Docetaxel +/- anti-angiogenic: Phase III second-line trials

Ramucirumab: REVEL trial Nintedanib LUME-Lung 1 Trial Ramucirumab + Docetaxel Placebo + Docetaxel Garon EB et al, Lancet 2014Reck M et al, Lancet Oncol 2014 Docetaxel +/- anti-angiogenic: All grades peculiar toxicity (%)

Docetaxel +/- anti-angiogenico in seconda-linea: considerazioni u 2 studi che dimostrano la possibilità di combinare anti-angiogenico alla CT in II linea u Approvazione EMA di nintedanib in ADK, FDA/EMA di ramucirumab in NSCLC u Vantaggio mediamente modesto (“incrementalist”), ma per la prima volta in II linea rispetto a docetaxel (non più standard of care) u Terapie ben tollerate (anche nel SCC) u Assenza di specifico biomarcatore/Costo?

2016: NSCLC treatment options in second-line in EU Non-SquamousSquamous 1LinePlatinum-based doublet +/- Bevacizumab Platinum-based doublet MaintenancePemetrexed or BevacizumabNone 2LineNivolumab Docetaxel + Nintedanib Docetaxel + Ramucirumab Nivolumab (Docetaxel + Ramucirumab) 3LineAlternative not-used in 2Line or Erlotinib or BSC Alternative not-used in 2Line or Erlotinib or BSC

Algoritmo per la terapia di II linea del NSCLC non-squamoso wt FIT per CT No controindicaz. Anti-angiogenesi Controindicaz.Anti-angiogenesi Doc + Nintedanib Doc + Ramucirumab Nivolumab (Erlotinib) PD dopo I linea con Platino (PS 0-1) No FIT per CT Controindicaz.Immuno Docetaxel Controindicaz.Immuno No- Controindicaz. Immuno ?

Algoritmo per la terapia di II linea del NSCLC non-squamoso wt FIT per CT No controindicaz. Anti-angiogenesi Controindicaz.Anti-angiogenesi Doc + Nintedanib Doc + Ramucirumab Nivolumab (Erlotinib) PD dopo I linea con Platino (PS 0-1) No FIT per CT Controindicaz.Immuno Docetaxel Controindicaz.Immuno No- Controindicaz. Immuno Stato di non-fumatore? EGFR mutato, T790M-/ALK positivo? Strategia oltre la II linea? carico di malattia? Early progression?

Agenda u Introduzione u Bevacizumab nel NSCLC u Anti-angiogenici in II linea nel NSCLC: Nintedanib e Ramucirumab u Fattori predittivi u Prospettive future

Predictive factors for anti-angiogenic therapy Franzini et al, Clin Cancer Res 2015

Can the Lung Cancer Pie divided into angiogenic slice? Cascone and Heymach, Clin Cancer Res 2015 Patients with tumor with a robust angiogenesis signature and a drecreased hypoxia-gene signature Patients with tumor with a decreased angiogenesis signature and an high hypoxia-gene signature

Agenda u Introduzione u Bevacizumab nel NSCLC u Anti-angiogenici in II linea nel NSCLC: Nintedanib e Ramucirumab u Fattori predittivi u Prospettive future

EGFR regulates VEGF in EGFR mutant cell lines Heymach et al, ASCO 2014 Naumov et al, Clin Cancer Res 2009

Erlotinib + Bevacizumab: JO25567 trial Seto et al, Lancet Oncol 2014

Prospettive future: Anti-angiogenici in ALK + NSCLC? u Hypoxia pathway was significantly enriched in ALK- rearranged NSCLC u Under hypoxic conditions, ALK directly regulated the abundance of HIFs u In vivo, ALK regulated VEGF production and tumor angiogenesis in NSCLC u Treatment with bevacizumab strongly impaired tumour growth in mouse xenografts Martinengo et al, Cancer Res 2014

Prospettive future: trials ongoing Clinicaltrials.go v PhaseMolecularsettingDrugsStatus NCT /2ALK + Alectinib + Bevacizumab Not yet open NCT (RELAY) 3EGFR + Erlotinib ± Ramucirumab Recruiting NCT b/2/ Anti-MET (LY ) + Ramucirumab Recruiting Trials combining target and antiangiogenic therapies

Prospettive future: Anti-angiogenici e Immunoterapia? u VEGF, in addition to its angiogenic role, suppresses the immune system u VEGF prevented dendritic cells from maturing, thus hampering the presentation of tumor antigen u Vascular normalizing anti-angiogenic treatment reprogram the immunosuppressive tumor microenvironment and enhance immunotherapy Carbone et al, Immunologic Res 2001 Jain et al, Cancer Cell 2014

Prospettive future: trials ongoing Clinicaltrials.govPhaseSettingDrugsStatus NCT (KEYNOTE-021) 1/21-line Pembrolizumab+Carbo+Pacl +/- Beva Recruit NCT (IMpower 150) 31-line Atezolizumab + Carbo+Pacl +/- Beva Recruit NCT (Check-Mate 370) 1/2 1-line, maint Nivolumab; Pemetr+Bev; Nivolumab+Pemetr+Beva Not yet open NCT Pre-treatedMEDI Ramucirumab Not yet open NCT Pre-treated Pembrolizumab + Ramucirumab Recruit Trials combining immune-checkpoints inhibitors and antiangiogenics agents

Anti-Angiogenic agents in NSCLC: research issues De Marinis et al, J Thoracic Oncol 2016

cisplatin (25 mg/m 2 d 1-3) etoposide (100 mg/m 2 d 1-3) bevacizumab (7.5 mg/kg d 1) every 3 weeks u 206 pts u SCLC ED u 1 st -line RANDOMRANDOM GOIRC TRIAL in SCLC cisplatin (25 mg/m 2 d 1-3) etoposide (100 mg/m 2 d 1-3) every 3 weeks for a maximum of 6 cycles End-point primario: OS (1-year from 40 to 58%) Non-PD after 6 cycles will continue bevacizumab until PD or for a maximum of 18 cycles ASCO 2016

Conclusioni u Bevacizumab: unico farmaco anti-angiogenico che prolunga OS in I linea; opzione in pazienti selezionati u Nintedanib e Ramcirumab: nuove opzioni in II linea in combinazione con docetaxel; necessità di definire un nuovo algoritmo terapeutico in II linea nell’adenocarcinoma u Prospettive di impiego degli anti-angiogenici anche in paziente oncogene-addicted ed in combinazione con l’immunoterapia u Necessario proseguire ricerca di markers predittivi e dei meccanismi di resistenza

Conclusioni (NSCLC-ADK) 1-line (and maintenance) Bevacizumab 2-line CT3-line 1-line (and maintenance)2-line CT3-line Nintedanib or Ramucirumab Standard in EGFR/ALK neg New option EGFR/ALK neg Bevacizumab In the future 1-line (and maintenance)2-line CT3-line Nintedanib or Ramucirumab Bevacizumab Immunotherapy TKI (EGFR) Anti-angiogenic agent

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