- Email: [email protected]
Phase II study of preoperative (PREOP) chemoradiotherapy (CTRT) plus avelumab (AVE) in patients (PTS) with locally advanced rectal cancer (LARC): The AVANA Study
abstracts
Annals of Oncology
Background: Preop CTRT is the standard of treatment of LARC and it results in significant tumor downstaging and local control with a complete pathological response (pCR) rate of about 15%. Immunotherapy can lead up to a 50% of response in metastatic colorectal cancer (mCRC) with deficient mismatch repair (MMR) status, but its activity is extremely low in MMR proficient mCRC. In this context, the role of RT in revert the tolerance to a low neoantigen-burden by the induction of antigen release from the tumour and activation of dendritic cells leading to a CD8þ T lymphocyte-mediated anticancer immune response has been widely elucidated. Furthermore, in LARC pts, preop CTRT increases PD-L1 expression in tumor cells, strongly suggesting a neoadjuvant combinatory strategy with RT and PD-1/PDL1 pathway blockade. On the basis of such premises we are conducting the AVANA study to explore the role of Ave in combination with preop CTRT in LARC. Trial design: This is an Italian multi-center, phase II study. Pts with resectable LARC, defined by the presence of at least one of the following features, cNþ, cT4, high risk cT3, receive standard preop CTRT (external-beam RT 50.4 Gray in 28 fractions over 5.5 weeks þ capecitabine 825 mg/sqm/bid 5 days/week) plus 6 cycles of Ave 10 mg/Kg every 2 weeks. Surgery with total mesorectal excision is performed at week 8-10 after the end of CTRT. Postop CT is recommended according to pathologic response. The primary end-point is pCR rate. Secondary end-points are R0 resection rate, tumor downstaging, local recurrence, sphincter preservation rate, progression-free survival, overall survival, safety profile and the evaluation of exploratory predictive and/or prognostic biomarkers. Assuming as null hypothesis p0 a pCR rate of 15%, a significance level of 5% (one-sided) and a power of 80%, a sample size of 101 pts is needed to detect an absolute increment of 10% in pCR rate (from 15% to 25%). The experimental regimen will be considered for further studies if in at least 22 pts we observe a pCR. The enrollment is ongoing. Sponsored by GONO and partially supported by Merck. Clinical trial identification: 2017-003582-10. Legal entity responsible for the study: GONO. Funding: Merck KGaA. Disclosure: All authors have declared no conflicts of interest.
663TiP
A phase II study of capecitabine plus concomitant radiation therapy followed by durvalumab (MEDI4736) as preoperative treatment in rectal cancer: PANDORA study
M.A. Barbera1, J. Corbelli1, G. Papiani1, E. Grassi2, G. Ugolini3, I. Montroni3, M. Di Bartolomeo4, S. Cascinu5, M. Marzola6, A. Bonetti7, G.L. Frassineti8, O. Nanni9, D. Zattoni3, F. Ghignone3, G. Taffurelli3, C. Pinto10, C. Carli Moretti11, G. Rossi12, S. Palazzi13, S. Tamberi14 1 Medical Oncology, Infermi Hospital - Faenza, Faenza, Italy, 2Department of Experimental, Diagnostic and Specialty Medicine - Dimes, AOU Policlinico S. OrsolaMalpighi, Bologna, Italy, 3Surgery Unit, Infermi Hospital - Faenza, Faenza, Italy, 4 Medical Oncology, Istituto Nazionale dei Tumori di Milano - Fondazione IRCCS, Milan, Italy, 5Oncology, Azienda Ospedaliero - Universitaria Policlinico di Modena, Modena, Italy, 6Medical Oncology, Sant’Anna Hospital Cona-University of Ferrara, Cona, Italy, 7 Oncology, Ospedale Mater Salutis di Legnago, Legnago, Italy, 8Oncology, Istituto a Scientifico Romagnolo per lo Studio e la Cura dei Tumori (I.R.S.T.), Meldola, Italy, 9Unit di Biostatistica e Sperimentazioni Cliniche, Istituto Scientifico Romagnolo per lo Studio 10 e la Cura dei Tumori, Meldola, Italy, Clinical Canncer Center, Medical Oncology Unit, Azienda Ospedaliera Arcispedale Santa Maria Nuova - IRCCS, Reggio Emilia, Italy, 11 Radiology Unit, Infermi Hospital - Faenza, Faenza, Italy, 12Pathology Unit, Ravenna Hospital, Ravenna, Italy, 13Radiotherapy Unit, Ravenna Hospital, Ravenna, Italy, 14 Medical Oncology, Infermi Hospital - Faenza, Faenza, Ravenna, Italy Background: The standard treatment for cT3-4 N0-1 rectal cancer is preoperative chemo-radiation therapy (CT/RT). The combination of capecitabine plus long course radiotherapy (RT) is standard therapy in locally advanced rectal cancer. Pathologic Complete remission (pCR) can be considered as surrogate end point of efficacy of treatment in terms of disease free survival (DFS). Clinical complete remission (cCR) is an important endpoint for “wait and see” strategy. In the PACIFIC trial in non-small cell lung cancer the patients were treated with durvalumab maintenance after CT/RT with advantage in progression free survival. “Abscopal effect” is proposed as mediator of systemic effects after localized RT. Preclinical data points heavily toward a strong synergy between RT and immune treatments. Recent reports already illustrate that such a systemic effect of RT is possible when enhanced by targeted immune treatments. Trial design: This is a prospective phase II, open label, single arm, multi-centre study to evaluate, in patients with operable rectal cancer, activity of an innovative sequence: standard concomitant CT/RT therapy with 825 mg/m2 twice daily capecitabine every day and 5040 cGy radiotherapy for 5 days per week for 5 weeks followed by 1500 mg Q4W durvalumab for 3 administration. After 9-10 weeks from neoadjuvant therapy will be performed re-staging with CT and MRI scan. Surgery will be performed at week 10-12 from the end of CT/RT. Primary Objective: pCR rate, defined as a TRG 3-4 according to DWORAK criteria. Secondary Objectives: Safety of treatment with durvalumab; cCR rate after durvalumab treatment before surgery and DFS. cCR will be evaluated with clinical, endoscopic and radiological assessment to look for evidence of residual disease. DFS will be evaluated during a follow up of 5 years. Exploratory Objective: Biological translational analysis of tumor biomarkers will be performed on the endoscopy biopsy done at the diagnosis and on the biopsy performed after the CT/ RT prior to treatment with durvavalumab. We have planned to enlist 60 patients in 7 centers with an enrollment period of 12 months, already underway. Clinical trial identification: 2018-004758-39. Legal entity responsible for the study: Tamberi Stefano. Funding: AstraZeneca. Disclosure: All authors have declared no conflicts of interest.
664TiP
Open label phase III study of arfolitixorin vs leucovorin in mFOLFOX6 for first-line treatment of metastatic colorectal cancer: AGENT
J. Tabernero1, G. Prager2, S. Stintzing3, H.J. Lenz4, H.P. Nygren5, C. Papadimitriou6 Oncology, Vall d’Hebron University Hospital and Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain, 2Comprehensive Cancer Center Vienna, Medical University Vienna, Vienna, Austria, 3Medical Department, Division of Oncology and Hematolgogy, Charite´ - Universit€ atsmedizin Berlin, Berlin, Germany, 4Medical Oncology, USC - Norris Comprehensive Cancer Center, Los Angeles, CA, USA, 5Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden, 6Oncology Unit, University General Hospital Aretaieio, Athens, Greece 1
Background: 5-fluorouracil (5-FU) in combination with the folate Leucovorin (LV) has been the cornerstone in the treatment of colorectal cancer (CRC) for decades. All folates currently approved for use in the clinical setting need to be metabolically activated to [6R] 5,10-methylenetetrahydrofolic acid ([6R]-MTHF), which is the active thymidylate synthase co-substrate that potentiates the effect of 5-FU. Arfolitixorin does not need multi step metabolic activation like currently available folates. It is therefore hypothesized that the administration of arfolitixorin will result in higher, and less individual variability, intracellular concentrations of the active thymidylate synthase cosubstrate [6R]-MTHF in all patients compared to LV administration. Trial design: Primary endpoint ORR by Blinded Independent Central Review (BICR) Key secondary endpoints Progression Free Survival (PFS) Duration of Response (DoR) Secondary endpoints Overall Survival (OS) Quality of Life (QoL) Safety and Tolerability Patients undergoing curative metastasis resection Study Design This is a randomized, multicenter, parallel-group, Phase III study to compare the efficacy of
Volume 30 | Supplement 5 | October 2019
doi:10.1093/annonc/mdz246 | v249
Downloaded from https://academic.oup.com/annonc/article-abstract/30/Supplement_5/mdz246.139/5578190 by guest on 25 October 2019
662TiP II study of preoperative (PREOP) chemoradiotherapy with tumourPhase response and survival. iSCORE is a single-centre phase II trial. (CTRT) avelumab (AVE) patients (PTS)will with advanced rectal Recruitmentplus opened in March 2019inand 25 patients be locally recruited in 36 months. cancer (LARC): The AVANA Study Clinical trial identification: NCT03867799. 4 5 6 Legal entity1,responsible the study:3,The Royal Marsden NHS Foundation Trust. M. Bensi2, F.for Pietrantonio A. Boccaccino , C. Barbara , A. Auriemma , L. Salvatore 8 9 10Bristol-Myers Funding: Royal Marsden NHS Foundation Trust, Tamburini , R. Bordonaro , M. Clavarezza , A. Avallone11,Squibb. F. Bergamo12, M. Ratti7, E.The 13 14 15 16 17 18 Bustreo , Research F. Di Fabio Smiroldo , B. Corvari , G. Tortora C. Granetto D., S. Disclosure: Cunningham: grant, /V. Funding (institution): AstraZeneca; Research grant / 1 Funding (institution): Celgene; Research grant / Funding (institution):Agostino MedImmune; Research grant / UOC Oncologia Medica, Fondazione Policlinico Universitario Gemelli IRCCS, Funding (institution): Bayer; Research grant / Funding (institution): 4SC; Research grant / Funding Fondazione Policlinico Universitario Agostino Rome, Italy, 2UOC Oncologia Medica, (institution): Clovis; Research grant / Funding (institution): Eli Lilly; Research grant / Funding (insti3 Fondazione IRCCS Istituto/ Consultancy: Nazionale dei GemelliJanssen; IRCCS, Research Rome, Italy, tution): grant Medical / FundingOncology, (institution): Merck. I. Chau: Advisory Eli of Translational Research and New Technologies in Tumori, Milan,/ Consultancy: Italy, 4Department Lilly; Advisory BMS; Advisory / Consultancy: MSD; Advisory / Consultancy: Bayer; 5 UO Oncologia Medica, Ospedale di Medicine and Surgery,Roche; University of Pisa, Pisa, Italy,Merck-Serono; Advisory / Consultancy: Advisory / Consultancy: Advisory / Consultancy: Five Prime Therapeutics; Advisory / Consultancy: Advisory / Consultancy: Oncologie AOU Integrata Verona "Borgo Livorno, Azienda Ospedaliera 6, Livorno, AstraZeneca; Italy, 6Oncology, 7Consultancy: Pierre Fabre; Research grant / Funding (institution): 8 Eli Lilly; International; Advisory / Trento", Verona, Italy, Oncology, Istituti Ospitalieri di Cremona, Cremona, Italy, UOC Research grant / FundingCardinale (institution): Janssen-Cilag; grant Oncologia / Funding (institution): Medica, Sanofi Oncologia, Ospedale G.Panico, Tricase,Research Italy, 9UOC Oncology; Research grant / Funding (institution): Merck-Serono; Honoraria (self): Eli-Lilly. M. Azienda Ospedaliera ARNAS Garibaldi, Catania, Italy, 10S.C. Oncologia Medica, E.O. Gerlinger: Research grant / Funding11(institution): BMS; Research grant / Funding (institution): Merck UOC(institution): Oncologia AstraZeneca; Medica, Istituto Nazionale Tumori (instiOspedali Galliera, Genoa, Italy, KG. N. Starling: Research grant / Funding Research grant / Funding IRCCS Fondazione Naples,(institution): Italy, 12Medical Unit 1, Veneto/ Expenses: Institute tution):- BMS; ResearchPascale, grant / Funding Pfizer;Oncology Travel / Accommodation 13 Oncologia Medica, Azienda Ospedaliera St. Eli of OncologyTravel IRCCS,/ Accommodation Padua, Italy, UOC AstraZeneca; / Expenses: BMS; Travel / Accommodation / Expenses: Lilly; Travel / Accommodation / Expenses: Merck; Travel / Accommodation / Expenses: Roche; Oncologia Medica, Azienda Ospedaliero-Universitaria Croce e Carle, Cuneo, Italy, 14 15 Honoraria (self): AstraZeneca; Honoraria (self): Eli Lilly; Honoraria (self): Merck; Honoraria (self): Citta della Salute e della Scienza di Torino, Turin, Italy, UOC Oncologia Medica, AOU 16 Servier; Advisory / Consultancy: Pfizer; Advisory AstraZeneca; / Medical Oncology andAdvisory Hematology Policlinico S. Orsola-Malpighi, Bologna, Italy,/ Consultancy: Consultancy: Servier. All other authors have declared no conflicts of interest. Unit, Humanitas Cancer Center, Humanitas Clinical and Research Center, IRCCS, Rozzano, Italy, 17UOC Radioterapia, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy, 18UOC Oncologia Medica, Fondazione Policlinico Universitario Agostino Gemelli IRCCS - Universita Cattolica del Sacro Cuore, Rome, Italy
Annals of Oncology
Background: Preop CTRT is the standard of treatment of LARC and it results in significant tumor downstaging and local control with a complete pathological response (pCR) rate of about 15%. Immunotherapy can lead up to a 50% of response in metastatic colorectal cancer (mCRC) with deficient mismatch repair (MMR) status, but its activity is extremely low in MMR proficient mCRC. In this context, the role of RT in revert the tolerance to a low neoantigen-burden by the induction of antigen release from the tumour and activation of dendritic cells leading to a CD8þ T lymphocyte-mediated anticancer immune response has been widely elucidated. Furthermore, in LARC pts, preop CTRT increases PD-L1 expression in tumor cells, strongly suggesting a neoadjuvant combinatory strategy with RT and PD-1/PDL1 pathway blockade. On the basis of such premises we are conducting the AVANA study to explore the role of Ave in combination with preop CTRT in LARC. Trial design: This is an Italian multi-center, phase II study. Pts with resectable LARC, defined by the presence of at least one of the following features, cNþ, cT4, high risk cT3, receive standard preop CTRT (external-beam RT 50.4 Gray in 28 fractions over 5.5 weeks þ capecitabine 825 mg/sqm/bid 5 days/week) plus 6 cycles of Ave 10 mg/Kg every 2 weeks. Surgery with total mesorectal excision is performed at week 8-10 after the end of CTRT. Postop CT is recommended according to pathologic response. The primary end-point is pCR rate. Secondary end-points are R0 resection rate, tumor downstaging, local recurrence, sphincter preservation rate, progression-free survival, overall survival, safety profile and the evaluation of exploratory predictive and/or prognostic biomarkers. Assuming as null hypothesis p0 a pCR rate of 15%, a significance level of 5% (one-sided) and a power of 80%, a sample size of 101 pts is needed to detect an absolute increment of 10% in pCR rate (from 15% to 25%). The experimental regimen will be considered for further studies if in at least 22 pts we observe a pCR. The enrollment is ongoing. Sponsored by GONO and partially supported by Merck. Clinical trial identification: 2017-003582-10. Legal entity responsible for the study: GONO. Funding: Merck KGaA. Disclosure: All authors have declared no conflicts of interest.
663TiP
A phase II study of capecitabine plus concomitant radiation therapy followed by durvalumab (MEDI4736) as preoperative treatment in rectal cancer: PANDORA study
M.A. Barbera1, J. Corbelli1, G. Papiani1, E. Grassi2, G. Ugolini3, I. Montroni3, M. Di Bartolomeo4, S. Cascinu5, M. Marzola6, A. Bonetti7, G.L. Frassineti8, O. Nanni9, D. Zattoni3, F. Ghignone3, G. Taffurelli3, C. Pinto10, C. Carli Moretti11, G. Rossi12, S. Palazzi13, S. Tamberi14 1 Medical Oncology, Infermi Hospital - Faenza, Faenza, Italy, 2Department of Experimental, Diagnostic and Specialty Medicine - Dimes, AOU Policlinico S. OrsolaMalpighi, Bologna, Italy, 3Surgery Unit, Infermi Hospital - Faenza, Faenza, Italy, 4 Medical Oncology, Istituto Nazionale dei Tumori di Milano - Fondazione IRCCS, Milan, Italy, 5Oncology, Azienda Ospedaliero - Universitaria Policlinico di Modena, Modena, Italy, 6Medical Oncology, Sant’Anna Hospital Cona-University of Ferrara, Cona, Italy, 7 Oncology, Ospedale Mater Salutis di Legnago, Legnago, Italy, 8Oncology, Istituto a Scientifico Romagnolo per lo Studio e la Cura dei Tumori (I.R.S.T.), Meldola, Italy, 9Unit di Biostatistica e Sperimentazioni Cliniche, Istituto Scientifico Romagnolo per lo Studio 10 e la Cura dei Tumori, Meldola, Italy, Clinical Canncer Center, Medical Oncology Unit, Azienda Ospedaliera Arcispedale Santa Maria Nuova - IRCCS, Reggio Emilia, Italy, 11 Radiology Unit, Infermi Hospital - Faenza, Faenza, Italy, 12Pathology Unit, Ravenna Hospital, Ravenna, Italy, 13Radiotherapy Unit, Ravenna Hospital, Ravenna, Italy, 14 Medical Oncology, Infermi Hospital - Faenza, Faenza, Ravenna, Italy Background: The standard treatment for cT3-4 N0-1 rectal cancer is preoperative chemo-radiation therapy (CT/RT). The combination of capecitabine plus long course radiotherapy (RT) is standard therapy in locally advanced rectal cancer. Pathologic Complete remission (pCR) can be considered as surrogate end point of efficacy of treatment in terms of disease free survival (DFS). Clinical complete remission (cCR) is an important endpoint for “wait and see” strategy. In the PACIFIC trial in non-small cell lung cancer the patients were treated with durvalumab maintenance after CT/RT with advantage in progression free survival. “Abscopal effect” is proposed as mediator of systemic effects after localized RT. Preclinical data points heavily toward a strong synergy between RT and immune treatments. Recent reports already illustrate that such a systemic effect of RT is possible when enhanced by targeted immune treatments. Trial design: This is a prospective phase II, open label, single arm, multi-centre study to evaluate, in patients with operable rectal cancer, activity of an innovative sequence: standard concomitant CT/RT therapy with 825 mg/m2 twice daily capecitabine every day and 5040 cGy radiotherapy for 5 days per week for 5 weeks followed by 1500 mg Q4W durvalumab for 3 administration. After 9-10 weeks from neoadjuvant therapy will be performed re-staging with CT and MRI scan. Surgery will be performed at week 10-12 from the end of CT/RT. Primary Objective: pCR rate, defined as a TRG 3-4 according to DWORAK criteria. Secondary Objectives: Safety of treatment with durvalumab; cCR rate after durvalumab treatment before surgery and DFS. cCR will be evaluated with clinical, endoscopic and radiological assessment to look for evidence of residual disease. DFS will be evaluated during a follow up of 5 years. Exploratory Objective: Biological translational analysis of tumor biomarkers will be performed on the endoscopy biopsy done at the diagnosis and on the biopsy performed after the CT/ RT prior to treatment with durvavalumab. We have planned to enlist 60 patients in 7 centers with an enrollment period of 12 months, already underway. Clinical trial identification: 2018-004758-39. Legal entity responsible for the study: Tamberi Stefano. Funding: AstraZeneca. Disclosure: All authors have declared no conflicts of interest.
664TiP
Open label phase III study of arfolitixorin vs leucovorin in mFOLFOX6 for first-line treatment of metastatic colorectal cancer: AGENT
J. Tabernero1, G. Prager2, S. Stintzing3, H.J. Lenz4, H.P. Nygren5, C. Papadimitriou6 Oncology, Vall d’Hebron University Hospital and Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain, 2Comprehensive Cancer Center Vienna, Medical University Vienna, Vienna, Austria, 3Medical Department, Division of Oncology and Hematolgogy, Charite´ - Universit€ atsmedizin Berlin, Berlin, Germany, 4Medical Oncology, USC - Norris Comprehensive Cancer Center, Los Angeles, CA, USA, 5Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden, 6Oncology Unit, University General Hospital Aretaieio, Athens, Greece 1
Background: 5-fluorouracil (5-FU) in combination with the folate Leucovorin (LV) has been the cornerstone in the treatment of colorectal cancer (CRC) for decades. All folates currently approved for use in the clinical setting need to be metabolically activated to [6R] 5,10-methylenetetrahydrofolic acid ([6R]-MTHF), which is the active thymidylate synthase co-substrate that potentiates the effect of 5-FU. Arfolitixorin does not need multi step metabolic activation like currently available folates. It is therefore hypothesized that the administration of arfolitixorin will result in higher, and less individual variability, intracellular concentrations of the active thymidylate synthase cosubstrate [6R]-MTHF in all patients compared to LV administration. Trial design: Primary endpoint ORR by Blinded Independent Central Review (BICR) Key secondary endpoints Progression Free Survival (PFS) Duration of Response (DoR) Secondary endpoints Overall Survival (OS) Quality of Life (QoL) Safety and Tolerability Patients undergoing curative metastasis resection Study Design This is a randomized, multicenter, parallel-group, Phase III study to compare the efficacy of
Volume 30 | Supplement 5 | October 2019
doi:10.1093/annonc/mdz246 | v249
Downloaded from https://academic.oup.com/annonc/article-abstract/30/Supplement_5/mdz246.139/5578190 by guest on 25 October 2019
662TiP II study of preoperative (PREOP) chemoradiotherapy with tumourPhase response and survival. iSCORE is a single-centre phase II trial. (CTRT) avelumab (AVE) patients (PTS)will with advanced rectal Recruitmentplus opened in March 2019inand 25 patients be locally recruited in 36 months. cancer (LARC): The AVANA Study Clinical trial identification: NCT03867799. 4 5 6 Legal entity1,responsible the study:3,The Royal Marsden NHS Foundation Trust. M. Bensi2, F.for Pietrantonio A. Boccaccino , C. Barbara , A. Auriemma , L. Salvatore 8 9 10Bristol-Myers Funding: Royal Marsden NHS Foundation Trust, Tamburini , R. Bordonaro , M. Clavarezza , A. Avallone11,Squibb. F. Bergamo12, M. Ratti7, E.The 13 14 15 16 17 18 Bustreo , Research F. Di Fabio Smiroldo , B. Corvari , G. Tortora C. Granetto D., S. Disclosure: Cunningham: grant, /V. Funding (institution): AstraZeneca; Research grant / 1 Funding (institution): Celgene; Research grant / Funding (institution):Agostino MedImmune; Research grant / UOC Oncologia Medica, Fondazione Policlinico Universitario Gemelli IRCCS, Funding (institution): Bayer; Research grant / Funding (institution): 4SC; Research grant / Funding Fondazione Policlinico Universitario Agostino Rome, Italy, 2UOC Oncologia Medica, (institution): Clovis; Research grant / Funding (institution): Eli Lilly; Research grant / Funding (insti3 Fondazione IRCCS Istituto/ Consultancy: Nazionale dei GemelliJanssen; IRCCS, Research Rome, Italy, tution): grant Medical / FundingOncology, (institution): Merck. I. Chau: Advisory Eli of Translational Research and New Technologies in Tumori, Milan,/ Consultancy: Italy, 4Department Lilly; Advisory BMS; Advisory / Consultancy: MSD; Advisory / Consultancy: Bayer; 5 UO Oncologia Medica, Ospedale di Medicine and Surgery,Roche; University of Pisa, Pisa, Italy,Merck-Serono; Advisory / Consultancy: Advisory / Consultancy: Advisory / Consultancy: Five Prime Therapeutics; Advisory / Consultancy: Advisory / Consultancy: Oncologie AOU Integrata Verona "Borgo Livorno, Azienda Ospedaliera 6, Livorno, AstraZeneca; Italy, 6Oncology, 7Consultancy: Pierre Fabre; Research grant / Funding (institution): 8 Eli Lilly; International; Advisory / Trento", Verona, Italy, Oncology, Istituti Ospitalieri di Cremona, Cremona, Italy, UOC Research grant / FundingCardinale (institution): Janssen-Cilag; grant Oncologia / Funding (institution): Medica, Sanofi Oncologia, Ospedale G.Panico, Tricase,Research Italy, 9UOC Oncology; Research grant / Funding (institution): Merck-Serono; Honoraria (self): Eli-Lilly. M. Azienda Ospedaliera ARNAS Garibaldi, Catania, Italy, 10S.C. Oncologia Medica, E.O. Gerlinger: Research grant / Funding11(institution): BMS; Research grant / Funding (institution): Merck UOC(institution): Oncologia AstraZeneca; Medica, Istituto Nazionale Tumori (instiOspedali Galliera, Genoa, Italy, KG. N. Starling: Research grant / Funding Research grant / Funding IRCCS Fondazione Naples,(institution): Italy, 12Medical Unit 1, Veneto/ Expenses: Institute tution):- BMS; ResearchPascale, grant / Funding Pfizer;Oncology Travel / Accommodation 13 Oncologia Medica, Azienda Ospedaliera St. Eli of OncologyTravel IRCCS,/ Accommodation Padua, Italy, UOC AstraZeneca; / Expenses: BMS; Travel / Accommodation / Expenses: Lilly; Travel / Accommodation / Expenses: Merck; Travel / Accommodation / Expenses: Roche; Oncologia Medica, Azienda Ospedaliero-Universitaria Croce e Carle, Cuneo, Italy, 14 15 Honoraria (self): AstraZeneca; Honoraria (self): Eli Lilly; Honoraria (self): Merck; Honoraria (self): Citta della Salute e della Scienza di Torino, Turin, Italy, UOC Oncologia Medica, AOU 16 Servier; Advisory / Consultancy: Pfizer; Advisory AstraZeneca; / Medical Oncology andAdvisory Hematology Policlinico S. Orsola-Malpighi, Bologna, Italy,/ Consultancy: Consultancy: Servier. All other authors have declared no conflicts of interest. Unit, Humanitas Cancer Center, Humanitas Clinical and Research Center, IRCCS, Rozzano, Italy, 17UOC Radioterapia, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy, 18UOC Oncologia Medica, Fondazione Policlinico Universitario Agostino Gemelli IRCCS - Universita Cattolica del Sacro Cuore, Rome, Italy