L’immunoterapia: discutiamo l’algoritmo terapeutico attraverso i casi clinici Giulia Barletta, San Martino - IST Genova Giorgio Sogno, San Paolo - ASL 2 Savona

Caso clinico 1 Uomo, 74 aa PS 2 (dispnea e algie dorsali) Forte fumatore 100 p/y Comorbidità: IA, diabete mellito insulino dipendente, trombosi carotidea bilaterale operata Diagnosi: Ebus- TBNA: ca squamoso del polmone Stadio IV: lesioni polmonari bilaterali, lesione osteolitica corpo vertebrale di D4, linfonodi sopraclaveari bilaterali e mediastinici Rt ossea a scopo antalgico Inizia I Linea: CDDP 75 mg/mq + Gem 1250 mg/mq gg 1-8 q21 PD strumentale dopo 4 cicli CT: invariate le lesioni polmonari e linfonodali, lesione ossea osteoaddensante e comparsa di nodulo surrenalico sx del diametro di circa 3,4 cm Inizia II linea: Nivolumab 3 mg/kg q 14

Caso clinico 1 Uomo, 74 aa PS 2 (dispnea e algie dorsali) Forte fumatore 100 p/y Comorbidità: IA, diabete mellito insulino dipendente, trombosi carotidea bilaterale operata Diagnosi: Ebus- TBNA: ca squamoso del polmone Stadio IV: lesioni polmonari bilaterali, lesione osteolitica corpo vertebrale di D4, linfonodi sopraclaveari bilaterali e mediastinici Rt ossea a scopo antalgico Inizia I Linea: CDDP 75 mg/mq + Gem 1250 mg/mq gg 1-8 q21 PD strumentale dopo 4 cicli CT : invariate le lesioni polmonari e linfonodali, lesione ossea osteoaddensante e comparsa di nodulo surrenalico sx del diametro di circa 3,4 cm Inizia II linea: Nivolumab 3 mg/kg q 14

REVEL: Randomized Phase III Study in 2 nd line NSCLC Stage IIIB/IV NSCLC Squamous/non Sq. PD after 1 st line Platinum based CT Stage IIIB/IV NSCLC Squamous/non Sq. PD after 1 st line Platinum based CT R 1:1 Docetaxel 75 mg/m 2 + Ramucirumab 10 mg/kg 1, q 21 Docetaxel 75 mg/m 2 + Ramucirumab 10 mg/kg 1, q 21 Docetaxel 75 mg/m 2 + Placebo 1, q 21 Docetaxel 75 mg/m 2 + Placebo 1, q 21 Primary Endpoint:OS Secondary Endpoints:PFS, RR Patients-reported symptoms and QoL Dec 2010 – Jan

REVEL: OS Primary endpoint: OS HR 0.86 (p=.023) Median OS 10.5 vs 9.1m

REVEL: PFS Secondary endpoint: PFS HR 0.76 (p<.001) Median PFS 4.5 vs 3.0m

CheckMate 017

Caso clinico 2 Donna, 78 aa PS 2(ipostenia arto superiore destro e tosse) Ex fumatrice da 5 aa 20 p/y Comorbidita: fibromatosi uterina, diverticolite, pregresso IMA (64 aa), noduli tiroidei (20 aa) Diagnosi citologica in broncoscopia: ca scarsamente diff + verosimilmente adenocarcinoma EGFR + (delezione 19) Stadio IV: polmone bilaterale, encefalo Inizia I Linea: Inibitore Tks prima generazione (11,5 mesi) PD strumentale dopo 11,5 somministrazioni di Tks:Invariate le lesioni encefaliche, aumento numerico e dimensionale dei noduli polmonari bilaterali e comparsa di plurimi secondarismi epatici Re-biopsy: WT per T 790 M Inizia II linea: Nivolumab 3mg/kg q14

Caso clinico 2 Donna, 78 aa PS 2 (ipostenia arto superiore destro e tosse) Ex fumatrice da 5 aa 20 p/y Comorbidità: fibromatosi uterina, diverticolite, pregresso IMA (64 aa), noduli tiroidei (20 aa) Diagnosi citologica in broncoscopia: ca scarsamente diff + verosimilmente adenocarcinoma EGFR + (delezione 19) Stadio IV: polmone bilaterale, encefalo Inizia I Linea: Inibitore Tks prima generazione (11,5 mesi) PD strumentale dopo 11,5 somministrazioni di Tks:Invariate le lesioni encefaliche, aumento numerico e dimensionale dei noduli polmonari bilaterali e comparsa di plurimi secondarismi epatici Re-biopsy : WT per T 790 M Inizia II linea: Nivolumab 3mg/kg q14

CheckMate 057

PD-L1 expression measured using the Dako/BMS automated IHC assay 14,15 –Fully validated with analytical performance having met all pre-determined acceptance criteria for sensitivity, specificity, precision, and robustness a Maintenance therapy included pemetrexed, bevacizumab, or erlotinib (not considered a separate line of therapy); b Per RECIST v1.1 criteria as determined by the investigator. Randomize 1:1 Stage IIIB/IV non-SQ NSCLC Pre-treatment (archival or recent) tumor samples required for PD-L1 ECOG PS 0–1 Failed 1 prior platinum doublet Prior maintenance therapy allowed a Prior TKI therapy allowed for known ALK translocation or EGFR mutation N = 582 Nivolumab 3 mg/kg IV Q2W until PD or unacceptable toxicity n = 292 Docetaxel 75 mg/m 2 IV Q3W until PD or unacceptable toxicity n = 290 Primary Endpoint –OS Additional Endpoints –ORR b –PFS b –Safety –Efficacy by tumor PD-L1 expression –Quality of life (LCSS) Patients stratified by prior maintenance therapy and line of therapy (second- vs third-line) Paz-Ares L, ASCO 2015

CheckMate 057

Caso clinico 3 Uomo, 63 aa PS 1 (tosse) Fumatore 45 p/y Comorbidità: pregressa HBV, ischemia coronarica (PTA e stent a 54 aa) Diagnosi tramite biopsia polmonare: adenocarcinoma EGFR WT Stadio IV: Linfonodi mediastinici bilaterali, sopra e sotto carenali, massa polmonare di circa 5 cm di diametro lobo inferiore destro, almeno 3 lesioni epatiche secondarie Inizia I Linea: CBDP AUC 5 + Pemetrexed 500 mg/mq PD strumentale dopo 2 cicli CT: incremento dimensionale della nota lesione polmonare, comparsa di noduli polmonari a sinistra, aumento numerico e dimensionale delle note lesioni secondarie epatiche Inizia II linea: taxotere 75 mg/mq + nintedanib 200 mg bid (studio Seneca) PD strumentale dopo 3 cicli: ulteriore progressione epatica e linfonodale mediastinica Inizia terza linea: Nivolumab 3mg/kg q14

Caso clinico 3 Uomo, 63 aa PS 1 (tosse) Fumatore 45 p/y Comorbidità: pregressa HBV, ischemia coronarica (PTA e stent a 54 aa) Diagnosi tramite biopsia polmonare: adenocarcinoma EGFR WT Stadio IV: Linfonodi mediastinici bilaterali, sopra e sotto carenali, massa polmonare di circa 5 cm di diametro lobo inferiore destro, almeno 3 lesioni epatiche secondarie Inizia I Linea: CBDP AUC 5 + Pemetrexed 500 mg/mq PD strumentale dopo 2 cicli CT: incremento dimensionale della nota lesione polmonare, comparsa di noduli polmonari a sinistra, aumento numerico e dimensionale delle note lesioni secondarie epatiche Inizia II linea: taxotere 75 mg/mq + nintedanib 200 mg bid (studio Seneca) PD strumentale dopo 3 cicli: ulteriore progressione epatica e linfonodale mediastinica Inizia terza linea: Nivolumab 3mg/kg q14

LUME-Lung 1 Nintedanib 200mg BID p.o., D2–21, + Docetaxel 75mg/m 2 IV, D1, 21-day cycles (n=655) Placebo BID p.o., D2–21, + Docetaxel 75mg/m 2 IV, D1, 21-day cycles (n=659) RANDOMIZERANDOMIZE Stratification:ECOG PS (0 vs 1) Prior bevacizumab (yes vs no) Histology (squamous vs non-squamous) Brain metastases (yes vs no) Stage IIIB/IV recurrent NSCLC patients after 1 st line chemotherapy (all histologies) 1:1 PD Number of docetaxel cycles not restricted Monotherapy allowed after ≥4 cycles of combination therapy Regions: Europe / Asia / South Africa Accrual: Dec 23, 2008 to Feb 9, 2011 M. Reck et al, Lancet Oncol 15 (2), (2014) Primary Endpoint: Primary Endpoint: PFS (Independent Central Review) Key Secondary Endpoint: Key Secondary Endpoint: OS (Powered Pre-planned Analyses of Adenocarcinoma and ITT population) N=1314

OS Adenocarcinoma T<9mo Key secondary endpoint: OS Stepwise testing time since start of 1 st line therapy (T) <9 months  all adenocarcinoma  all histologies 80% power, HR 0.80 Two sided stratified log-rank test, α= ** Primary endpoint: Independently assessed PFS All histologies 90% power after 713 PFS events, HR 0.78 Two-sided stratified log-rank test, α=0.05 LUME-Lung 1: Statistical Design p< Next analysis step only allowed if PFS confirmed with all PFS events at time point of OS analysis OS *Fixed-sequence order testing implemented prior to database lock to validate biomarker findings from independent study **Overall α=0.05 All adenocarcinomaAll histologies M. Reck et al, Lancet Oncol 15 (2), (2014)

Nintedanib Placebo No. at risk Probability of survival (%) 0 Time (months) LUME-Lung 1: OS in ADK pts progressed in <9 months after start of 1 st line therapy 22 CI = confidence interval; HR = hazard ratio; OS = overall survival. Reck M, et al. Lancet Oncol. 2014;15:143-55; Boehringer Ingelheim data on file. Key Secondary Endpoint, Pre-specified Hierarchical Analysis Nintedanib + docetaxel Placebo + docetaxel Median OS (months) HR = 0.75 (95% CI: 0.60–0.92); p= % 34.3% 20.7% 1-YEAR SURVIVAL 2-YEAR SURVIVAL 10.4%

LUME-Lung 1: OS in ADK pts who showed PD as best response to first-line Mellemgaard A, ESMO 2013

CheckMate 057 PD-L1 expression measured using the Dako/BMS automated IHC assay 14,15 –Fully validated with analytical performance having met all pre-determined acceptance criteria for sensitivity, specificity, precision, and robustness a Maintenance therapy included pemetrexed, bevacizumab, or erlotinib (not considered a separate line of therapy); b Per RECIST v1.1 criteria as determined by the investigator. Randomize 1:1 Stage IIIB/IV non-SQ NSCLC Pre-treatment (archival or recent) tumor samples required for PD-L1 ECOG PS 0–1 Failed 1 prior platinum doublet Prior maintenance therapy allowed a Prior TKI therapy allowed for known ALK translocation or EGFR mutation N = 582 Nivolumab 3 mg/kg IV Q2W until PD or unacceptable toxicity n = 292 Docetaxel 75 mg/m 2 IV Q3W until PD or unacceptable toxicity n = 290 Primary Endpoint –OS Additional Endpoints –ORR b –PFS b –Safety –Efficacy by tumor PD-L1 expression –Quality of life (LCSS) Patients stratified by prior maintenance therapy and line of therapy (second- vs third-line) Paz-Ares L, ASCO 2015

Treatment Algorithm for Patients with Advanced Squamous NSCLC, PS 0-2 Platinum doublet / monoCT Nivolumab Docetaxel (+/- Ramucirumab) Erlotinib (Afatinib)

Treatment Algorithm for Patients with Advanced Non Squamous NSCLC, PS 0-2 ALK Gene Fusion EGFR + Wild type Erlotinib Gefitinib Afatinib Platinum + Pemetrexed Bevacizumab Pemetrexed Pemetrexed ** Docetaxel (+/- Ramucirumab/ Nintedanib) Erlotinib(Nivolumab) (Crizotinib) (Ceritinib/ Alectinib) T790M + - (Osimertinib)* * Platinum doublet/ monoCT* Platinum with Taxane +/- Beva MonoCT

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