Docetaxel - clomuch.cl
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Docetaxel - clomuch.cl
Cáncer Pulmonar Inmunoterapia y Nuevas Alternativas Francisco J. Orlandi Jefe Unidad de Medicina Oncológica (UMO) Instituto Nacional del Tórax Conflictos de Interés Empleo: No Consultor / Asesor externo/ board de speakers: AstraZeneca, BMS, Boehringer Ingelheim, Eli Lilly, Hospira, MSD, Novartis, SANOFI Accionista o propietario: No Honorarios: No Grants de Investigación: Amgen, Astrazeneca, BI, BMS, Genentech, Novartis, Pfizer, Roche, sanofi. Testimonio Experto: Sanofi INVIMA COFEPRIS >1.5 Million New Cases of Lung Cancer: >25% in G7 Countries Estimated age-standardized incidence rate per 100,000; both genders, all ages Incidence Age-adjusted incidence rate (per 100,000) US 221,130 62.0 UK 40,390 31.3 France 40,040 29.9 Germany 34,799 28.1 Italy 37,240 26.6 Spain 26,720 28.7 Japan 86,818 24.6 China 652,842 36.1 India 58,567 6.6 Country • Lung cancer is a wide-reaching public health concern in the United States and worldwide, with more than 200,000 cases diagnosed in the United States in 2011 and more than 160,000 cases in EU5 Source: Cancer incidence and mortality patterns in Europe: Estimates for 40 countries in 2012 Thea,⇑, incidence of lung cancer is high in G7a,countries, J.• Ferlay E. Steliarova-Foucher a, J. Lortet-Tieulent S. Rosso b, J.W.W. Coebergh c,d, H. Comber e, D. Forman a, F. Bray 3 Cancer Survival Statistics - Chile Estimated age-standardised incidence and mortality rates: both sexes WHO-IARS. GLOBOCAN 2012 http://globocan.iarc.fr/Pages/fact_sheets_population.aspx (acceso 04 nov 2014) Chile 2012 Total de muertes 98.711 por Tumores = 25.421 Hombres Mujeres 2.181 Gástrico 1.367 Mama 2.045 Próstata 1.173 Gástrico 1.680 Pulmón 1.168 Pulmón 2.848 Total Pulmón – INE Estadisticas Vitales 2012 Tipo Histológico Instituto Nacional del Tórax (2013) Escamoso 22% Células Pequeñas 10% Sin histología 3% Otros 19% No Células Pequeñas NOS 8% Células Grandes 4% Indiferenciado 3% Adenocarcinoma 46% Carcinoide 2% Sarcoma 2% Adenoescamoso 0% Santana G., et al Cáncer Pulmonar en el INT Déficit de registros completos y actualizados Esfuerzo del Comité Oncológico centraliza parte de la información ETAPA IV INT 2015 (2) Cáncer Pulmonar 2013 (1) Tipo Histológico Adenocarcinoma (>50%) Escamoso Otros Células Pequeñas Sin histología N % Tipo Histológico 2012-13 2014-15 134 65 55 30 7 46% 22% 19% 10% 2% Adenocarcinoma 59% 67%% Escamoso 12% 18% Células Grandes 6.5% 8.33% Células Pequeñas 21% 5.2% Total 291 100% Total 132 112 1. Santana G., et al 2 Saavedra M.P., et al Dabrafenib + Trametinib in BRAF V600E– Mutant NSCLC: Background BRAF V600E accounts for ~ 2% of NSCLC mutations and associated with poorer outcomes on platinum regimens Dabrafenib: reversible, small molecule inhibitor of BRAF V600 kinase – Single-agent activity in BRAF V600E–mutant NSCLC[1] Trametinib: reversible, small molecule inhibitor of MEK1/MEK2 – Addition to dabrafenib more active than monotherapy in melanoma[2,3] Current study (BRF113928) evaluated safety and efficacy of dabrafenib + trametinib in BRAF V600E–mutant advanced NSCLC[4] 1. Planchard D, et al. ESMO 2014. Abstract LBA38_PR. 2. Long GV, et al. N Engl J Med. 2014;371:18771888. 3. Robert C, et al. N Engl J Med. 2015;372:30-39. 4. Planchard D, et al. ASCO 2015. Abstract 8006. Dabrafenib + Trametinib in Previously Treated NSCLC With a BRAF Mutation BRF113928: Single-arm, multicenter, open-label phase II trial Pts with progressing stage IV BRAF V600E–mutant NSCLC after 1-3 prior regimens (≥ 1 platinum-based) ECOG PS 0-2 (N = 40) Stage 1 Stage 2 If ≥ 6 Dabrafenib 150 mg BID + responses Dabrafenib 150 mg BID + Trametinib 2 mg QD Trametinib 2 mg QD (n = 20) (n = 20) Interim analysis with N = 33 (safety population) – 24 pts evaluated for efficacy Primary endpoint: ORR (by investigator); secondary endpoints: PFS, OS, DoR, safety, tolerability, PK Planchard D, et al. ASCO 2015. Abstract 8006. Individual Patients BRF113928: Responses With Dabrafenib + Trametinib Best Confirmed Response Partial Response Stable Disease Progressive Disease Not Evaluable Not Available First Partial Response Disease Progressed Still on Study Treatment 0 1 2 3 4 5 Treatment Duration (Mos) 6 7 8 *1st-line patient (protocol deviation) Median time on study treatment (dabrafenib and trametinib) = 108 days (range, 1 to 244 days) Planchard D, et al. ASCO 2015. Abstract 8006. Reprinted with permission. 9 BRF113928: Safety With Dabrafenib + Trametinib AE, % All Treated (n = 33) Any AE 88 Any grade ≥ 3 AE 45 Any serious AEs Serious AEs ≥ 2 pts Pyrexia Confusional state Hyponatremia 42 AE leading to discontinuation 6 18 6 6 Most common AEs: pyrexia, diarrhea, nausea, vomiting, decreased appetite, asthenia, cough, peripheral edema, rash 1 death due to pleural effusion and disease progression Planchard D, et al. ASCO 2015. Abstract 8006. Rol del Sistema Inmune en el proceso de Inmunoedicion Eliminacion Inmunovigilancia • Procesamiento y Presentacion efectivas • Efectiva activacion y funcionamiento de celulas efectoras Equilibrio Escape Durmiente Progresion tumoral • Inestabilidad Genetica • Heterogeneidad Tumoral • Seleccion • Inmune Tumores impiden eliminacion por expresion de clones que pueden suprimir, disrumpir o escapar del sistema inmune ‒ P.ej., T cell activation without co-inhibitory signals CD8+ T cell CD4+ T cell NK cell Tumor cells Normal cells NK=natural killer; Treg=regulatory T cell. Vesely MD et al. Ann Rev Immunol. 2011;29:235-271. Treg Desarrollo clínico de Anticuerpos inmunomoduladores Anti-CTLA-4 Ipilimumab* Tremelimumab Anti-PD-1 nivolumab* pembrolizumab (Merck) pidilizumab (CureTech) Anti-PD-L1 BMS-936559 atezolizumab (Roche) durvalumab (AZ) RG7446 (Genentech) Anti-PD-L2 AMP-224 (GSK) * Aprobado por agencias regulatorias (FDA, EMA, ISP) Modificado de Melero et al. Clin Cancer Res 2013;19(5):997–1008 Tratamiento en NSCLC Estrategia debe considerar histologia,patologia molecular,edad, PS, comorbilidad y preferencias del enfermo Histologia No Escamosa Erlotinib (PS 0-3) • QT Mono • droga o CPAD PS 0-1 CPAD • Afa • Erlo • Gefi •Crizo •Ceri • Pareja con Platino PS 2 • QT Monodroga o CPAD • No Hay • Docetaxel • Gemcitabina CPAD CPAD=Cuidados Paliativos y Alivio del Dolor 1.Adaptado de : PETERS S, et al. Metastatic non-small-cell lung cancer (NSCLC): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Annals of Oncology. 2012;23(Supplement 7):vii56–vii64. 1a Linea • Docetaxel • Pemetrexed (N-E) PS 3-4 Maint. 1a Linea Mant. • Pemetrexed (continuacion o cambio) • Erlotinib (cambio)…? 2aLinea • QT Mono • droga o CPAD • Pareja con Platino +/Bevacizumab ALK + 2a Linea PS 2 3a Linea PS 0-1 EGFR + 3a Linea EGFR/ALK (—) Escamosa • Stage IIIB/IV SQ NSCLC • 1 prior platinumdoublet based chemotherapy • ECOG PS 0–1 N = 272 Randomize 1:1 CheckMate 017: Study Design Nivolumab 3 mg/kg IV q2w, until PD or unacceptable toxicity Docetaxel 75 mg/m2 IV q3w, until PD or unacceptable toxicity Endpoints • Primary: OS • Secondary: ORR, PFS, correlation between PD-L1 expression and efficacy (ORR, OS, PFS), quality of life (LCSS) • Patients stratified by region (US/Canada vs Europe vs rest of world) and prior paclitaxel use • ORR and PFS secondary endpoints assessed by investigator, confirmed by IRC – Tumor response assessment (RECIST v1.1) performed at Week 9 and every 6 weeks thereafter until PD or discontinuation of study therapy • Minimum follow-up of approximately 10.6 months • Results based on a 15 December 2014 database lock ECOG = Eastern Cooperative Oncology Group; IV = intravenous; LCSS = lung cancer symptom scale; ORR = objective response rate; OS = overall survival; PD = progressive disease; PD-L1 = programmed cell death ligand 1; PFS = progression-free survival; PS = performance status; RECIST = response evaluation criteria in solid tumors; SQ = squamous. N Engl J Med 2015;372:320-30. 15 CHECKMATE 017: SOBREVIDA GLOBAL mOS, months (95% CI) 100 90 # events 80 Docetaxel n = 137 9.2 (7.33, 12.62) 6.0 (5.29, 7.39) 103 122 HR = 0.62 (0.48, 0.81); P = 0.0004 70 OS (%) Nivolumab n = 135 12-month OS rate = 42% 60 50 18-month OS rate = 28% 18-month OS rate = 13% 40 30 Nivolumab 20 12-month OS rate = 24% Docetaxel 10 0 0 3 6 9 12 15 18 21 24 27 30 33 Time (months) Number of Patients at Risk Nivolumab 135 113 86 69 57 51 37 25 14 6 0 0 Docetaxel 137 104 69 46 33 22 15 11 7 3 1 0 Based on August 2015 DBL. Minimum follow-up for survival: 18 months mOS = median overall survival. Symbols refer to censored observations. Reckamp K, et al. Presented at the 16th World Conference on Lung Cancer; September 6–9, 2015; Denver, Colorado, USA. Oral 02.01. 16 EUROPEAN LUNG CANCER CONFERENCE 2016 CheckMate 057: Phase III Study of Nivolumab vs Docetaxel in 2/3L NSQ NSCLC A randomized, open-label, phase III study of nivolumab versus docetaxel in previously treated advanced or metastatic non-squamous cell NSCLC N=582 Nivolumab 3 mg/kg IV q2w Key Inclusion Criteria • Stage IIIb/IV or recurrent non-squamous NSCLC • Pretreatment (archival or recent) tumor samples required for PD-L1 analysis • One prior Pt doublet-based chemotherapy • Prior maintenance therapy with pemetrexed, bevacizumab, or erlotinib allowed • Prior TKI therapy allowed for known ALK translocation or known EGFR mutation • ECOG PS ≤1 • Until progression, unacceptable toxicity, or withdrawal of consent Docetaxel 75 mg/m2 IV q3w Primary Outcome Measure: – • R 1:1 OS Secondary Outcome Measures: – ORR, PFS, efficacy by tumor PD-L1 expression, patient-reported outcomes ALK = anaplastic lymphoma kinase; ECOG PS = Eastern Cooperative Oncology Group Performance Status; EGFR = epidermal growth factor receptor; IV = intravenous; NSCLC = non-small cell lung cancer; NSQ = non-squamous; ORR = objective response rate; OS = overall survival; PD-L1 = programmed death ligand 1; PFS = progression-free survival; pt = platinum; q2w = every 2 weeks; q3w = every 3 weeks; R = randomized; TKI = tyrosine kinase inhibitor. Borghaei H et al. N Engl J Med. 2015;373(17):1627-1639. 17 CheckMate 057: Overall Survival in ITT Population at 18 Months mOS, mos # events 100 Nivolumab (n=292) 12.2 Docetaxel (n=290) 9.4 206 236 HR (95% CI) =0.72 (0.60, 0.88); Posthoc P=0.0009 90 80 OS (%) 70 60 12-mo OS rate=51% 50 18-mo OS rate=39% 40 12-mo OS rate=39% 30 20 Nivolumab 18-mo OS rate=23% 10 Docetaxel 0 0 3 No. of patients at risk (18-mo OS) Nivolumab 292 233 290 244 Docetaxel 6 9 12 15 18 21 24 27 30 107 61 55 23 27 6 4 4 0 0 Time (mos) 195 194 171 150 148 111 128 89 12-month OS based on a March 18, 2015, DBL. 18-month OS based on a July 2, 2015, DBL. 17.1-month minimum follow-up. Symbols represent censored observations. DBL = database lock; HR = hazard ratio; ITT = intent-to-treat; mOS = median OS; mos = months; OS = overall survival. Horn L et al. Oral presentation at ECC 2015. 3010. 18 Overall Survival (%) CheckMate 057: OS by PD-L1 Expression ≥1% PD-L1 expression level 1 0 0 9 0 8 0 7 0 6 0 5 0 4 0 3 0 2 0 1 0 0 mOS (mo) 17.2 Nivolum ab Docetaxe l 9.0 HR (95% CI) = 0.59 (0.43, 0.82) 0 3 6 9 1 1 1 5 8 Time2 (months) 2 1 ≥5% PD-L1 expression level 1 0 9 0 0 8 0 7 0 6 0 5 0 4 0 3 0 2 0 1 0 0 mOS (mo) 0 3 6 <1% PD-L1 expression level 10 0 90 Overall Survival (%) 10.4 Nivoluma b Docetaxel 70 60 10.1 50 40 30 20 10 HR (95% CI) = 0.90 (0.66, 1.24) 0 0 3 6 9 1 1 1 2 2 9 1 1 1 5 8 Time2 (months) 2 1 2 4 2 7 mOS (mo) 2 0 3 3 6 9 1 1 1 9.7 10.1 2 2 6 9 1 1 1 5 8 Time2 (months) 2 1 2 7 2 mOS (mo) 9.9 Nivoluma b Docetaxel 10.3 HR (95% CI) = 1.00 (0.76, 1.31) 0 3 6 9 1 1 1 2 5 8 1 5 observations. 8 1 4CI = confidence 7 5 ratio; 8 1 4= median 7 2(months) Time2 (months) Time (months) Symbols representTime censored interval; HR =2hazard mOS overall survival; PD-L1 = programmed cell death ligand 1. Paz-Ares N et al. ASCO 2015 2 4 <10% PD-L1 expression level HR (95% CI) = 1.01 (0.77, 1.34) 0 8.0 HR (95% CI) = 0.40 (0.26, 0.59) 1 0 9 0 0 8 0 7 0 6 0 5 0 4 0 3 0 2 0 1 0 0 mOS (mo) Nivoluma b Docetaxel 19.4 Nivolum ab Docetaxe l <5% PD-L1 expression level 1 0 9 0 0 8 0 7 0 6 0 5 0 4 0 3 0 2 0 1 0 0 mOS (mo) 80 8.1 HR (95% CI) = 0.43 (0.30, 0.63) 2 7 2 4 18.2 Nivolum ab Docetax el ≥10% PD-L1 expression level 1 0 9 0 0 8 0 7 0 6 0 5 0 4 0 3 0 2 0 1 0 0 2 4 2 7 19 CheckMate 057: Survival by PD-L1 Expression PD-L1 Expression OS 1% <1% 5% <5% 10% <10% Not quantifiable PFS 1% <1% 5% <5% 10% <10% Not quantifiable aInteraction Patients, n Unstratified HR (95% Cl) Nivo Doc 123 108 95 136 86 145 61 123 101 86 138 79 145 66 0.59 0.90 0.43 1.01 0.40 1.00 0.91 (0.43, 0.82) (0.66, 1.24) (0.30, 0.63) (0.77, 1.34) (0.26, 0.59) (0.76, 1.31) (0.61, 1.35) 123 108 95 136 86 145 61 123 101 86 138 79 145 66 0.70 1.19 0.54 1.31 0.52 1.24 1.06 (0.53, 0.94) (0.88, 1.61) (0.39, 0.76) (1.01, 1.71) (0.37, 0.75) (0.96, 1.61) (0.73, 1.56) Interaction P-valuea PD-L1 expressors PD-L1 non-expressors PD-L1 not quantifiable 0.06 <0.001 <0.001 0.02 <0.001 <0.001 P-value from Cox proportional hazard model with treatment, PD-L1 expression, and treatment by PD-L1 expression interaction. Based on a March 18, 2015, DBL. DBL = database lock; Doc = docetaxel; HR = hazard ratio; Nivo = nivolumab; OS = overall survival; PD-L1 = programmed death ligand 1; PFS = progression-free survival. Borghaei H et al. N Engl J Med. 2015;373(17):1627-1639. 0.25 0.5 Nivolumab 1.0 2.0 Docetaxel 20 CHECKMATE 063: STUDY DESIGN AND BASELINE CHARACTERISTICS Patients Nivolumab 3 mg/kg Q2W N = 117 Treatment • Stage IIIB/IV SQ NSCLC Nivolumab 3 mg/kg IV q2w, until PD or unacceptable toxicity • ≥2 prior systemic therapies Median age, years (range) 65 (37–87) Male, % 73 Disease stage, % IIIB IV 17 83 ECOG PS, % 0 1 22 78 Primary • IRC-assessed confirmed ORR Smoking status, % Current/former Never 92 8 Secondary • Investigator-assessed confirmed ORR PD-L1 quantifiable, %a ≥1% ≥5% ≥10% 65 59 33 33 Number of prior systemic regimens, % 2 3 ≥4 35 44 21 • ECOG PS 0–1 (N = 117) Endpoints Exploratory • Safety and tolerability • PFS and OS • Efficacy by PD-L1 expression aPercentages based on number of patients with evaluable samples (n = 76) IRC = independent radiology review committee; PD = progressive disease; PFS = progression-free survival Rizvi NA, et al. Lancet Oncol. 2015;16(3):257-65. 21 EUROPEAN LUNG CANCER CONFERENCE 2016 CHECKMATE 063 2-YEAR UPDATE: EFFICACY Nivolumab 3 mg/kg Q2W, N = 117 IRC-assessed, 6 monthsa Investigator-assessed, 6 monthsa ORR, % (95% CI) 12 (7, 19) 13 (7, 20) Ongoing responders, % (n/N) 71 (10/14) 93 (14/15) Median TTR, months (range) 3.0 (1.7-4.8) 2.2 (1.3-6.0) Median DOR, months (range) NR (2.8 to 6.9+) NR (1.2+ to 7.0+) Median PFS, months (95% CI) 1.9 (1.8, 3.2) 2.2 (1.8, 3.3) 27 (18, 36) - 0 12 29 43 16 1 12 32 44 11 Efficacy PFS rate, % (95% CI) Best overall response, % CR PR SD PD Unable to determine/not reported At the 24-month data cutoff, 4 (3%) patients were still on treatment Five of 26 patients treated beyond initial PD demonstrated a non-conventional pattern of benefit CR, complete response; DOR, duration of response; NR, not reached; ORR, overall response rate; OS, overall survival; PD, progressive disease; PFS, progression-free survival; PR, partial response; SD, stable disease; TTR, time to response. aMarch 2014 database lock. 22 EUROPEAN LUNG CANCER CONFERENCE 2016 CHECKMATE 063 2-YEAR UPDATE: EFFICACY Nivolumab 3 mg/kg Q2W, N = 117 IRC-assessed, 6 monthsa Investigator-assessed, 6 monthsa Investigator-assessed, 24 monthsb ORR, % (95% CI) 12 (7, 19) 13 (7, 20) 15 (9, 22) Ongoing responders, % (n/N) 71 (10/14) 93 (14/15) 29 (5/17)c Median TTR, months (range) 3.0 (1.7-4.8) 2.2 (1.3-6.0) 3.3 (1.6-7.4) Median DOR, months (range) NR (2.8 to 6.9+) NR (1.2+ to 7.0+) 19 (4.5+ to 27.5+) Median PFS, months (95% CI) 1.9 (1.8, 3.2) 2.2 (1.8, 3.3) 2.0 (1.8, 3.2) 27 (18, 36) - 9 (4, 15) 0 12 29 43 16 1 12 32 44 11 2 13 30 45 10 Efficacy PFS rate, % (95% CI) Best overall response, % CR PR SD PD Unable to determine/not reported At the 24-month data cutoff, 4 (3%) patients were still on treatment Five of 26 patients treated beyond initial PD demonstrated a non-conventional pattern of benefit CR, complete response; DOR, duration of response; NR, not reached; ORR, overall response rate; OS, overall survival; PD, progressive disease; PFS, progression-free survival; PR, partial response; SD, stable disease; TTR, time to response. aMarch 2014 database lock. bDecember 2015 database lock. cTwo additional patients had ongoing responses but were censored prior to the database lock (1 was lost to follow-up and 1 withdrew consent). 23 EUROPEAN LUNG CANCER CONFERENCE 2016 CHECKMATE 063 2-YEAR UPDATE: OVERALL SURVIVAL 100 DBL 90 Dec 2015 80 Median follow-up, months (range) Median OS, months (95% CI) 1-year OS rate, % (95% CI) 2-year OS rate, % (95% CI) Events, n/N 8.0 (0.0, 32.7) 8.1 (6.1, 10.9) 39 (30, 48) 22 (15, 30) 96/117 OS (%) 70 60 1-year OS 39% 50 18-month OS 27% 40 2-year OS 22% 30 20 10 0 0 3 6 9 12 15 18 21 24 27 30 33 27 24 17 5 0 Time (months) Number of patients at risk: Dec 2015 database lock 117 24 93 69 54 45 38 30 EUROPEAN LUNG CANCER CONFERENCE 2016 KEYNOTE-010: Phase II/III Study of Pembrolizumab vs Docetaxel in 2L+ PD-L1–Selected NSCLC Pembrolizumab 2 mg/kg IV q3w for 24 months Patients • • • • • • • Advanced NSCLC Confirmed PD after ≥ 1 line of chemotherapya No active brain metastases ECOG PS 0–1 PD-L1 TPS ≥1% No serious autoimmune disease No ILD or pneumonitis requiring systemic steroids R 1:1:1 Stratification factors: • ECOG PS (0 vs 1) • Region (East Asia vs non-East Asia) • PD-L1 statusb (TPS ≥50% vs 1%–49%) Pembrolizumab 10 mg/kg IV q3w for 24 months Docetaxel 75 mg/m2 q3w per local guidelines End points in the TPS ≥50% stratum and TPS ≥1% population • Primary: PFS and OS • Secondary: ORR, duration of response, safety therapy must have included ≥2 cycles of platinum-doublet chemotherapy. An appropriate tyrosine kinase inhibitor was required for patients whose tumors had an EGFR sensitizing mutation or an ALK translocation. bAdded after 441 patients enrolled based on results from KEYNOTE-001 (Garon EB et al. N Engl J Med. 2015;372:2018-2028). cPatients received the maximum number of cycles permitted by the local regulatory authority. ECOG PS = Eastern Cooperative Oncology Group Performance Status; NSCLC = non-small cell lung cancer; ORR = objective response rate; OS = overall survival; PD = progressive disease; PD-L1 = programmed death ligand 1; PFS = progression-free survival; q3w = every 3 weeks; R = randomized; TPS = tumor proportion score. Herbst RS et al. Oral presentation at ESMO Asia 2015. aPrior 25 KEYNOTE-010: Overall Survival at TPS ≥1% and TPS ≥50% ≥1% PD-L1 Expression 100 90 90 80 60 50 40 30 10 0 Number of Patients at Risk 2 mg/kg 344 10 mg/kg 346 Docetaxel 343 259 255 212 115 124 79 15 20 25 12 6 1 0 0 0 Time (mos) 10.4 (9.4, 11.9) 40 Pembro 2 mg/kg Pembro 10 mg/kg Docetaxel 10 10 Pembro 2 mg/kg 50 20 5 Median Treatment Arm (95% CI), mo 60 30 Pembro 2 mg/kg Pembro 10 mg/kg Docetaxel 20 2 vs 10 mg/kg: HR 1.12, 95% CI 0.77, 1.62 70 OS (%) OS (%) 80 2 vs 10 mg/kg: HR 1.17, 95% CI 0.94, 1.45 70 0 ≥50% PD-L1 Expression 100 Rate at 1-yr 49 56 33 HRa (95% CI) P value 43.2% 0.71 (0.58, 0.88) 0.0008 Pembro 10 mg/kg 12.7 (10.0, 17.3) 52.3% 0.61 (0.49, 0.75) <0.0001 Docetaxel 8.5 (7.5-9.8) 34.6% – – 0 0 Number of Patients at Risk 2 mg/kg 139 10 mg/kg 151 Docetaxel 152 5 10 110 115 90 51 60 38 15 20 25 3 1 1 0 0 0 Time (mos) 20 25 19 Treatment Arm Median (95% CI), mo HRa (95% CI) P value Pembro 2 mg/kg 14.9 (10.4, NR) 0.54 (0.38, 0.77) 0.0002 Pembro 10 mg/kg 17.3 (11.8, NR) 0.50 (0.36, 0.70) <0.0001 Docetaxel 8.2 (6.4, 10.7) – aComparison of pembrolizumab vs docetaxel. Analysis cut-off date: September 30, 2015. HR = hazard ratio; mos = months; NR = not reached; OS = overall survival; PD-L1 = programmed death ligand 1; Pembro = pembrolizumab; TPS = tumor proportion score. Herbst RS et al. Oral presentation at ESMO Asia 2015. 26 KEYNOTE-010: Progression-Free Survival at TPS ≥1% and TPS ≥50% ≥1% PD-L1 Expression 100 90 80 70 PFS (%) PFS (%) 70 60 50 40 60 50 40 30 30 20 20 10 10 0 0 Number of Patients at Risk 2 mg/kg 344 10 mg/kg 346 Docetaxel 343 5 10 122 137 103 46 60 27 15 20 25 1 1 0 0 0 0 Time (mos) 12 19 6 Treatment Arm Median (95% CI), mo HRa (95% CI) P value Pembro 2 mg/kg 3.9 (3.1, 4.1) 0.88 (0.74, 1.05) Pembro 10 mg/kg 4.0 (2.7, 4.3) Docetaxel 4.0 (3.1, 4.2) Pembro 2 mg/kg Pembro 10 mg/kg Docetaxel 90 Pembro 2 mg/kg Pembro 10 mg/kg Docetaxel 80 ≥50% PD-L1 Expression 100 0 0 Number of Patients at Risk 2 mg/kg 139 10 mg/kg 151 Docetaxel 152 5 10 66 72 45 29 36 17 15 20 25 0 0 0 0 0 0 Time (mos) 6 12 5 Treatment Arm Median (95% CI), mo HRa (95% CI) P value 0.07 Pembro 2 mg/kg 5.0 (4.0, 6.5) 0.59 (0.44, 0.78) 0.0001 0.79 (0.66, 0.94) 0.004 Pembro 10 mg/kg 5.2 (4.1, 8.1) 0.59 (0.45, 0.78) <0.0001 – – Docetaxel 4.1 (3.6, 4.3) – – aComparison of pembrolizumab vs docetaxel. Analysis cut-off date: September 30, 2015. HR = hazard ratio; mos = months; PD-L1 = programmed death ligand 1; Pembro = pembrolizumab; PFS = progression-free survival; TPS = tumor proportion score. Herbst RS et al. Oral presentation at ESMO Asia 2015. 27 POPLAR: Study of Atezolizumab vs Docetaxel in 2/3L NSCLC Patients • Metastatic or locally advanced NSCLC • Disease progression on a prior platinumbased therapy R 1:1 Stratification Factors • PD-L1 IC expression (0 vs 1 vs 2 vs 3)a • Histology (squamous vs non-squamous) • Prior chemotherapy regimens (1 vs 2) Atezolizumab 1200 mg IV q3w until loss of clinical benefit Docetaxel 75 mg/m2 IV q3w until disease progression N=287Phase II • Primary study objective: – Estimate OS in ITT and PD-L1 expression subgroups • Secondary study objectives: – Estimate PFS, ORR and DOR in ITT and PD-L1 expression subgroups – Evaluate safety aArchival or new tissue required for pre-dose testing. DOR = duration of response; IC = tumor-infiltrating immune cell; ITT = intent-to-treat; IV = intravenous; NSCLC = non-small cell lung cancer; ORR = objective response rate; OS = overall survival; PD-L1 = programmed death ligand 1; PFS = progression-free survival; q3w = every 3 weeks; R = randomized. Vansteenkiste J et al. Oral presentation at ECC 2015. 14LBA. LOCAL APPROVAL MAY BE REQUIRED BEFORE EXTERNAL USE. REFER TO LOCAL GUIDELINES 28 POPLAR: Overall Survival and Safety of Atezolizumab vs Docetaxel 100 HR 0.73a (95% CI 0.53, 0.99) P=0.040 80 20 Atezolizumab Docetaxel Censored 0 0 2 4 OS (%) TC3 or IC3 47 TC2/3 or IC2/3 TC1/2/3 or IC1/2/3 Median 9.7 mo (8.6, 12.0) 40 Patients, n 0.49 Median 12.6 mo (9.7, 16.4) 60 PD-L1 Subgroup 0.54 105 0.59 198 TC0 and IC0 92 ITT 287 1.04 0.73 0.2 6 8 10 12 Time (mos) 14 16 18 20 1 2 b Hazard Ratio Atezolizumab Docetaxel • Treatment-related AEs: 67% for atezolizumab vs 88% for docetaxel • Treatment-related Grade ≥3 AEs: 11% for atezolizumab vs 39% for docetaxel • Treatment-related AEs leading to discontinuation: 8% for atezolizumab vs 22% for docetaxel aStratified HR. bStratified HR for ITT and unstratified HR for PD-L1 subgroups. Data cut-off May 8, 2015. Minimum follow-up = 13 months. AE = adverse event; HR = hazard ratio; IC = tumor-infiltrating immune cell; ITT = intent-to-treat; mos = months; OS = overall survival; PD-L1 = programmed death ligand 1; TC = tumor cell. Vansteenkiste J et al. Oral presentation at ECC 2015. 14LBA. 29 Summary: Monotherapy in 2L PD-L1–Unselected NSCLC Overall Survival Progression-Free Survival CheckMate KEYNOTE-010 POPLAR SQ: 017 NSQ: 057 2 mg/kg 10 mg/kg SQ=34% 14 12,2 SQ=22% NSQ=70% SQ=23% NSQ=71% CheckMate KEYNOTE-010 POPLAR SQ: 017 NSQ: 057 2 mg/kg 10 mg/kg SQ=34% NSQ=66% SQ=22% NSQ=70% 12,6 SQ=23% NSQ=71% NSQ=66% Time (mos) 12 10 9,2 8 6 3,5 4 2 2,7 2,3 NA NA NA NA 0 Safety: Grade 3–4 Treatment-Related Adverse Events CheckMate 0171-2 Ph III 2L SQ CheckMate 0573,4 Ph III 2/3L NSQ KEYNOTE-0105 Ph II/III PD-L1+ 2L+ POPLAR6 Ph II 2/3L Nivo 8% vs doc 56% Nivo 10% vs doc 54% Pembro 16% vs doc 35%a Atezo 11% vs doc 39% Cross-study comparison is not intended. aGrade 3–5 AEs for pembrolizumab (10 mg/kg) and docetaxel treatment arms. Atezo = atezolizumab; doc = docetaxel; mos = months; NA = not available; Nivo = nivolumab; NSCLC = non-small cell lung cancer; NSQ = non-squamous; PD-L1 = programmed death ligand 1; Pembro = pembrolizumab; Ph = phase; SQ = squamous. 1. Brahmer J et al. New Engl J Med. 2015;373:123–135. 2. Reckamp K et al. WCLC 2015. 3. Borghaei H et al. N Engl J Med. 2015;373(17):1627-1639. 4. Horn et al. ECC 2015. 3010. 5. Herbst R et al. Oral presentation at ESMO Asia 2015. 6. Vansteenkiste J et al. Presented at ECC 2015. 14LBA. 30 Summary: Monotherapy in 2L PD-L1+ (≥1%) NSCLC Overall Survival Progression-Free Survival Time (mos) CheckMate KEYNOTE-010 POPLAR SQ: 017 NSQ: 057 2 mg/kg 10 mg/kg SQ=34% 20 18 16 14 12 10 8 6 4 2 0 17,7 SQ=22% NSQ=70% SQ=23% NSQ=71% CheckMate KEYNOTE-010 POPLAR SQ: 017 NSQ: 057 2 mg/kg 10 mg/kg SQ=34% NSQ=66% SQ=22% NSQ=70% SQ=23% NSQ=71% NSQ=66% 15,5 12,7 10,4 9,3 3,3 4,2 3,9 4 2,8 Safety: Grade 3–4 Treatment-Related Adverse Events CheckMate 0171-2 Ph III 2L SQ CheckMate 0573,4 Ph III 2/3L NSQ KEYNOTE-0105 Ph II/III PD-L1+ 2L+ POPLAR6 Ph II 2/3L Nivo 8% vs doc 56% Nivo 10% vs doc 54% Pembro 16% vs doc 35%a Atezo 11% vs doc 39% Cross-study comparison is not intended. aGrade 3–5 AEs for pembrolizumab (10 mg/kg) and docetaxel treatment arms. Atezo = atezolizumab; doc = docetaxel; mos = months; Nivo = nivolumab; NSCLC = non-small cell lung cancer; NSQ = non-squamous; PD-L1 = programmed death ligand 1; Pembro = pembrolizumab; Ph = phase; SQ = squamous. 1. Brahmer J, et al. New Engl J Med. 2015;373:123–135. 2. Reckamp K et al. WCLC 2015. 3. Borghaei H et al. N Engl J Med. 2015;373(17):1627-1639. 4. Horn et al. ECC 2015. 3010. 5. Herbst R et al. Oral presentation at ESMO Asia 2015. 6. Vansteenkiste J et al. Presented at ECC 2015. 14LBA. 31 FIR and BIRCH: Efficacy and Safety of Atezolizumab in 1L NSCLC Phase II Studies of Atezolizumab Monotherapy in 1L Advanced/Metastatic NSCLC BIRCH1 Efficacy ORR, % (95% CI) mPFS, mos (95% CI) 6-Month PFS Rate, % mOS, mos (95% CI) 6-Month OS Rate, % Safety Treatment-related AEs (any grade), % Grade 3–4, % Discontinuation, % Immune-related AEs (any grade), % FIR2 TC2/3 or IC2/3 (n=139) TC3 or IC3 (n=65) TC2/3 or IC2/3 (n=31) TC3 or IC3 (n=7) 19 5.5 (3.0, 6.9) 46 14.0 (14.0, NE) 82 26 5.5 (2.7, 8.3) 48 NE (10.4, NE) 79 26 (12, 45) 4.5 (0.9, 11.0+) 34 NR 80 29 (4, 71) 5.4 (3.3, 8.1+) 29 NR 86 57 74 9 6 20 6 6 NA AE = adverse event; IC = tumor-infiltrating immune cell; mOS = median overall survival; mPFS = median progression-free survival; NA = not available; NE = not evaluable; NR = not reached; NSCLC = non-small cell lung cancer; ORR = objective response rate; TC = tumor cell. 1. Besse B et al. Oral presentation at ESMO 2015. 16LBA. 2. Spigel DR et al. Poster presentation at ASCO 2015. 8028. 32 Summary: Monotherapy in 1L PD-L1–Unselected NSCLC Objective Response Rate CM 012 25 BIRCH FIR CM 012 25 27 23 KN-001 BIRCH FIR NA NA 22,6 20 mOS, mos Response Rate, % 30 KN-001 Median Overall Survival 20 15 10 15 10 5 5 NA 0 NRa NA 0 0 0 Safety: Grade 3–4 Treatment-Related Adverse Events CheckMate 0121 Ph I 1L KEYNOTE-0012 Ph 1 1L BIRCH3 Ph II 1L FIR4 Ph II 1L Nivolumab 19% Pembrolizumab 11% Atezolizumab 9% Atezolizumab 6% Cross-study comparison is not intended. aMedian follow up 14.4 months. mos = months; mOS = median overall survival; NA = not available; NR = not reached; NSCLC = non-small cell lung cancer; PD-L1 = programmed death ligand 1; Ph = phase. 1. Gettinger SN et al. Poster presentation at ECC 2015. 3094. 2. Rizvi NA, et al. Poster presentation at ASCO 2015. 8026. 3. Besse B et al. Oral presentation at ESMO 2015. 16LBA. 4. Spigel DR et al. Poster presentation at ASCO 2015. 8028. 33 Summary: I-O Monotherapy in 1L PD-L1+ (≥50%) NSCLC 55 50 45 40 35 30 25 20 15 10 5 0 CM 012 KN-001 50 52 BIRCH Median Overall Survival FIR CM 012 KN-001 BIRCH FIR NEb NRc 10 26 29 mOS, mos Response Rate, % Objective Response Rate 5 NA NRa 0 Safety: Grade 3–4 Treatment-Related Adverse Events CheckMate 0121 Ph I 1L KEYNOTE-0012 Ph 1 1L BIRCH3 Ph II 1L FIR4 Ph II 1L Nivolumab 19% Pembrolizumab 11% Atezolizumab 9% Atezolizumab 6% Cross-study comparison is not intended. aMedian follow-up 14.4 months. bMedian follow-up 8.8 months. cMinimum follow-up 6 months. dBIRCH/FIR TC3/IC3 defined as PD-L1 expression ≥50% on tumor cells and ≥10% on immune cells. mos = months; mOS = median overall survival; NA = not available; NE = not evaluable; NR = not reached; NSCLC = non-small cell lung cancer; PD-L1 = programmed death ligand 1; Ph = phase. 1. Gettinger SN et al. Poster presentation at ECC 2015. 3094. 2. Rizvi NA, et al. Poster presentation at ASCO 2015. 8026. 3. Besse B et al. Oral presentation at ESMO 2015. 16LBA. 4. Spigel DR et al. Poster presentation at ASCO 2015. 8028. 34 CheckMate 057: OS by PD-L1 Expression Median OS by PD-L1 Expression Level, Mos Nivolumab Docetaxel Unstratified HR (95% CI) Interaction P Value ≥ 1% < 1% 17.2 10.4 9.0 10.1 0.59 (0.43-0.82) 0.90 (0.66-1.24) .0646 ≥ 5% < 5% 18.2 9.7 8.1 10.1 0.43 (0.30-0.63) 1.01 (0.77-1.34) .0004 ≥ 10% < 10% 19.4 9.9 8.0 10.3 0.40 (0.26-0.59) 1.00 (0.76-1.31) .0002 Similar interaction results based on baseline PD-L1 expression observed for PFS and ORR Paz-Ares L, et al. ASCO 2015. Abstract LBA109. Reprinted with permission. POPLAR: Efficacy of Atezolizumab Increased With Higher PD-L1 Expression Atezolizumab (n = 144) Docetaxel (n = 143) HR (95% CI) P Value ITT population (N = 287) 11.4 9.5 0.77 (0.55-1.06) .11 Subgroups based on PD-L1 expression* TC0 and IC0 (n = 92) TC1/2/3 or IC1/2/3 (n = 195) TC2/3 or IC2/3 (n = 105) TC3 or IC3 (n = 47) 9.7 NR 13.0 NR 9.7 9.1 7.4 11.1 1.12 (0.64-1.93) 0.63 (0.42-0.94) 0.56 (0.33-0.94) 0.46 (0.19-1.09) .70 .024 .026 .070 Interim Median OS Outcomes *PD-L1 expression measured by SP142 IHC assay (low expression, TC0/IC0; high expression, TC3/IC3). PFS and ORR: similar trends in outcome for atezolizumab vs docetaxel based on PD-L1 expression ‒ ‒ ‒ ‒ Median PFS in ITT population: 2.8 vs 3.4 mos (HR: 0.98) Median PFS in TC3 or IC3 population: 7.8 vs 3.9 mos (HR: 0.57) ORR in ITT population: 15% vs 15% ORR in TC3 or IC3 population: 38% vs 13% Interim data based on minimum of 10 mos of follow-up Spira AI, et al. ASCO 2015. Abstract 8010. Impact of Baseline Serum Cytokines on Survival in Patients With Advanced Squamous Non-Small Cell Lung Cancer Treated With Nivolumab or Docetaxel: Exploratory Analyses From CheckMate 063 and CheckMate 017 Benedetto Farsaci,1 William J Geese,1 Kaushal Desai,1 Chelsea Jin,1 Scott J. Antonia,2 Hervé Lena,3 Leora Horn,4 David Planchard,5 Karen Reckamp,6 Thomas Stinchcombe,7 Scott Gettinger,8 Hossein Borghaei,9 Matthew D. Hellmann,10 Christopher Harbison,1 Dong Xu,1 Anne Blackwood-Chirchir,11 Naiyer Rizvi10 1Bristol-Myers Squibb, Princeton, NJ, USA; 2H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA; Hospitalier Universitaire de Rennes, Rennes, France; 4Vanderbilt University Medical Center, Nashville, TN, USA; 5Gustave Roussy, Villejuif, France; 6City of Hope Comprehensive Cancer Center, Duarte, CA, USA; 7University of North Carolina School of Medicine, Chapel Hill, NC, USA; 8Yale Cancer Center, New Haven, CT, USA; 9Fox Chase Cancer Center, Philadelphia, PA, USA; 10Memorial Sloan Kettering Cancer Center, New York, NY, USA; 11Innovators BioPharma Consulting, LLC, Woodside, CA, USA 3Centre CYTOKINE SELECTION PATIENT POPULATION CYTOKINE PROFILING ANALYSES IN PATIENTS WITH SQ NSCLC: METHODS Nivolumab-treated patients n = 222 (-063/-017)a Docetaxel-treated patients n = 118 (-017)a Training set: 60% of patients Validation set: 40% of patients 1) Analysis of levels of 28 evaluable serum cytokines prior to therapy using a custom HumanMAP quantitative multiplexed immunoassay (Myriad RBM, Austin, TX) 2) Identification of cytokines associated with OSb in nivolumab-treated pts in the training set (60%) via stepwise variable selection in a Cox model EFFECT ON OS 3) Time-varying ROC in the validation set Calculation of the cytokine score (SQ-cytoscore) in both nivolumab- and docetaxeltreated patients and impact on OS as measured by Kaplan-Meier analysis aRepresents the proportion of patients with evaluable baseline cytokine levels (nivolumab [n/N]: 222/252, 88% and docetaxel [n/N]: 118/137, 86%). bBased on 18-month data from CheckMate 063 (June 2015 database lock) and CheckMate 017 (August 2015 database lock). ROC = receiver operating characteristic 38 EUROPEAN LUNG CANCER CONFERENCE 2016 CYTOKINES ASSOCIATED WITH OS IN PATIENTS WITH SQ NSCLC Cytokines associated with OS identified via stepwise variable selection in Cox model using AIC: IL-8 IP-10 VWF IL-18 MICA MIP1B CRP ICAM1 IL-6 IL-1RA FRTN MMP3 MIG VDBP Some key cytokines, such as IFNg and TNF, were not evaluable, so were not considered in the cytokine selection Model Evaluation of the Selected Cytokines in the Validation Set Month 9 Month 12 Month 15 Month 18 1.0 1.0 0.8 0.8 0.8 0.8 0.8 0.6 0.4 0.2 0.6 0.4 0.2 0 0.2 0.4 0.6 0.8 1.0 1- Specificity AUC = 0.847 0.4 0.2 0 0 0.6 0.2 0.4 0.6 0.8 1.0 1- Specificity AUC = 0.846 0.6 0.4 0.2 0 0 Sensitivity 1.0 Sensitivity 1.0 Sensitivity 1.0 Sensitivity Sensitivity Month 6 0.2 0.4 0.6 0.8 1.0 1- Specificity AUC = 0.817 0.4 0.2 0 0 0.6 0 0 0.2 0.4 0.6 0.8 1.0 1- Specificity AUC = 0.846 0 0.2 0.4 0.6 0.8 1.0 1- Specificity AUC = 0.858 AIC = Akaike information criterion. AUC = area under the curve. 39 EUROPEAN LUNG CANCER CONFERENCE 2016 CALCULO DEL CITOSCORE SQ Representative cytokine positively associated with OS Calculation of the cytokine score (SQ-cytoscore) in the entire dataset 700 Scorepoint 1 Scorepoint 0 Scorepoint 2 1. Tertile bin distribution of each cytokine Baseline Level 600 500 400 300 200 100 337 325 313 301 289 277 265 253 241 229 217 205 193 181 169 157 145 133 121 97 109 85 73 61 49 37 25 1 2. 0, 1, or 2 points assigned to each cytokine by bin membership 13 0 Patients Representative cytokine negatively associated with OS 1200 Scorepoint 0 1000 800 600 400 200 339 326 313 300 287 274 261 248 235 222 209 196 183 170 157 144 131 118 105 92 79 66 53 40 27 1 0 14 Baseline Level 4. Kaplan-Meier OS curves using median SQ-cytoscore Scorepoint 1 Scorepoint 2 3. Patient cytokine score: sum of points Patients 40 MEDIAN OS WAS LONGER WITH NIVOLUMAB VS DOCETAXEL IN BOTH SQ-CYTOSCORE GROUPS Patients with low SQ-cytoscore Patients with high SQ-cytoscore 100 100 SQ-cytoscore: Nivolumab Docetaxel 80 80 mOS: 9.1 months 40 OS (%) mOS: 15.6 months 60 OS (%) SQ-cytoscore: Nivolumab Docetaxel Δ 6.5 months 20 mOS: 5.3 months 60 Δ 0.4 months 40 P=0.0009 HR: 0.51; 95% CI: 0.37-0.71 mOS: 4.9 months 20 P=0.0051 HR: 0.63; 95% CI: 0.45-0.88 0 0 0 5 10 15 20 25 30 0 5 10 Time (Months) Number of Patients at Risk Nivolumab 102 62 Docetaxel 70 30 41 15 20 25 30 Time (Months) 33 11 0 1 Number of Patients at Risk Nivolumab 120 38 Docetaxel 48 4 24 0 EUROPEAN LUNG CANCER CONFERENCE 2016 1 -- PATIENTS WITH HIGH SQ-CYTOSCORE SHOWED LONGER MEDIAN OS Docetaxel-treated patients Nivolumab-treated patients 100 100 SQ-cytoscore: High Low 80 60 mOS: Δ 10.3 months 5.3 months 40 OS (%) 80 OS (%) SQ-cytoscore: High Low mOS: 15.6 months mOS: 9.1 months 60 40 mOS: 4.9 months 20 20 Δ 4.2 months P<0.0001 HR: 0.39; 95% CI: 0.27-0.56 P<0.0001 HR: 0.48; 95% CI: 0.36-0.64 0 0 0 5 10 15 20 25 30 0 5 10 Time (Months) Number of Patients at Risk High 102 62 Low 120 38 15 20 25 33 24 0 0 Number of Patients at Risk High 70 30 Low 48 4 11 0 mOS = median overall survival 42 30 Time (Months) EUROPEAN LUNG CANCER CONFERENCE 2016 1 -- CheckMate 063 and 017: Overall Survival CheckMate 0631 CheckMate 0172 100 100 90 90 80 80 70 70 60 60 50 OS (%) OS (%) Nivolumab 1-year OS rate = 39% 40 18-month OS rate = 28% 2-year OS rate = 22% 30 20 20 10 10 0 0 0 3 6 9 12 15 18 21 24 27 30 1-year OS rate = 42% 50 40 18-month OS rate = 27% 30 Docetaxel 33 1-year OS rate = 24% 0 3 6 9 12 Time (Months) 15 18 21 24 27 30 33 Time (Months) Nivolumabb Nivolumaba 117 18-month OS rate = 13% 93 69 54 45 38 30 27 24 17 5 0 135 113 86 69 57 51 37 25 14 6 0 0 104 69 46 33 22 17 11 7 3 1 0 Docetaxelb 137 aDecember 2015 database lock. bAugust 2015 database lock. Symbols represent censored observations. 1Lena H, et al. Presented at the ELCC 2016 European Lung Cancer Conference, April 13–16, 2016; Geneva, Switzerland. Oral 389. K, et al. Presented at the 16th World Conference on Lung Cancer; September 6–9, 2015; Denver, Colorado, USA. Oral 02.01. 2Reckamp 43 High SQ-cytoscore Was Associated With Improved OS in Nivolumab- and Docetaxel-treated Patients Nivolumab-treated patients Docetaxel-treated patients 100 100 SQ-cytoscore: High Low 80 SQ-cytoscore: High Low 80 mOS: 9.1 months OS (%) 60 OS (%) 60 mOS: 15.6 months mOS: Δ 10.3 months 5.3 months 40 40 P < 0.0001 HR: 0.48 95% CI: 0.36, 0.64 20 mOS: 4.9 months Δ 4.2 months P < 0.0001 HR: 0.39 95% CI: 0.27, 0.56 20 0 0 0 5 10 15 20 25 30 0 5 10 Time (Months) 15 20 25 30 Time (Months) Number of Patients at Risk Number of Patients at Risk High 102 62 33 0 High 70 30 11 1 Low 120 38 24 0 Low 48 4 0 -- Based on 18-month OS data from CheckMate 063 (June 2015 database lock) and CheckMate 017 (August 2015 database lock). mOS = median overall survival 44 SQ-cytoscore May Be Prognostic but Not Predictive Treatment/SQ-cytoscore Nivolumab, high SQ-cytoscore Nivolumab, low SQ-cytoscore Docetaxel, high SQ-cytoscore Docetaxel, low SQ-cytoscore 100 80 OS (%) 60 mOS: 15.6 months 40 mOS: 9.1 months mOS: 5.3 months 20 0 5 10 HR Treatment (Nivolumab vs Docetaxel) 0.60 0.45 0.72 <0.00 01 SQcytoscore (High vs Low) 0.44 0.35 0.56 <0.00 01 Treatment/ SQcytoscore interaction mOS: 4.9 months 0 Factor 15 20 25 1.23 95% CI Chi sq = 0.7799 (df = 1) P 0.377 2 30 Time (Months) • OS was consistently longer with nivolumab vs docetaxel in both high and low SQ-cytoscore subgroups • There was no interaction between SQ-cytoscore and treatment • In separate analyses, no interaction was observed between SQ-cytoscore and ECOG PS (P = 0.72) 45 Summary of Exploratory Cytokine Analyses • In patients with advanced SQ NSCLC pooled from CheckMate 063 and CheckMate 017 – SQ-cytoscore, derived from select serum cytokines at baseline, appears to be associated with prognosis, independent of ECOG PS and PD-L1 expression – SQ-cytoscore is not associated with treatment; therefore, it is not predictive – Nivolumab was consistently associated with longer OS vs docetaxel in both high and low SQ-cytoscore subgroups • This study was hypothesis-generating; prospective validation of these preliminary findings is required 46 CONCLUSIONS Nivolumab continues to demonstrate clinically meaningful efficacy in previously treated patients with advanced SQ NSCLC in CheckMate 063 Two-year OS: 22% (95% CI: 15, 30) mOS: 8.1 months (95% CI: 6.1, 10.9) The safety profile of nivolumab is manageable and consistent with previous studies SQ-cytoscore, derived from select serum cytokines at baseline, appears to be associated with better prognosis in patients with advanced SQ NSCLC These preliminary findings require prospective validation in future studies 47 EUROPEAN LUNG CANCER CONFERENCE 2016 Fases III de inhibidores de PD-1/PD-L1 ongoing: Monoterapia en 1L NSCLC etapas avanzadas Objetivo Principal Nivolumab Nivolumab CheckMate 227 Etapa IV o recidivado NSCLC N=1980 Nivolumab + ipilimumab Nivolumab + QT basada en platino OS, PFS Anti-PD-1 QT a base de platino CheckMate 026 Pembrolizumab KEYNOTE-024 KEYNOTE-042 Durvalumab Anti-PD-L1 MYSTIC Atezolizumab IMpower 110 IMpower 111 Avelumab JAVELIN Lung 100 Etapa IV o recidivado PD-L1+ NSCLC N=535 PD-L1 strong NSCLC N=300 PD-L1+ NSCLC N=1240 Nivolumab QT a eleccion del Investigador PFS Pembrolizumab QT a base de Platino PFS Pembrolizumab OS QT standard Durvalumab NSCLC avanzado N=675 Durvalumab + tremelimumab OS, PFS QT porSOC Etapa IV No escamosos PD-L1+ NSCLC N=400 Etapa IV escamosos PD-L1+ NSCLC N=400 Stage IV or recurrent PD-L1+ NSCLC N=420 Atezolizumab Cis o carbo + pemetrexed PFS Atezolizumab PFS Gem + cisplatino o carboplatino Avelumab PFS Platinum-based chemotherapy SOC = standard of care. ClinicalTrials.gov. http://www.clinicaltrials.gov/. Accessed March 2016. 48 Combinaciones Seran el camino? Querriamos estar Survival Survival Aqui estamos ? Time Time Control Immune checkpoint blockade Targeted therapies Combinations/sequencing Hypothetical slide illustrating a scientific concept that is beyond data available so far. These charts are not intended to predict what may actually be observed in clinical studies. Adapted from Sharma P, Allison JP. Cell. 2015;161(2):205-214. LOCAL APPROVAL MAY BE REQUIRED BEFORE EXTERNAL USE. REFER TO LOCAL GUIDELINES 49 Durvalumab + Tremelimumab: Phase Ib Study Design1,2 I-O Dose escalation for 12 months N=102 Key Inclusion Criteria T1 Cohort Durvalumab 3–20 mg/kg q4/2wa Tremelimumab 1 mg/kg q4w x6 then q12w x3 • Immunotherapy-naïve • ≥1 line(s) of prior therapy • Locally advanced or metastatic NSCLC • ECOG PS 0–1 • Primary objective: T3 Cohort Durvalumab 10–20 mg/kg q4/2wa Tremelimumab 3 mg/kg q4w x6 then q12w x3 T10 Cohort Durvalumab 15 mg/kg q4w Tremelimumab 10 mg/kg q4w x6 then q12w x3 – Safety, DLT/MTD • Secondary objective: – ORR, PK, disease control at 24 weeks, immunogenicity DLT = dose-limiting toxicity; ECOG PS = Eastern Cooperative Oncology Group performance status; IHC = immunohistochemistry; MTD = maximum tolerated dose; NSCLC = non-small cell lung cancer; ORR = objective response rate; PD-L1 = programmed death ligand 1; PK = pharmacokinetics; q#w = every # weeks. aDurvalumab dose escalation = 3, 10, 15, or 20 mg/kg administered q4w or 10 mg/kg administered q2w. 1. Antonia S et al. Lancet Oncol. 2016;17(3):299-308. 2. Rizvi N et al. Oral presentation at ESMO Asia 2015. 4180. LOCAL APPROVAL MAY BE REQUIRED BEFORE EXTERNAL USE. REFER TO LOCAL GUIDELINES 50 Durvalumab + Tremelimumab: Objective Response Rate and Safety1,2 I-O D10–20 q4/2w T1 D10–20 q4/2w T3 D15 q4w T10 D10 q2w monotherapy n/N (%) n/N (%) n/N (%) n/N (%) 6/26 (23) 5/25 (20) 0/9 (0) 32/200 (16) ≥25% 2/9 (22) 2/5 (40) 0/4 (0) 23/84 (27) <25% 4/14 (29) 2/17 (12) 0/4 (0) 5/92 (5) 0% 4/10 (40) 1/10 (10) 0/3 (0) 1/33 (3) PD-L1 status All patients PD-L1 expression • Most frequent treatment-related AEs: diarrhea (32%), fatigue (24%), pruritus (21%) • Treatment-related AEs leading to discontinuation: 28% • Most frequent treatment-related Grade 3–4 AEs: diarrhea (11%), colitis (9%), increased lipase (8%) • Phase III dose identified: durvalumab 20 mg/kg plus tremelimumab 1 mg/kg q4w AEs = adverse events; D = durvalumab; NSCLC = non-small cell lung cancer; PD-L1 = programmed death ligand 1; q#w = every # weeks; T = tremelimumab. 1. Antonia S et al. Lancet Oncol. 2016;17(3):299-308. 2. Rizvi N et al. Oral presentation at ESMO Asia 2015. 4180. LOCAL APPROVAL MAY BE REQUIRED BEFORE EXTERNAL USE. REFER TO LOCAL GUIDELINES 51 CheckMate 032: Nivolumab ± Ipilimumab Phase I/II Study in ≥2L Advanced/Metastatic SCLC1,2 I-O Nivo 3 mg/kg IV q2w (n = 80)a N=183 Nivo 1 mg/kg + Ipi 1 mg/kg IV q3w for 4 cycles (n = 3)b Key Inclusion Criteria • Progressive disease after ≥1 prior line of therapy, including Platinum-based regimen • Measurable disease • ECOG PS ≤1 R 1:1 Nivolumab 3 mg/kg IV q2w Nivo 1 mg/kg + Ipi 3 mg/kg IV q3w for 4 cycles (n = 47)c • Primary objective: – ORR per RECIST v1.1 • Secondary objective: – Safety • Exploratory objectives: – PFS, OS, biomarker analysis Nivo 3 mg/kg + Ipi 1 mg/kg IV q3w for 4 cycles (n = 53)d aNivolumab 3: 15 patients in this arm had a follow-up of <6 weeks; follow-up defined as day of first dose to day of database lock; bNivolumab 1 + ipilimumab 1: minimum follow-up of 546 days; cNivolumab 1 + ipilimumab 3: minimum follow-up of 120 days; dNivolumab 3 + ipilimumab 1: minimum follow-up of 71 days. ECOG PS = Eastern-Cooperative Oncology Group Performance Status; Ipi = ipilimumab; Nivo = nivolumab; ORR = objective response rate; OS = overall survival; PD-L1 = programmed death ligand 1; PFS = progression-free survival; q2w = every 2 weeks; q3w = every 3 weeks; R = randomized; SCLC = small cell lung cancer. 1. Calvo E et al. Poster presentation at ECC 2015. 3098. 2. Clinicaltrials.gov. NCT01928394. LOCAL APPROVAL MAY BE REQUIRED BEFORE EXTERNAL USE. REFER TO LOCAL GUIDELINES 52 CheckMate 032: Nivolumab ± Ipilimumab Changes in Tumor Burden by Platinum Sensitivity Percent Change From Baseline Nivolumab 3 mg/kg Nivolumab 1 mg/kg + Ipilimumab 3 mg/kg 100 100 75 75 50 50 25 25 0 0 -25 -25 -50 -50 -75 -75 -100 -100 0 6 12 18 24 30 I-O 36 42 48 Platinum-sensitive Platinum-resistant/refractory Unknown First occurrence of new lesion Confirmed partial or complete response Patients still on treatment % change truncated 100% 0 Time (Weeks) 6 12 18 24 30 36 42 48 Time (Weeks) • Tumor responses occurred in patients with both platinum-sensitive and platinum-resistant disease Only patients with target lesion at baseline and ≥1 on-treatment tumor assessment were included (nivolumab 3, n = 18; nivolumab 1 + ipilimumab 3, n = 22). Calvo E et al. Poster presented at ESMO 2015. 3098. LOCAL APPROVAL MAY BE REQUIRED BEFORE EXTERNAL USE. REFER TO LOCAL GUIDELINES 53 KEYNOTE-028: Pembrolizumab in Advanced SCLC Multicohort, open-label phase Ib trial SCLC Cohort Pts with PD-L1– positive SCLC and failure or inability to receive standard therapy; ECOG PS 0-1; ≥ 1 measurable lesion; no autoimmune disease or interstitial lung disease (n = 20) CR, PR, or SD Pembrolizumab 10 mg/kg IV q2w for 24 mos or until progression or intolerable toxicity Pembrolizumab 10 mg/kg IV q2w Discontinue treatment Progressive disease or unacceptable toxicity Primary Endpoint: ORR (per RECIST v. 1.1), safety Secondary Endpoints: PFS, OS, duration of response PD-L1 expression assessed by centrally reviewed IHC (22C3 antibody) Ott PA, et al. ASCO 2015. Abstract 7502. KEYNOTE-028: Tumor Response Pembrolizumab therapy associated with partial response in 7 pts – 5/7 responders with tumor reduction > 50% in size – 6/7 responders with reduction in tumor size by Wk 8 Change From Baseline in Tumor Size (RECIST v1.1, Investigator Review) Response n % (95% CI) ORR CR PR 0 7 0 35 (15-59) Stable disease 1 5 (0-25) Progressive disease 9 45 (23-69) No assessment 3 15 (3-38) Change From Baseline, % Outcomes 100 80 60 40 20 0 -20 -40 -60 -80 -100 Ott PA, et al. ASCO 2015. Abstract 7502. Reprinted with Permission. CheckMate 032: Nivolumab ± Ipilimumab in Previously Treated SCLC 4 cycles Nivolumab 3 mg/kg IV q2w (n = 40) Pts with recurrent SCLC + prior platinum-based treatment (N = 128) Endpoints - Primary: ORR - Secondary: safety - Exploratory: PFS, OS, biomarker analysis Nivolumab 1 mg/kg + Ipilimumab 1 mg/kg IV q3w (n = 3) Nivolumab 3 mg/kg IV q2w Nivolumab 1 mg/kg + Ipilimumab 3 mg/kg IV q3w (n = 47) Nivolumab 3 mg/kg + Ipilimumab 1 mg/kg IV q3w (n = 38) Antonia SJ, et al. ASCO 2015. Abstract 7503. Analyzed separately CheckMate 032: Efficacy Outcomes Nivolumab (n = 40) Nivolumab + Ipilimumab (n = 46) ORR, % 18 17* CR, % 0 2.2 PR, % 18 15 SD, % 20 37 PD, % 53 37 Median time to response, mo 1.6 2.2 NR (4.1 to > 11) 6.9 (1.5 to > 11.1) 4.4 8.2 Response Median DoR, mos (range) Median OS, mos *7 additional PRs after database lock increased ORR to 32.6% in combination arm. Antonia SJ, et al. ASCO 2015. Abstract 7503. Futuro en CPNCP Potential of I-O Therapies: Select Phase III Combo Trials in Advanced NSCLC I-O Anti-PD-L1 Anti-PD-1 Objetivo Principal Nivolumab Nivolumab CheckMate 227 NSCLC Etapa IV o recidivado virgen de tto. N=1980 Nivolumab + ipilimumab Nivolumab + QT a base de platino OS, PFS QT a base de Platino Durvalumab MYSTIC NEPTUNE NSCLC Etapa IV virgen de tratamiento N=780 NSCLC EtapaIV virgen de tto. N=800 Durvalumab Durvalumab + tremelimumab PFS QT SOC Durvalumab + tremelimumab OS SOC chemotherapy National Institutes of Health. ClinicalTrials.gov. http://www.clinicaltrials.gov/. Accessed March 2016. LOCAL APPROVAL MAY BE REQUIRED BEFORE EXTERNAL USE. REFER TO LOCAL GUIDELINES 59 Response to PD-1/PD-L1 Inhibitors/Chemotherapy Combination Therapy in NSCLC: All Patients CheckMate 012 100 10 mg/kg KEYNOTE-021 5 mg/kg 2 mg/kg ORR (%) 10 mg/kg 15 mg/kg 77 75 80 60 40 Atezolizumab 47 47 50 43 38 33 56 42 17 20 0 Safety: Grade 3–4 Treatment-Related Adverse Events CheckMate 012, Ph I 1L1 KEYNOTE-021, Ph I/II 1L2 Atezolizumab + Chemo, Ph Ib 1L+3,4 Nivolumab 45% Pembrolizumab 25%–42% Atezolizumab 69% Cross-study comparison is not intended. aNon-squamous NSCLC only. Chemo = chemotherapy; Carb = carboplatin; Cis = objective response rate; Pac = paclitaxel; PD-1 1. Antonia SJ et al. Oral presentation at CMSTO 3. Giaccone G et al. Presentation at ESMO 2015. cisplatin; Gem = gemcitabine; Nab=pac = nab-paclitaxel; NSCLC = non-small cell lung cancer; ORR = = programmed death receptor-1; PD-L1 = programmed death ligand 1; Pem = pemetrexed; Ph = phase. 2014. 2. Papadimitrakopoulou V et al. Poster presentation at ASCO 2015. 8031. 513. 4. Camidge DR et al. Oral presentation at WCLC 2015. 2208. LOCAL APPROVAL MAY BE REQUIRED BEFORE EXTERNAL USE. REFER TO LOCAL GUIDELINES 60 Response to PD-1/PD-L1 Inhibitors/Chemotherapy Combination Therapy in NSCLC: PD-L1–Selected CheckMate 012 KEYNOTE-021 75 ORR (%) 80 60 Atezolizumab 53 46 41 40 40 20 NA 0 Safety: Grade 3–4 Treatment-Related Adverse Events CheckMate 012, Ph I 1L1 KEYNOTE-021, Ph I/II 1L2 Atezolizumab + Chemo, Ph Ib 1L+3,4 Nivolumab 45% Pembrolizumab 25–42% Atezolizumab 69% Cross-study comparison is not intended. Chemo = chemotherapy; IC = tumor-infiltrating immune cell; NA = not available; NSCLC = non-small cell lung cancer; ORR = objective response rate; PD-1 = programmed death receptor-1; PD-L1 = programmed death ligand 1; Ph = phase; TC = tumor cell. 1. Antonia SJ et al. Oral presentation at CMSTO 2014. 2. Papadimitrakopoulou V et al. Poster presentation at ASCO 2015. 8031. 3. Giaccone G et al. Presentation at ESMO 2015. 513. 4. Camidge DR et al. Oral presentation at WCLC 2015. 2208. LOCAL APPROVAL MAY BE REQUIRED BEFORE EXTERNAL USE. REFER TO LOCAL GUIDELINES 61 Potential of I-O Therapies: Select Phase III I-O/Chemo Combo Trials in NSCLC I-O Primary Endpoints Anti-PD-1 Nivolumab Nivolumab CheckMate 227 Nivolumab + ipilimumab Nivolumab + platinum-based chemotherapy OS, PFS Platinum-based chemotherapy Pembrolizumab KEYNOTE-189 Atezolizumab IMpower 130 Anti-PD-L1 Treatment-naïve Stage IV or recurrent NSCLC N=1980 IMpower 131 IMpower 150 Treatment-naïve Stage IV non-squamous NSCLC N=570 Pembrolizumab + pemetrexed/platinum Treatment naïve Stage IV non-squamous NSCLC N=550 Atezolizumab + carboplatin + nab-paclitaxel Treatment naïve Stage IV squamous NSCLC N=1200 Atezolizumab + carboplatin + nab-paclitaxel Treatment naïve Stage IV non-squamous NSCLC N=1200 PFS Pemetrexed/platinum Carboplatin + nab-paclitaxel Atezolizumab + carboplatin + paclitaxel PFS PFS Carboplatin + nab-paclitaxel Atezolizumab + carboplatin + paclitaxel Atezolizumab + bevacizumab + paclitaxel + carboplatin PFS Bevacizumab + paclitaxel + carboplatin National Institutes of Health. ClinicalTrials.gov. http://www.clinicaltrials.gov/. Accessed March 2016. LOCAL APPROVAL MAY BE REQUIRED BEFORE EXTERNAL USE. REFER TO LOCAL GUIDELINES 62 Durvalumab + Gefitinib: Phase I Study in NSCLC I-O Efficacy Data Safety Data Durvalumab + gefitinib Durvalumab + gefitinib Patient Response, n/N Arm 1 Arm 2 Partial Response 5/6 3/5 Stable Disease ≥ 8 weeks 1/6 2/5 Arm 1, n=7 Arm 2, n=8 Total, N=15 7 6 13 Any AE, # Events Most Common Adverse Events, # Events Rash 5 2 7 Diarrhea 3 3 6 ALT increased 3 2 5 Dry Skin 2 3 5 Pruritus 1 3 4 AST increased 1 2 3 Nausea 2 1 3 AE = adverse event; ALT = alanine aminotransferase; AST = aspartate aminotransferase; NSCLC = non-small cell lung cancer. 1. Creelan et al. ASCO 2015. 3047. 2. Clinicaltrials.gov. NCT02143466. LOCAL APPROVAL MAY BE REQUIRED BEFORE EXTERNAL USE. REFER TO LOCAL GUIDELINES 63 TATTON: Durvalumab + Osimertinib Phase Ib Study in NSCLC Efficacy Data1 Patient Response, n/N Complete Response Partial Response I-O Safety Data1 Osimertinib + durvalumab 3 mg/kg q2w (n=13) Osimertinib + durvalumab 1/14 8/14 (4 confirmed) Osimertinib + durvalumab 10 mg/kg q2w (n=10) All-Causality Adverse Events, # Events Diarrhea Vomiting Anemia Constipation Cough Nausea 5 6 4 4 2 3 2 1 2 2 4 3 WBC count decreased 5 2 UTI 3 0 Dose-Limiting Toxicities, # Events 0 1 (neutropenia) • 8/23 patients (35%) had received ≥2 prior TKIs; 7/23 (30%) had received ≥2 prior chemotherapies1 • On October 9, 2015, TATTON (and CAURAL) were halted due to reports of interstitial lung disease2. Updates will be presented in an upcoming presentation at ELCC Only data for the osimertinib plus durvalumab arm are shown. q2w = every 2 weeks; q3w = every 3 weeks; TKI = tyrosine kinase inhibitors; UTI = urinary tract infection; WBC = white blood cell. 1. Oxnard GR et al. Poster presented at ASCO 2015. 2509. 2. Bloomberg Business. October 9, 2015. Accessed March 2016. LOCAL APPROVAL MAY BE REQUIRED BEFORE EXTERNAL USE. REFER TO LOCAL GUIDELINES 64 Potential of I-O Therapies: Select I-O/Targeted Therapy Trialsa in Advanced NSCLC I-O Primary Endpoints Nivolumab Anti-PD-1 CheckMate 370a NCT02393625 Pembrolizumab KEYNOTE-021a NCT02511184 Anti-PD-L1 Atezolizumab NCT02013219 NCT02630186 Advanced or Metastatic NSCLC (EGFR-mutant or ALK-positive) N=1953 ALK-positive NSCLC N=78 Advanced or Metastatic NSCLC N=308 ALK-positive NSCLC N=70 Advanced or Metastatic NSCLC (EGFR-mutant or ALK-positive) N=53 Advanced EGFR-mutant NSCLC N=93 Group D: Nivolumab + erlotinib PFS Group D: erlotinib Group E: Nivolumab + crizotinib AEs Nivolumab + ceritinib MTD, ORR Cohort E: Pembrolizumab + erlotinib RP2D Cohort F: Pembrolizumab + gefitinib Pembrolizumab + crizotinib DLTs Atezolizumab + alectinib DLTs Atezolizumab + erlotinib Atezolizumab + rociletinib AEs, PK, ORR a Only I-O/targeted therapy combination arms depicted. RP2D = recommended phase II dose. National Institutes of Health. ClinicalTrials.gov. http://www.clinicaltrials.gov/. Accessed March 2016. LOCAL APPROVAL MAY BE REQUIRED BEFORE EXTERNAL USE. REFER TO LOCAL GUIDELINES 65 The Role of Radiation in Cancer Immunotherapy Immune stimulatory signals RT CRT DCs Draining lymph node Activated DCs IFNβ DNA ATP HMGB-1 DC activation TGFβ LAP Cancer cells Dying cancer cells CTLs Naïve CD8+ CSF-1 MDSC Cross-priming Treg Immune suppressive signals ATP = adenosine triphosphate; CRT = calreticulin; CSF-1 = colony stimulating factor 1; CTL = cytotoxic CD8+ T cell; DC = dendritic cell; HMGB-1 = high-mobility group box-1; IFNβ = interferon β; LAP = leukocyte alkaline phosphatase; MDSC = myeloid-derived suppressor cell; RT = radiotherapy; TFGβ = transforming growth factor β; Treg = regulatory T cell. Adapted from Demaria S et al. JAMA Oncol. 2015;1(9):1325-1332. LOCAL APPROVAL MAY BE REQUIRED BEFORE EXTERNAL USE. REFER TO LOCAL GUIDELINES 66 I-O I-O/Radiotherapy Combination Studies I-O Agent Clinical Trials Nivolumab (anti-PD-1) Consolidation after concurrent and sequential chemo/RT (NICOLAS/NCT02434081) Post-chemotherapy/RT (vs obs) + RT ± ipilimumab for intracranial metastases from NSCLC (NCT02696993) + RT post 1L chemotherapy (NivoRAD) Pembrolizumab (anti-PD-1) + hypo-fractionated stereotactic RT (NCT02444741) + stereotactic body RT (NCT02492568; NCT02407171; NCT02608385) + hypo-fractionated RT (NCT02303990) + single fraction non-ablative RT (NCT02658097) + chemoRT (NCT02402920) Durvalumab (anti-PD-L1) Consolidation after concurrent chemoRT (PACIFIC/NCT02125461) + hypo-fractionated RT + tremelimumab (NCT02639026) Atezolizumab (anti-PD-L1) + stereotactic ablative RT (NCT02400814) + stereotactic body RT (NCT02599454) + hypo-fractionated image-guided RT (NCT02463994) + chemoRT (NCT02525757) Ipilimumab (anti-CTLA-4) + RT (NCT02221739) + stereotactic body RT (NCT02239900) Tremelimumab (anti-CTLA-4) + hypo-fractionated RT + durvalumab (NCT02639026) RT = radiotherapy. www.clinicaltrials.gov. Accessed March 2016. LOCAL APPROVAL MAY BE REQUIRED BEFORE EXTERNAL USE. REFER TO LOCAL GUIDELINES 67 Treatment Effect on Overall Survival by Age CheckMate 0171 (N=272) CheckMate 0572 (N=582) KEYNOTE-0103 (N=1034) Unstratified HR (95% CI) Age (years) <65 0.52 n=152 0.81 (0.35, 0.75) n=339 0.63 (0.62, 1.04) n=604 (0.50, 0.79) ≥65 0.76 n=429 (0.57, 1.02) ≥65 to <74 ≥75 0.56 n=91 0.63 (0.34, 0.91) (0.45, 0.89) 1.85 n=29 0.90 (0.76, 4.51) (0.43, 1.87) 0.25 0.5 1.0 Nivolumab 2.0 4.0 Docetaxel 0.25 0.5 n=200 n=43 1.0 Nivolumab 2.0 4.0 Docetaxel 0.25 0.5 1.0 2.0 4.0 Pembrolizumab Docetaxel • OS data for KEYNOTE-010 is pooled across 2 mg/kg q3w and 10 mg/kg q3w doses, in PD-L1–selected patients Cross-study comparison is not intended. HR = hazard ratio; OS = overall survival; q3w = every 3 weeks. 1. Brahmer J et al. N Engl J Med. 2015;373(2):123-135. Supplementary Appendix. 2. Borghaei H et al. N Engl J Med. 2015; 373(17):1627-1639. 3. Herbst RS et al. Lancet. 2015 pii: S0140-6736(15)01281-7 [Epub ahead of print]. LOCAL APPROVAL MAY BE REQUIRED BEFORE EXTERNAL USE. REFER TO LOCAL GUIDELINES 68 Treatment Effect on Overall Survival by Histology CheckMate 0171 (N=272) CheckMate 0572 (N=582) KEYNOTE-0103 (N=1034) POPLAR4 (N=287) Unstratified HR (95% CI) Histology Squamous 0.59 (0.44, 0.78) N=272 0.74 (0.50, 1.09) n=222 0.80 n=97 Non-squamous 0.75 (0.62, 0.91) N=582 0.63 (0.50, 0.79) n=708 0.69 n=190 0.25 0.5 1.0 Nivolumab 2.0 4.0 Docetaxel 0.25 0.5 1.0 2.0 4.0 Pembrolizumab Docetaxel 0.2 1 Atezolizumab 2 Docetaxel • OS data for KEYNOTE-010 is pooled across 2 mg/kg q3w and 10 mg/kg q3w doses, in PD-L1–selected patients Cross-study comparison is not intended. HR = hazard ratio; OS = overall survival; q3w = every 3 weeks. 1. Brahmer J et al. N Engl J Med. 2015;373(2):123-135. 2. Borghaei H et al. N Engl J Med. 2015; 373(17):1627-1639. Supplemental Appendix. 3. Herbst RS et al. Lancet. 2015 pii: S0140-6736(15)01281-7 [Epub ahead of print]. 4. Vansteenkiste et al. Oral presentation at ESMO 2015. 14LBA. LOCAL APPROVAL MAY BE REQUIRED BEFORE EXTERNAL USE. REFER TO LOCAL GUIDELINES 69 Treatment Effect on Overall Survival of Brain Metastases CheckMate 0171 (N=272) CheckMate 0572 (N=582) Unstratified HR (95% CI) CNS Metastases 1.04 n=68 (0.62, 1.76) Yes No 0.60 (0.45, 0.80) 0.25 0.5 Nivolumab n=255 1.0 2.0 0.71 n=514 (0.58, 0.88) 4.0 Docetaxel 0.25 0.5 1.0 Nivolumab 2.0 4.0 Docetaxel Cross-study comparison is not intended. HR = hazard ratio. 1. Brahmer J et al. N Engl J Med. 2015;373(2):123-135. 2. Borghaei H et al. N Engl J Med. 2015; 373(17):1627-1639. Supplemental Appendix. LOCAL APPROVAL MAY BE REQUIRED BEFORE EXTERNAL USE. REFER TO LOCAL GUIDELINES 70 Treatment Effect on Overall Survival by Driver Mutation and Smoking Status CheckMate 0171 (N=272) CheckMate 0572,3 (N=582) KEYNOTE-0104 (N=1034) Unstratified HR (95% CI) EGFR Mutation Status Positive Negative KRAS Mutation Status Positive 0.88 n=86 (0.45, 1.70) 0.66 n=340 (0.51, 0.86) 0.66 n=875 (0.55, 0.80) 0.52 n=62 (0.29, 0.95) 0.98 n=123 (0.66, 1.48) Negative ALK Translocation Status Negative Smoking Status Current/former 1.18 n=82 (0.69, 2.00) 0.71 n=243 (0.52, 0.96) 0.59 n=250 (0.44, 0.80) 0.70 n=458 (0.56, 0.86) 1.02 n=118 (0.64, 1.61) Never smoked 0.25 0.5 Nivolumab 1.0 2.0 4.0 Docetaxel 0.25 0.5 Nivolumab 1.0 2.0 4.0 Docetaxel 0.25 0.5 1.0 2.0 4.0 Pembrolizumab Docetaxel • OS data for KEYNOTE-010 is pooled across 2 mg/kg q3w and 10 mg/kg q3w doses, in PD-L1–selected patients Cross-study comparison is not intended. 1. Brahmer J et al. N Engl J Med. 2015;373(2):123-135. 2. Borghaei H et al. N Engl J Med. 2015; 373(17):1627-1639. 3. Borghaei H et al. N Engl J Med. 2015; 373(17):1627-1639. Supplemental Appendix. 4. Herbst RS et al. Lancet. 2015 pii: S0140-6736(15)01281-7 [Epub ahead of print]. LOCAL APPROVAL MAY BE REQUIRED BEFORE EXTERNAL USE. REFER TO LOCAL GUIDELINES 71 Treatment Effect on Overall Survival by Driver Mutation and Smoking Status CheckMate 0171 (N=272) CheckMate 0572,3 (N=582) KEYNOTE-0104 (N=1034) Unstratified HR (95% CI) EGFR Mutation Status Positive Negative KRAS Mutation Status Positive 0.88 n=86 (0.45, 1.70) 0.66 n=340 (0.51, 0.86) 0.66 n=875 (0.55, 0.80) 0.52 n=62 (0.29, 0.95) 0.98 n=123 (0.66, 1.48) Negative ALK Translocation Status Negative Smoking Status Current/former 1.18 n=82 (0.69, 2.00) 0.71 n=243 (0.52, 0.96) 0.59 n=250 (0.44, 0.80) 0.70 n=458 (0.56, 0.86) 1.02 n=118 (0.64, 1.61) Never smoked 0.25 0.5 Nivolumab 1.0 2.0 4.0 Docetaxel 0.25 0.5 Nivolumab 1.0 2.0 4.0 Docetaxel 0.25 0.5 1.0 2.0 4.0 Pembrolizumab Docetaxel • OS data for KEYNOTE-010 is pooled across 2 mg/kg q3w and 10 mg/kg q3w doses, in PD-L1–selected patients Cross-study comparison is not intended. 1. Brahmer J et al. N Engl J Med. 2015;373(2):123-135. 2. Borghaei H et al. N Engl J Med. 2015; 373(17):1627-1639. 3. Borghaei H et al. N Engl J Med. 2015; 373(17):1627-1639. Supplemental Appendix. 4. Herbst RS et al. Lancet. 2015 pii: S0140-6736(15)01281-7 [Epub ahead of print]. LOCAL APPROVAL MAY BE REQUIRED BEFORE EXTERNAL USE. REFER TO LOCAL GUIDELINES 72 Potencial de la Terapia Oncoinmunologica en CP Actividad en Varias poblaciones con tipos y lineas variados1 Adaptabilidad y memoria, provee potencial de SV a largo plazo1–5 Oportunidad forpara combinaciones6 Perfil de seguridad diferente y manejable7 Potencial para mejorar resultados en Cancer Pulmonar 1. Eggermont AM. Ann Oncol. 2012;23(suppl 8):viii53–viii57. 2. Finn OJ. Ann Oncol. 2012;23(suppl 8):viii6–viii9. 3. Hamid O et al. N Engl J Med. 2013;369:134–144. 4. Hodi FS et al. N Engl J Med. 2010;363:711–723. 5. Kantoff PW et al. N Engl J Med. 2010;363:411–422. 6. Brahmer JR et al. IASCL 15th WCLC 2013. MO18.03. 7. Gangadhar TC, Vonderheide RH. Nat Rev Clin Oncol. 2014;11:91–99. 73 GRACIAS FJ Orlandi-Abril-2016