Nuevos horizontes en inmunología: Atezolizumab. Dra. Margarita Majem Hospital de la Santa Creu i Sant Pau Barcelona

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1 Nuevos horizontes en inmunología: Atezolizumab Dra. Margarita Majem Hospital de la Santa Creu i Sant Pau Barcelona

2 ATEZOLIZUMAB Ac monoclonal IgG1 humanizado anti-pd-l1 Unión a PD-L1. Bloquea interacción de PD-L1 con PD-1 y B7-1. No inhibe PD-L2 (menor expresión en tumores) menor probabilidad de toxicidad inflamatoria severa?. Aprobado en CPNM localmente avanzado o metastásico en pacientes tratados previamente con quimioterapia, independientemente del nivel de expresión de PD-L1

3 Ensayo fase II 2L/3L POPLAR: Beneficio significativo a largo plazo, independiente de PD-L1 3-y OS rate by PD-L1 Park, et al. WCLC 2017

4 Ensayo fase III 2L OAK. Beneficio significativo a 2 años con Atezolizumab Locally advanced or metastatic NSCLC Atezolizumab 1200 mg IV q3w PD or loss of clinical benefit LTS (Long-term survivors) Patients who lived 24 months since randomization 1 2 prior lines of chemotherapy including at least 1 platinum-based therapy Any PD-L1 status R 1:1 Docetaxel 75 mg/m 2 IV q3w No crossover to atezolizumab allowed PD Survival follow-up Non-LTS a (Non long-term survivors) Patients that died within 24 months of randomization Satouchi, et al. WCLC 2017

5 Ensayo fase III 2L OAK. Beneficio en todos los subgrupos de PD-L1 Survival benefit with atezolizumab is observed across all PD-L1 expression subgroups (SP142 assay) and the ITT population, including the PD-L1 negative population (TC0 and IC0) 2-y OS rate by PD-L1 TC0 and IC0 Subgroup 5 a Stratified HRs for ITT and TC1/2/3 or IC1/2/3. Unstratified HR for other PD-L1 subgroups. TC0 and IC0, PD-L1 expression on <1% TC and IC; TC1/2/3 or IC1/2/3, 1% TC or IC; TC2/3 or IC2/3, 5% TC or IC; TC3 or IC3, 50% TC or 10% IC. IC, tumor-infiltrating immune cell; TC, tumor cell. Barlesi F, et al. ESMO 2016; Rittmeyer A, et al. Lancet, Satouchi, et al. WCLC 2017

6 Overall Survival (%) Overall Survival (%) Ensayo fase III 2L OAK. Beneficio independiente del test de IHQ SP142 TC0 and IC0 22C3 TPS < 1% Atezolizumab Docetaxel + Censored Atezolizumab Docetaxel + Censored OS HR (95% CI) SP142 Dx- (N = 150) 22C3 Dx- (N = 218) 0.55 (0.37, 0.80) 0.61 (0.45, 0.84) Months Months OS benefit observed in PD-L1 negative populations as defined by either assay 6 SP142 assay: TC0 and IC0, PD-L1 expression on <1% TC and IC. 22C3 assay: TPS <1%, PD-L1 expression on <1% TC. Dx-, no or low PD-L1 expression. Gadgeel S, et al. 22C3 vs SP142 in OAK

7 Ensayo fase III 2L OAK. Beneficio independiente del test de IHQ SP142 TC3 or IC3 22C3 TPS 50 % OS HR (95% CI) SP142 TC3 or IC3 (N = 73) 22C3 TPS 50% (N = 100) 0.37 (0.20, 0.66) 0.49 (0.29, 0.80) High PD-L1 expression, as defined by either IHC assay, enriches for improved survival benefit 7 Dx+, TC3 or IC3 (SP142) or TPS 50% (22C3); Dx, not TC3 or IC3 (SP142) or TPS < 50% (22C3); IC, tumor infiltrating immune cell; TC, tumor cell; TPS, tumor proportion score. Gadgeel S, et al. 22C3 vs SP142 in OAK

8 Overall Survival (%) Overall Survival (%) Overall Survival (%) Ensayo fase II BIRCH. Beneficio en primera línea en CPNM PD-L1 TC2/3 y/o IC2/3 Locally advanced or metastatic NSCLC Tumor PD-L1 expression by IHC a (TC2/3 and/or IC2/3) ECOG PS 0 or 1 No brain metastases N = 667 Cohort 1 (1L) No prior chemo n = 138 Cohort 2 (2L) 1 prior platinum chemo n = 271 Cohort 3 (3L+) 2 prior chemos (including 1 platinum) n = 254 PD Until loss of clinical benefit Median duration of survival follow-up = 34.3 months TC2/3 or IC2/3 (n = 138) TC3 or IC3 (n = 65) TC2 or IC2 (n = 73) mos (95% CI) 24.0 mo (18.1, 30.8) mos (95% CI) 26.9 mo (12.0, NE) mos (95% CI) 23.5 mo (18.1, 29.5) 24-mo OS rate (95% CI) 50% (41.5, 59.2) 24-mo OS rate (95% CI) 52% (39.3, 65.2) 24-mo OS rate (95% CI) 49% (37.0, 61.1) OS event rate = 58% OS event rate = 52% OS event rate = 63% Median = 24.0 mo Months Median = 26.9 mo Months Median = 23.5 mo Months Carcereny et al. WCLC 2017

9 Atezolizumab en 2º línea CPNM Eficacia demostrada vs Docetaxel. Largos supervivientes. Beneficio independiente del nivel de expresión de PD-L1.

10 Nuevos horizontes en inmunología

11 RATIONALE FOR COMBINATION CT causes direct/indirect immunoestimulation Angiogenic factors influence lymphocyte trafficking across endothelia into tumor deposits. VEGF has negative effects on immune regulatory cell function By inhibiting dendritic cell maturation and antigen presentation By inhibiting T-cell responses (upregulation PD-L1, PD-L2, IDO-1, IL-6, IL-10 ) By inducing proliferation of regulatory Tcells

12 Survival follow-up Phase III study of carboplatin + paclitaxel +/ bevacizumab, with or without atezolizumab in 1L non-squamous metastatic NSCLC (IMpower150) Maintenance therapy (no crossover permitted) Stage IV or recurrent metastatic non-squamous NSCLC Chemotherapy-naive a Tumour tissue available for biomarker testing Any PD-L1 IHC status Stratification factors: Sex PD-L1 IHC expression Liver metastases N = 1202 R 1:1:1 Arm A Atezolizumab b + Carboplatin c + Paclitaxel d 4 or 6 cycles Arm B Atezolizumab b + Carboplatin c + Paclitaxel d + Bevacizumab e 4 or 6 cycles Arm C (control) Carboplatin c + Paclitaxel d + Bevacizumab e 4 or 6 cycles Atezolizumab b Atezolizumab b + Bevacizumab e Bevacizumab e Treated with atezolizumab until PD by RECIST v1.1 or loss of clinical benefit AND/OR Treated with bevacizumab until PD by RECIST v1.1 The principal question is to assess whether the addition of atezolizumab to Arm C provides clinical benefit Co-primary objectives: Investigator-assessed PFS in ITT-WT, Investigator-assessed PFS in Teffhigh WT, OS in ITT-WT a WT refers to patients without EGFR or ALK genetic alterations. T-effector (Teff) gene signature : expression of PD-L1, CXCL9 and IFNγ Reck M, et al. IMpower150 PFS analysis. ESMO IO 2017

13 IMpower150. INV-assessed PFS in ITT-WT (Arm B vs Arm C) Arm B: atezo + bev + CP Arm C: bev + CP 67% 56% 37% HR, (95% CI: 0.517, 0.737) P < Minimum follow-up: 9.5 mo Median follow-up: ~15 mo 6.8 mo (95% CI: 6.0, 7.1) 18% 8.3 mo (95% CI: 7.7, 9.8) INV, investigator. Data cutoff: September 15, 2017 Reck M, et al. IMpower150 PFS analysis.

14 IMpower150. INV-assessed PFS in Teff-high WT (Arm B vs Arm C) Landmark PFS, % Arm B: atezo + bev + CP Arm C: bev + CP 6-month 72% 57% 12-month 46% 18% HR, (95% CI: 0.377, 0.675) P < Minimum follow-up: 9.5 mo 6.8 mo (95% CI: 5.9, 7.4) 11.3 mo (95% CI: 9.1, 13.0) co-primary endpoint T-effector gene signature allows enrichment INV, investigator. Data cutoff: September 15, 2017 Reck M, et al. IMpower150 PFS analysis.

15 Impower 150. Preliminary OS in ITT-WT (Arm B vs Arm C) Arm B: atezo + bev + CP Arm C: bev + CP HR, (95% CI: 0.619, 0.970) P = Minimum follow-up: 9.5 mo 14.4 mo (95% CI: 12.8, 17.1) 19.2 mo (95% CI: 16.8, 26.1) 1 5 Promising preliminary OS benefit for Arm B vs Arm C was observed; next OS interim data are anticipated in 1H 2018 Data cutoff: September 15, 2017 Reck M, et al. IMpower150 PFS analysis.

16 Atezolizumab clinical trials in NSCLC Phase Ia Preliminary safety and efficacy in NSCLC Phase II Preliminary efficacy in 1L and 2L+ NSCLC PCD4989g PhI solid tumours including NSCLC [safety and DLT] N=88 (NCT ) FIR PhII 1/2L+ Dx+ atezo single-arm [ORR] N=128 (NCT ) BIRCH PhII 1/2L+ Dx+ atezo single-arm [ORR] N=667 (NCT ) 2020 onwards 2L+ phase II and III Efficacy and safety of monotherapy in 2L+ NSCLC 2L phase I (combos) Preliminary safety and efficacy 1L phase III (monotherapy) Efficacy and safety of monotherapy in 1L NSCLC 1L phase I (combinations) Preliminary safety and efficacy of combination therapy in 1L NSCLC 1L phase III (combinations) Efficacy and safety of combination therapy in 1L NSCLC POPLAR PhII 2/3L all-comer atezo vs doc [OS] N=287 (NCT ) OAK PhIII 2/3L all-comer atezo vs doc [OS] N=1225 (NCT ) ECHO-110 PhI 2L atezo + epacadostat (IDO inhibitor) combined vs sequential [safety, tolerability] N=80 (NCT ) IMpower 111 PhIII 1L squamous Dx+ atezo vs gem + cis/carbo [PFS] N=400 (NCT ) IMpower 110 PhIII 1L non-squamous Dx+ atezo vs pem + cis/carbo [PFS] N=400 (NCT ) GP28328 PhIb solid tumours including 1L NSCLC atezo + carbo + pac/pem [safety, DLT] N 75 (NCT ) WP29158 PhIb 1L atezo + erlotinib (EGFR WT or Mut+) or alectinib (ALK+) [DLT, safety] N=53 (NCT ) IMpower 150 PhIII 1L non-squamous all-comer atezo + carbo + pac ± bev vs carbo + pac + bev [PFS] N=1200 (NCT ) IMpower 130 PhIII 1L non-squamous all-comer atezo + carbo + nab-pac vs carbo + nab-pac [PFS] N=550 (NCT ) IMpower 131 PhIII 1L squamous all-comer atezo + carbo + pac/nab-pac vs carbo + nab-pac [PFS] N= 1200 (NCT ) IMpower 132 PhIII 1L non-squamous all-comer atezo + cis/carbo + pem vs cis/carbo + pem [PFS] N=680 (NCT ) Adjuvant monotherapy IMpower 010 PhIII adjuvant atezo vs BSC [DFS] N=845 (NCT ) Estimated study timelines based on start date and completion date from clinicaltrials.gov Arrow length indicates study start date to final data collection date for the primary outcome measure Figure includes study name, NCT number, n, primary endpoint, study arms, line of treatment Confidential - for internal use only Last updated: 25 February 2016

17 IMpower110 (GO29431): 1L Monotherapy phase III Stage IV NSCLC No prior treatment Non-squamous histology PD-L1 selected ECOG PS 0 1 R N=400 1:1 Atezolizumab 1,200mg IV q3w* Pemetrexed 500mg/m 2 IV q3w + either carboplatin AUC 6 IV q3w or cisplatin 75mg/m 2 IV q3w (4 or 6 cycles) Pemetrexed 500mg/m 2 IV q3w Primary endpoint: PFS (investigator-assessed by RECIST v1.1) Secondary endpoints: ORR, DoR and time in response (investigator-assessed by RECIST v1.1), OS, TTD in patient-reported symptoms, PK, AEs Spain participates Unido a IMpower111 Available at clinicaltrials.gov/show/nct Accessed 30 April 2015

18 Impower 111 (GO29432): 1L Monotherapy phase III Stage IV NSCLC No prior treatment Squamous histology PD-L1 selected ECOG PS 1 N=400 R 1:1 Atezolizumab 1,200mg IV q3w* Gemcitabine 1,000 or 1,250mg/m 2 IV q3w + either carboplatin AUC 5 IV q3w or cisplatin 75mg/m 2 IV q3w (4 or 6 cycles) Primary endpoint: PFS (investigator-assessed by RECIST v1.1) Secondary endpoints: AEs, ORR, DoR and time in response (investigator-assessed by RECIST v1.1), OS, TTD in patient-reported symptoms, PFS (IRF-assessed by RECIST v1.1), PK Gemcitabine dose 1,000mg/m 2 when combined with carboplatin, or 1,250mg/m 2 when combined with cisplatin Spain participates Unido a IMpower110 Available at clinicaltrials.gov/show/nct Accessed 30 April 2015

19 WP29158: phase Ib atezolizumab + erlotinib Locally advanced/ metastatic NSCLC Tumour specimen available (FFPE) ECOG PS 0 1 EGFR Mut+ (expansion phase only) N=32 Safety evaluation phase Atezolizumab 1,200mg IV q3w + erlotinib 150mg PO qd until PD Expansion phase (safety evaluation, response assessment) Atezolizumab IV q3w* + erlotinib PO qd until PD Primary endpoint: DLT Secondary endpoints: AEs, ATAs, PK, OS, PFS and OR (investigator-assessed by RECIST v1.1) Spain participates Available at clinicaltrials.gov/show/nct Accessed 30 April 2015

20 Impower130 (GO29537): phase III QT + Atezolizumab Locally advanced/ metastatic NSCLC Chemotherapy naïve Non-squamous histology All comers (PD-L1-positive/- negative) ECOG PS 0 1 N=550 R 2:1 Atezolizumab 1,200mg IV q3w + nab-paclitaxel 100mg/m 2 IV q1w + carboplatin AUC 6 IV q3w Nab-paclitaxel 100mg/m 2 IV q1w + carboplatin AUC 6 IV q3w Primary endpoint: PFS (investigator-assessed by RECIST v1.1) Secondary endpoints: OR and DoR (investigator-assessed by RECIST v1.1), PFS (IRF by RECIST v1.1), OS, TTD, safety Spain participates Available at clinicaltrials.gov/show/nct Accessed 30 April 2015

21 Impower131 (GO29538): phase III QT + Atezolizumab Locally advanced/ metastatic NSCLC Chemotherapy naïve Squamous histology All comers (PD-L1-positive/- negative) ECOG PS 0 1 N=550 R 2:1 Atezolizumab 1,200mg IV q3w + nab-paclitaxel 100mg/m 2 IV q1w + carboplatin AUC 6 IV q3w Nab-paclitaxel 100mg/m 2 IV q1w + carboplatin AUC 6 IV q3w Primary endpoint: PFS (investigator-assessed by RECIST v1.1) Secondary endpoints: OR and DoR (investigator-assessed by RECIST v1.1), PFS (IRF by RECIST v1.1), OS, TTD, safety Spain participates Available at clinicaltrials.gov/show/nct Accessed 30 April 2015

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23 IMpower132 (GO29438): phase III QT + Atezolizumab Open Label Non-Squamous NSCLC Atezolizumab + (Carboplatin or Cisplatin) + Pemetrexed Atezolizumab + Pemetrexed All comers (PD- L1-positive/- negative) R Maintenance EGFR/ALK excluded N=568 1:1 (Carboplatin or Cisplatin) + Pemetrexed 4 OR 6 cycles Pemetrexed Co-Primary endpoint: PFS and OS Secondary endpoints: OR, OS, TTD, PFS (IRF), DoR, TIR Spain participates Available at clinicaltrials.gov/show/nct Accessed 30 April 2015

24 IMpower010: adjuvant NSCLC trial Atezolizumab 1,200mg q3w x 16 cycles NSCLC CT R 1:1 N=480 90% Power for DFS 85% Power for OS Total 1-sided α=0.025 Observation Survival F/U No crossover Key eligibility Resected IB - IIIA PS 0-1 >lobectomy No planned XRT TC3 or IC3 Stratification factors Male/female Stage Histology PDL1 IHC status:* TC3 & any IC TC<3 & IC3 Primary endpoint: DFS Secondary endpoints: OS, PFS Spain participates

25 TAIL: Study design Stage IIIb/IV NSCLC that has progressed following: Chemo (1L), Chemo (1L) + chemo (2L), Anti-PD-1 (1L) + chemo (2L), Anti-PD-1/chemo (1L), or Anti-PD-1/chemo (1L) + chemo (2L) a ECOG PS 0, 1, or 2 FFPE tumor tissue RBR Plasma (optional) Atezolizumab 1200 mg IV q3w RBR Plasma (optional) Anticpated duration : 4 years from first pa tient screened Until loss of clinical benefit, unacceptable toxicity, investigator or patient decision to withdraw, or death b, c Asymptomatic, treated or untreated CNS metastases allowed N = 600 Primary endpoint: Incidence of SAEs and iraes Secondary endpoints: OS rates at 2 and 3 years OS PFS, ORR, DOR (RECIST v1.1 and mrecist) QoL

26 Mujer de 54 años fumadora ADK pulmonar EGFR WT, ALK no traslocado estadio IV (SNC, hepática, peritoneal, renal, retroperitoneal) Impower 130: CBDCA-NabPaclitaxel + Atezolizumab (Marzo 2017). RTP SNC previa Marzo 2017 Marzo 2018

27 CONCLUSIONES Eficacia demostrada en 2º línea, independiente de la histología y del nivel de expresión de PD-L1. LARGOS SUPERVIVIENTES Perfil de toxicidad manejable, en monoterapia o en combinación con QT. Numerosos estudios en marcha (monoterapia, Combos) en distintas indicaciones. Posibilidad de beneficiarse en un futuro de Atezolizumab en diferentes escenarios (adyuvancia, 1º línea, monoterapia, combinación,.)

28 Gracias!!!!! Dra. Margarita Majem Hospital de la Santa Creu i Sant Pau Barcelona