nuevos horizontes en inmunología: atezolizumab · pd-1 y b7-1. • no inhibe pd-l2 (menor...

Nuevos horizontes en inmunología: Atezolizumab

Dra. Margarita Majem

Hospital de la Santa Creu i Sant Pau

Barcelona

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

Ensayo fase II 2L/3L POPLAR: Beneficio significativo a largo plazo, independiente de PD-L1

Park, et al. WCLC 2017

3-y OS rate by PD-L1

Satouchi, et al. WCLC 2017

Ensayo fase III 2L OAK. Beneficio significativo a 2 años con Atezolizumab

Non-LTSa

(Non‒long-term survivors) Patients that died within 24

months of randomization

LTS (Long-term survivors)

Patients who lived ≥ 24 months since randomization

R

1:1

Locally advanced or

metastatic NSCLC

• 1–2 prior lines of

chemotherapy

including at least 1

platinum-based therapy

• Any PD-L1 status

Atezolizumab 1200 mg IV q3w

Docetaxel 75 mg/m2 IV q3w

PD or loss of clinical benefit

PD

Survival follow-up

No crossover to

atezolizumab allowed

• 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)

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, 2017.

Ensayo fase III 2L OAK. Beneficio en todos los subgrupos de PD-L1

TC0 and IC0 Subgroup

Satouchi, et al. WCLC 2017

2-y OS rate by PD-L1

• 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

OS HR

(95% CI)

SP142 Dx-

(N = 150)

0.55

(0.37, 0.80)

22C3 Dx-

(N = 218)

0.61

(0.45, 0.84)

+ Censored

Atezolizumab

Docetaxel

SP142 TC0 and IC0

Months

+ Censored

Atezolizumab

Docetaxel

22C3 TPS < 1%

Ove

rall

Su

rviv

al (%

)

Months

Ove

rall

Su

rviv

al (%

)

Ensayo fase III 2L OAK. Beneficio independiente del test de IHQ

• 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

OS HR

(95% CI)

SP142

TC3 or IC3

(N = 73)

0.37

(0.20, 0.66)

22C3

TPS ≥ 50%

(N = 100)

0.49

(0.29, 0.80)

SP142 TC3 or IC3

22C3 TPS ≥ 50 %

Ensayo fase III 2L OAK. Beneficio independiente del test de IHQ

Ensayo fase II BIRCH. Beneficio en primera línea en CPNM PD-L1 TC2/3 y/o IC2/3

Carcereny et al. WCLC 2017

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

• Locally advanced or

metastatic NSCLC

• Tumor PD-L1

expression by IHCa

(TC2/3 and/or IC2/3)

• ECOG PS 0 or 1

• No brain metastases

N = 667

Median duration of survival follow-up = 34.3 months

TC2/3 or IC2/3

(n = 138)

mOS (95% CI) 24.0 mo (18.1, 30.8)

24-mo OS rate (95% CI) 50% (41.5, 59.2)

TC3 or IC3

(n = 65)

mOS (95% CI) 26.9 mo (12.0, NE)

24-mo OS rate (95% CI) 52% (39.3, 65.2)

TC2 or IC2

(n = 73)

mOS (95% CI) 23.5 mo (18.1, 29.5)

24-mo OS rate (95% CI) 49% (37.0, 61.1)

Ove

rall

Su

rviv

al (%

)

Months

Ove

rall

Su

rviv

al (%

)

Months O

ve

rall

Su

rviv

al (%

) Months

Median = 26.9 mo Median = 24.0 mo Median = 23.5 mo

OS event rate = 52% OS event rate = 58% OS event rate = 63%

Atezolizumab en 2º línea CPNM

• Eficacia demostrada vs Docetaxel.

• Largos supervivientes.

• Beneficio independiente del nivel de expresión de PD-L1.

Nuevos horizontes en inmunología

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

Reck M, et al. IMpower150 PFS analysis.

Phase III study of carboplatin + paclitaxel +/− bevacizumab, with or without atezolizumab in 1L non-squamous metastatic NSCLC (IMpower150)

Arm A

Atezolizumabb +

Carboplatinc +

Paclitaxeld

4 or 6 cycles

Atezolizumabb

Arm C (control)

Carboplatinc +

Paclitaxeld

+ Bevacizumabe

4 or 6 cycles

Bevacizumabe

Su

rviv

al fo

llo

w-u

p

Stage IV or

recurrent metastatic

non-squamous NSCLC

Chemotherapy-naivea

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 B

Atezolizumabb +

Carboplatinc +

Paclitaxeld

+ Bevacizumabe

4 or 6 cycles

Atezolizumabb

+

Bevacizumabe

Maintenance therapy

(no crossover permitted)

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

ESMO IO 2017

• Co-primary objectives: Investigator-assessed PFS in ITT-WT, Investigator-assessed PFS in Teff-

high WT, OS in ITT-WT

T-effector (Teff) gene signature : expression of PD-L1, CXCL9 and IFNγ

a WT refers to patients without EGFR or ALK genetic alterations.


IMpower150. INV-assessed PFS in ITT-WT (Arm B vs Arm C)

INV, investigator. Data cutoff: September 15, 2017

6.8 mo (95% CI: 6.0, 7.1)

8.3 mo (95% CI: 7.7, 9.8)

HR, 0.617 (95% CI: 0.517, 0.737)

P < 0.0001 Minimum follow-up: 9.5 mo

Median follow-up: ~15 mo

Arm B: atezo + bev + CP

Arm C: bev + CP

18%

37% 56%

67%


INV, investigator. Data cutoff: September 15, 2017

IMpower150. INV-assessed PFS in Teff-high WT (Arm B vs Arm C)

6.8 mo (95% CI: 5.9, 7.4)

11.3 mo (95% CI: 9.1, 13.0)

HR, 0.505 (95% CI: 0.377, 0.675)

P < 0.0001 Minimum follow-up: 9.5 mo

Landmark PFS, % Arm B:

atezo + bev + CP

Arm C:

bev + CP

6-month 72% 57%

12-month 46% 18%

co-primary endpoint T-effector gene signature allows enrichment


Promising preliminary OS benefit for Arm B vs Arm C was observed; next OS interim data are anticipated in 1H 2018 1

5 Data cutoff: September 15, 2017

Impower 150. Preliminary OS in ITT-WT (Arm B vs Arm C)

HR, 0.775 (95% CI: 0.619, 0.970)

P = 0.0262 Minimum follow-up: 9.5 mo

14.4 mo

(95% CI: 12.8, 17.1)

19.2 mo

(95% CI: 16.8, 26.1)

Arm B: atezo + bev + CP

Arm C: bev + CP

1L phase I (combinations)

Preliminary safety and efficacy of combination therapy in 1L NSCLC

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

Last updated: 25 February 2016

2013 2016 2017 2018 2019 2020

onwards

2L+ phase II and III

Efficacy and safety of monotherapy in 2L+ NSCLC

2015

1L phase III (combinations)

Efficacy and safety of combination therapy

in 1L NSCLC

Adjuvant monotherapy

IMpower 111 PhIII 1L squamous Dx+ atezo vs gem + cis/carbo [PFS] N=400 (NCT02409355)

PCD4989g PhI solid tumours including NSCLC [safety and DLT] N=88 (NCT01375842)

POPLAR PhII 2/3L all-comer atezo vs doc [OS] N=287 (NCT01903993)

IMpower 131 PhIII 1L squamous all-comer atezo + carbo + pac/nab-pac vs carbo + nab-pac [PFS] N= 1200 (NCT02367794)

GP28328 PhIb solid tumours including 1L NSCLC atezo + carbo + pac/pem [safety, DLT] N≤75 (NCT01633970)

FIR PhII 1/2L+ Dx+ atezo single-arm [ORR] N=128 (NCT01846416)

BIRCH PhII 1/2L+ Dx+ atezo single-arm [ORR] N=667 (NCT02031458)

IMpower 132 PhIII 1L non-squamous all-comer atezo + cis/carbo + pem vs cis/carbo + pem [PFS] N=680 (NCT02657434)

IMpower 110 PhIII 1L non-squamous Dx+ atezo vs pem + cis/carbo [PFS] N=400 (NCT02409342)

WP29158 PhIb 1L atezo + erlotinib (EGFR WT or Mut+) or alectinib (ALK+) [DLT, safety] N=53 (NCT02013219)

OAK PhIII 2/3L all-comer atezo vs doc [OS] N=1225 (NCT02008227)

2014

IMpower 010 PhIII adjuvant atezo vs BSC [DFS] N=845 (NCT02486718)

Phase Ia

Preliminary safety and efficacy in NSCLC

1L phase III (monotherapy)

Efficacy and safety of monotherapy

in 1L NSCLC

Phase II

Preliminary efficacy in 1L and 2L+ NSCLC

IMpower 150 PhIII 1L non-squamous all-comer atezo + carbo + pac ± bev vs carbo + pac + bev [PFS] N=1200 (NCT02366143)

IMpower 130 PhIII 1L non-squamous all-comer atezo + carbo + nab-pac vs carbo + nab-pac [PFS] N=550 (NCT02367781)

Atezolizumab clinical trials in NSCLC

Confidential - for internal use only

≥2L phase I (combos)

Preliminary safety and efficacy

ECHO-110 PhI 2L atezo + epacadostat (IDO inhibitor) combined vs sequential [safety, tolerability] N=80 (NCT02298153)

IMpower110 (GO29431): 1L Monotherapy phase III

Available at

clinicaltrials.gov/show/NCT02409342

Accessed 30 April 2015

• 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

Pemetrexed 500mg/m2 IV q3w + either carboplatin AUC 6 IV q3w or

cisplatin 75mg/m2 IV q3w (4 or 6 cycles)

Atezolizumab 1,200mg IV q3w* • Stage IV NSCLC

• No prior treatment

• Non-squamous histology

• PD-L1 selected

• ECOG PS 0–1

N=400 1:1

R

Pemetrexed 500mg/m2 IV q3w

Spain participates

Unido a IMpower111

Impower 111 (GO29432): 1L Monotherapy phase III

‡Gemcitabine dose 1,000mg/m2 when combined with carboplatin, or

1,250mg/m2 when combined with cisplatin

Spain participates

Unido a IMpower110

Available at




• 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 1,000 or 1,250mg/m2‡ IV q3w + either carboplatin AUC 5 IV q3w

or cisplatin 75mg/m2 IV q3w (4 or 6 cycles)

Atezolizumab 1,200mg IV q3w* • Stage IV NSCLC

• No prior treatment

• Squamous histology

• PD-L1 selected

• ECOG PS –1

N=400 1:1

R

WP29158: phase Ib atezolizumab + erlotinib

• Primary endpoint: DLT

• Secondary endpoints: AEs, ATAs, PK, OS, PFS and OR (investigator-assessed by RECIST v1.1)

Available at



• Locally advanced/ metastatic NSCLC

• Tumour specimen available (FFPE)

• ECOG PS 0–1

• EGFR Mut+ (expansion phase only)

N=32

Expansion phase (safety evaluation,

response assessment) Atezolizumab IV q3w* +

erlotinib PO qd until PD

Safety evaluation phase Atezolizumab

1,200mg IV q3w + erlotinib 150mg PO qd until

PD

Spain participates

Impower130 (GO29537): phase III QT + Atezolizumab


• Secondary endpoints: OR and DoR (investigator-assessed by RECIST v1.1), PFS (IRF by RECIST v1.1), OS, TTD, safety

Spain participates

Available at



Nab-paclitaxel 100mg/m2 IV q1w + carboplatin AUC 6 IV q3w

Atezolizumab 1,200mg IV q3w + nab-paclitaxel 100mg/m2 IV q1w +

carboplatin AUC 6 IV q3w


• Chemotherapy naïve

• Non-squamous histology

• ‘All comers’ (PD-L1-positive/-negative)

• ECOG PS 0–1

N=550 2:1

R

Impower131 (GO29538): phase III QT + Atezolizumab


• Secondary endpoints: OR and DoR (investigator-assessed by RECIST v1.1), PFS (IRF by RECIST v1.1), OS, TTD, safety

Spain participates

Available at



Nab-paclitaxel 100mg/m2 IV q1w + carboplatin AUC 6 IV q3w

Atezolizumab 1,200mg IV q3w + nab-paclitaxel 100mg/m2 IV q1w +

carboplatin AUC 6 IV q3w


• Chemotherapy naïve

• Squamous histology


• ECOG PS 0–1

N=550 2:1

R

IMpower132 (GO29438): phase III QT + Atezolizumab

• Co-Primary endpoint: PFS and OS

• Secondary endpoints: OR, OS, TTD, PFS (IRF), DoR, TIR

Spain participates

Available at



(Carboplatin or Cisplatin) + Pemetrexed

Atezolizumab + (Carboplatin or

Cisplatin) + Pemetrexed

• Open Label

• Non-Squamous NSCLC


• EGFR/ALK excluded

N=568 1:1

R

Atezolizumab + Pemetrexed

Pemetrexed

Maintenance

4 OR 6 cycles

IMpower010: adjuvant NSCLC trial

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

Atezolizumab 1,200mg q3w x 16 cycles

Observation

NSCLC

No crossover

Survival F/U

N=480 90% Power for DFS 85% Power for OS

Total 1-sided α=0.025

1:1

R CT

Spain participates

• Primary endpoint: DFS

• Secondary endpoints: OS, PFS

StageIIIb/IVNSCLCthathasprogressedfollowing:• 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

ECOGPS0,1,or2

Asymptomatic,treatedoruntreatedCNSmetastasesallowed

Untillossofclinicalbenefit,unacceptabletoxicity,

investigatororpatientdecisiontowithdraw,ordeath b,c

Atezolizumab1200mgIVq3w

FFPEtumortissueRBRPlasma(optional) RBRPlasma(optional)

N=600

TAIL: Study design

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

Anticpated duration:

4 years from first patient screened

• 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

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, ….)

Gracias!!!!!

Dra. Margarita Majem

Hospital de la Santa Creu i Sant Pau

Barcelona

nuevos horizontes en inmunología: atezolizumab · pd-1 y b7-1. • no inhibe pd-l2 (menor...

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