Título de la dispositiva

Inmunoterapia en tratamiento de segunda línea

y sucesivas en cáncer renal avanzado

José Luis Pérez Gracia

Departamento de OncologíaClínica Universidadde Navarra

Inmunoterapia en tratamiento de segunda líneay sucesivas en cáncer renal avanzado

• Bloqueo PD-1/PDL1

• Fases II

• Fase III

• Estudios poblacionales

• Combinaciones

• Bloqueo PD-1/PDL1

• Fases II

• Fase III

• Estudios poblacionales

• Combinaciones

Topalian, NEJM 2012

Motzer, JCO 2014

Motzer, JCO 2014

Motzer, JCO 2014

Motzer, JCO 2014

0.3 mg/kg 18.2 months

2 mg/kg 25.5 months

10 mg/kg 24.7 m

Motzer, JCO 2014

0.3 mg/kg 18.2 months

2 mg/kg 25.5 months

10 mg/kg 24.7 m

McDermott, JCO 2016

ORR: 15%IC0 (34%): 9%IC 1/2/3 (53%): 18%

Furhman 4 y sarcomatoide: 22%

Mediana spv. global: 28.9 m

McDermott, JCO 2016

McDermott, JCO 2016

Inmunoterapia en tratamiento de segunda líneay sucesivas en cáncer renal avanzado

• Bloqueo PD-1/PDL1

• Fases II

• Fase III

• Estudios poblacionales

• Combinaciones

• Bloqueo PD-1/PDL1

• Fases II

• Fase III

• Estudios poblacionales

• Combinaciones

Advanced RCC withclear-cell

component

One or two prioranti-angiogenic

therapies

Progression within6 months

Advanced RCC withclear-cell

component

One or two prioranti-angiogenic

therapies

Progression within6 months

Nivolumab3 mg/kg intravenously

every 2 weeks

Nivolumab3 mg/kg intravenously

every 2 weeks

Ran

dom

ize

1:1

• Primaryendpoint: OS

• Key secondaryendpoint: ORR

• Primaryendpoint: OS

• Key secondaryendpoint: ORR

Advanced RCC withclear-cell

component

One or two prioranti-angiogenic

therapies

Progression within6 months

Advanced RCC withclear-cell

component

One or two prioranti-angiogenic

therapies

Progression within6 months

Everolimus10 mg orallyonce daily

Everolimus10 mg orallyonce daily

Ran

dom

ize

1:1

• Primaryendpoint: OS

• Key secondaryendpoint: ORR

• Primaryendpoint: OS

• Key secondaryendpoint: ORR

• 821 patients randomized from October 2012 through March 2014• Study halted July 2015 at preplanned interim analysis of OS

Motzer, NEJM 2015

Motzer, NEJM 2015

Motzer, NEJM 2015

Response characteristics

ORR, %

Nivolumab 25

Everolimus 5Odds ratio (95% CI),

5.98 (3.68–9.72)P < 0.0001

Indi

vidu

al re

spon

ders

Ongoing responseFirst responseOff treatment

NivolumabEverolimus On treatment

Odds ratio (95% CI),5.98 (3.68–9.72)

P < 0.0001

0 16 32 6448 80Time (Weeks)

96 112 128

Indi

vidu

al re

spon

ders

Motzer, NEJM 2015

¿Porqué sale positiva OS y no PFS?– Fenómeno habitual en inmunoterapia:

• Sipuleucel (Kantoff, NEJM 2010)• Nivolumab vs txt en CNMP no escamoso (Borghaei, NEJM 2015)• Pembrolizumab en CNMP (Herbst, Lancet 2016)

– Descrito con TKI: Intorsect (sorafenib vs temsirolimus: =SLP,mejor SPV para sorafenib) (Hutson JCO 2014)

– PFS es una variable subjetiva (respuesta)– Pseudoprogresión …

– ¿Diferencias biológicas de inmunoterapia?... PFS es “surrogate” de OS, no al revés

– Fenómeno habitual en inmunoterapia:• Sipuleucel (Kantoff, NEJM 2010)• Nivolumab vs txt en CNMP no escamoso (Borghaei, NEJM 2015)• Pembrolizumab en CNMP (Herbst, Lancet 2016)

– Descrito con TKI: Intorsect (sorafenib vs temsirolimus: =SLP,mejor SPV para sorafenib) (Hutson JCO 2014)

– PFS es una variable subjetiva (respuesta)– Pseudoprogresión …

– ¿Diferencias biológicas de inmunoterapia?... PFS es “surrogate” de OS, no al revés

Landmark Overall Survival Analysis in PatientsTreated and Not Treated Beyond Progression

Ove

rall

Surv

ival

(Pro

babi

lity)

1.0

0.9

Median OS, months (95% CI)Treated beyond progression 28.1 (23.2–NE)Not treated beyond progression 15.0 (12.1–18.2)

HR (95% CI), 0.41 (0.29–0.57)Overall survival with nivolumab

Months

Ove

rall

Surv

ival

(Pro

babi

lity)

0.00 3 6 9 12 15 18 21 24 27 30 33

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

Not treated beyond progression

Treated beyond progression

Escudier, ASCO 2016.

Tumor Burden Change Post-Progression• A total of 142 of 153 patients treated with nivolumab beyond progression had tumor measurements pre- and post-

progression– Of these 142 patients, approximately half had a reduction in tumor burden post-progression and 14%

(n = 20) had a ≥30% reduction in tumor burden post-progression

Best reduction in target lesions with nivolumab

*

50

25

Best

Red

uctio

n fro

m F

irst P

rogr

essi

on in

Targ

et L

esio

n (%

)

*

**

*

Reported as of June 2016.Asterisks represent responders before first progression. Square symbols represent % change truncated to 100%.nivo = nivolumab; q2w = every 2 weeks.Escudier B et al. Poster presentation at ASCO 2016. 4509.

Patients

* * *

* * *

* * *

*

****

0

-25

-50

-75

-100

Best

Red

uctio

n fro

m F

irst P

rogr

essi

on in

Targ

et L

esio

n (%

) * **

* ** * ****

□□□□

Escudier, ASCO 2016.

Tumor Burden Change Based on Best Overall Response

Complete/Partial Response

(n = 31)Stable Disease

(n = 51)Progressive Disease

(n = 70)

Cha

nge

From

Bas

elin

e (%

)

25

50

75

100

* *

*

25

50

75

100

25

50

75

100

Time Since Randomization (Weeks)Before Progression Patients Still on Treatment

**C

hang

e Fr

om B

asel

ine

(%)

-1000 12 24 36 48 60 72 84 96 108120

-75

-50

-25

0* *

*

-1000 12 24 36 48 60 72 84 96 108120

-75

-50

-25

0

-1000 12 24 36 48 60 72 84 96 108

-75

-50

-25

0

After Progression

Escudier, ASCO 2016.

Changes in serum interleukin-8 (IL-8) levels reflect andpredict response to anti-PD-1 treatment in melanoma

and non-small cell lung cancer patients

Sanmamed, Ann Oncol 2017

Changes in serum interleukin-8 (IL-8) levels reflect andpredict response to anti-PD-1 treatment in melanoma

and non-small cell lung cancer patients

Sanmamed, Ann Oncol 2017

Motzer, NEJM 2015

Motzer, NEJM 2015

25% 75%

Long-term Overall Survival (OS) WithNivolumab in Previously Treated Patients

With Advanced Renal Cell Carcinoma(aRCC) From Phase I and Phase II Studies

David F. McDermott,1 Robert J. Motzer,2 Michael B. Atkins,3 Elizabeth R. Plimack,4Mario Sznol,5 Saby George,6 Charles G. Drake,7 Brian Rini,8 Toni K. Choueiri,9 Timothy Kuzel,10

JeffreyA. Sosman,11 David C. Smith,12 Ulka Vaishampayan,13 John D. Powderly,14

Suzanne L. Topalian,7 Huanyu Zhao,15 Ian M. Waxman,15 Hans J. Hammers7

4507

David F. McDermott,1 Robert J. Motzer,2 Michael B. Atkins,3 Elizabeth R. Plimack,4Mario Sznol,5 Saby George,6 Charles G. Drake,7 Brian Rini,8 Toni K. Choueiri,9 Timothy Kuzel,10

JeffreyA. Sosman,11 David C. Smith,12 Ulka Vaishampayan,13 John D. Powderly,14

Suzanne L. Topalian,7 Huanyu Zhao,15 Ian M. Waxman,15 Hans J. Hammers7

1Beth Israel Deaconess Medical Center, Dana-Farber/Harvard Cancer Center, Boston, MA, USA; 2Memorial Sloan Kettering Cancer Center, NewYork, NY, USA; 3Georgetown-Lombardi Comprehensive Cancer Center, Washington, DC, USA; 4Fox Chase Cancer Center, Philadelphia, PA,USA; 5Yale University School of Medicine and Smilow Cancer Center, Yale–New Haven Hospital, New Haven, CT, USA; 6Roswell Park CancerInstitute, Buffalo, NY, USA; 7Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA; 8Cleveland Clinic Taussig

Cancer Institute, Cleveland, OH, USA; 9Dana-Farber Cancer Institute/Brigham and Women’s Hospital, Boston, MA, USA; 10NorthwesternUniversity Feinberg School of Medicine, Chicago, IL, USA; 11Vanderbilt University Medical Center, Nashville, TN, USA; 12University of Michigan

Comprehensive Cancer Center, Ann Arbor, MI, USA; 13Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA; 14CarolinaBioOncology Institute, Huntersville, NC, USA; 15Bristol-Myers Squibb, Princeton, NJ, USA

ASCO 2016- 1506ES16NP04829-01

Overall Survival in Phase I and II StudiesStudy

Median OS, months(95% CI)

Phase IPhase II

22.4 (12.5–NE)23.4 (17.7–26.9)

1.00.90.80.70.60.50.40.30.20.10.0O

vera

llSu

rviv

al (P

roba

bilit

y)

38%

29%

34%

1.00.90.80.70.60.50.40.30.20.10.0

0

No. of patients at risk

6 12 18 24 30 36 42Months

48 54 60 66 72 78 84

Ove

rall

Surv

ival

(Pro

babi

lity)

• In phase I and II studies, minimum follow-up was 50.5 months and 49.2 months, respectively

NE, not estimable.

ASCO 2016

Phase I 34 28 24 18 14 13 12 12 11 8 6 6 2 1 0Phase II 167 142 113 93 80 65 58 51 47 2 0 0 0 0 0

ASCO 2016- 1506ES16NP04829-01

– Approximately one-third of patients are alive at 4 years (phase I and II)and 5 years (phase I)

– Long-term survival is achievable regardless of risk group,performance status, or best overall response (phase II)

McDermott, ASCO 2016

45

40

35

30

25

20

15

10

5

0

Emergence of Select Treatment-related AEs(Any Grade) Over Time in Phase II Study

Even

ts/p

atie

nts

at ri

sk(%

)45

40

35

30

25

20

15

10

5

0

Even

ts/p

atie

nts

at ri

sk(%

)

Overall ≤6 >6–≤12 >12–≤18 >18–≤24

Months

>24–≤30 >30–≤36 >36

No. of patients at risk 167 167 88 62 44 36 25 21

• Select treatment-relatedAEs included endocrine, gastrointestinal, hepatic, pulmonary, renal, and skin

ASCO 2016

ASCO 2016- 1506ES16NP04829-01 McDermott, ASCO 2016

Conclusions second linetreatment of RCC

“Official”• Nivolumab, cabozantinib and

lenvatinib are standard 2nd lineoptions for RCC– They all improve survival– Nivolumab does not improve PFS– Nivolumab less toxic

Personal• Nivolumab will be widely used in

second line therapy in RCC– Toxicity profile– New mechanism of action– Long term survivors (?)

• Lenvatinib + everolimus andcabozantinib will likely replaceother TKI and everolimus in 2ndor 3rd line, very specially in youngand fit patients

• Nivolumab, cabozantinib andlenvatinib are standard 2nd lineoptions for RCC– They all improve survival– Nivolumab does not improve PFS– Nivolumab less toxic

• Nivolumab will be widely used insecond line therapy in RCC– Toxicity profile– New mechanism of action– Long term survivors (?)

• Lenvatinib + everolimus andcabozantinib will likely replaceother TKI and everolimus in 2ndor 3rd line, very specially in youngand fit patients

Inmunoterapia en tratamiento de segunda líneay sucesivas en cáncer renal avanzado

• Bloqueo PD-1/PDL1

• Fases II

• Fase III

• Estudios poblacionales

• Combinaciones

• Bloqueo PD-1/PDL1

• Fases II

• Fase III

• Estudios poblacionales

• Combinaciones

Efficacy and safety of nivolumab in patients with metastatic renalcell carcinoma (mRCC) and brain metastases: Preliminary resultsfrom the GETUG-AFU 26 (Nivoren) study.

55 pacientes con metástasis cerebrales de 588 incluidos (35 (67%) ,6(12%) and 11 (21%) with 1, 2 o > 2 metástasis).

10 pts (23%) con PS 2 y 25 (58%) PS 1.

16 pacientes (29%) tratados con > 2 líneas

67% (n = 37) sin tratamiento previo para mts SNC ,

En 44 pacientes evaluables se observaron 10 respuestas (23%)

21 pacientes (48%) presentaron progresión de la enfermedad

55 pacientes con metástasis cerebrales de 588 incluidos (35 (67%) ,6(12%) and 11 (21%) with 1, 2 o > 2 metástasis).

10 pts (23%) con PS 2 y 25 (58%) PS 1.

16 pacientes (29%) tratados con > 2 líneas

67% (n = 37) sin tratamiento previo para mts SNC ,

En 44 pacientes evaluables se observaron 10 respuestas (23%)

21 pacientes (48%) presentaron progresión de la enfermedad

Escudier, ASCO 2017, abstract 4563

Safety and efficacy of nivolumab for metastatic renal cell carcinoma(mRCC): Real world data from an Italian expanded access program (EAP).

389 pts median age was 65 years (range, 34-85)

70 (18%) aged ≥ 75 yrs. Pts had a clear-cell RCC in 92% of cases, bonemetastases in 50% and brain metastases in 8%, and received more thanone previous line in 79% of cases.

Median number of doses received was 10 (1-31). 82 (21%) pts treated beyondprogression.

18 pts (5%) discontinued treatment due to AE.

Best overall response rate was 17% (1 CR, 66 PR). SD: 31%

6-month and 9-month survival rates were 83% and 77%, respectively.Response and survival rates were comparable regardless age,presence of brain or bone metastases and number of prior therapies.

Conclusions: This EAP represents the most extensive reported real-worldexperience with nivolumab in pre-treated RCC pts. These first data seemto confirm efficacy and safety data of the pivotal trial in a real worldsetting.

389 pts median age was 65 years (range, 34-85)

70 (18%) aged ≥ 75 yrs. Pts had a clear-cell RCC in 92% of cases, bonemetastases in 50% and brain metastases in 8%, and received more thanone previous line in 79% of cases.

Median number of doses received was 10 (1-31). 82 (21%) pts treated beyondprogression.

18 pts (5%) discontinued treatment due to AE.

Best overall response rate was 17% (1 CR, 66 PR). SD: 31%

6-month and 9-month survival rates were 83% and 77%, respectively.Response and survival rates were comparable regardless age,presence of brain or bone metastases and number of prior therapies.

Conclusions: This EAP represents the most extensive reported real-worldexperience with nivolumab in pre-treated RCC pts. These first data seemto confirm efficacy and safety data of the pivotal trial in a real worldsetting.

De Giorgi, ASCO 2017, abstract 4577

Inmunoterapia en tratamiento de segunda líneay sucesivas en cáncer renal avanzado

• Bloqueo PD-1/PDL1

• Fases II

• Fase III

• Estudios poblacionales

• Combinaciones

• Bloqueo PD-1/PDL1

• Fases II

• Fase III

• Estudios poblacionales

• Combinaciones

2-to-1 Format1 Flexible range of motion in Fabs1,2

CEA-TCB is the first T-cell bispecific antibody with a novel2-to-1 format, optimized for efficacy and safety

• Binds simultaneously with 1 arm to CD3 on T cells and with 2 arms to CEA on tumor cells• Flexible 2-to-1 format enables high-avidity binding and selective killing of high CEA-expressing tumor cells• Longer half-life compared with other TCB formats• Silent Fc results in reduced risk of FcγR-related cytokine release/IRRs

Fab, fragment antigen-binding region; IRR, infusion-related reaction. 1. Bacac M, et al. Clin Cancer Res. 2016;22:3286-3296; 2. Roche. Data on file.

35

Untargeted TCB CEA TCBIntravital two-photon imaging of anti-tumor activity

Combination Strategies – Enhancing Direct T cell Killing ofTumor Cells: T cell Bispecific Antibodies (TCBs)

Significantly higher number of T cells and high apoptotic tumor fractionalready 24 h after single CEA TCB treatment

LS174T-RFP (red)/hPBMCs co-grafting (5:1) for 4 days;T cells labeled with CFSE (green); imaging 1 day after therapyBacac, et al. ITOC 2014

T Cells:Tumor Cells:

CEA-TCB + atezolizumab demonstrated promising clinical activityin 3L+ patients with MSS mCRC

Study 2: CEA-TCB + atezolizumab (n = 11, 80 and 160 mg of CEA-TCB)

Cha

nge

in ta

rget

lesi

ons

from

bas

elin

e, %

p

*p*

p

-50

0

50

100 *p

WithdrawalProgressionOngoingFirst new lesion

a

160 mg80 mg

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24

Data reported by investigators, cutoff: March 3, 2017. a Patient had the confirmatory CT scan on March 23, 2017.

38

Presented by: Dr. Josep Tabernero,Phase I Studies of CEA-TCB in mCRC. http://tago.ca/BfO

Weeks after treatment start

Cha

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ons

from

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e, %

p

*p*

p

-50

0

50

100 *p

WithdrawalProgressionOngoingFirst new lesion

a

160 mg80 mg

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24

Tumor targetanti-CEA or anti-FAP

Tumor-targeted immune cell growth factorEngineered Immunoglobulin-cytokine fusion

protein• CEA (Carcinoembryonic Antigen)

= adenocarcinoma cell antigen• FAP (Fibroblast Activation Protein α )

= cancer associated fibroblast/stroma cell antigen• High affinity binding for tumor targeting

pMAffinity

IL2vcytokine

• IL2v = IL-2 variant, IL-15 like cytokinePromoting immune effector cells (CD8 T & NKcells) over suppressor cells (Tregs &Macrophages)

Immunomodulator designed for combination with cytolysis-triggering moleculessuch as ADCC-mAbs, T-Cell bispecific mAbs and anti-PD1/PD-L1.

nM

Affinity

• Inert Fc-partImproved PK & Safety over aldesleukin

Obinutuzumab pre-treatmentTiming differs based on development of ADAs

CONCLUSIONES• La inmunoterapia es uno de los pilares del

tratamiento del cáncer renal– Nivolumab aprobado en cáncer renal avanzado

previamente tratado– Varios estudios en marcha en primera línea

• Desarrollo futuro– Biomarcadores– Nuevas combinaciones– Fases tempranas de la enfermedad

• La inmunoterapia es uno de los pilares deltratamiento del cáncer renal– Nivolumab aprobado en cáncer renal avanzado

previamente tratado– Varios estudios en marcha en primera línea

• Desarrollo futuro– Biomarcadores– Nuevas combinaciones– Fases tempranas de la enfermedad

Muchas gracias por vuestra atención

jlgracia@unav.es

José Luis Pérez Gracia

Departamento de OncologíaClínica Universidad

de Navarra