"DELS BIOLÒGICS A LES TERÀPIES CEL.LULARS IMMUNOMEDIADES EN EL

TRACTAMENT DE MALALTS AMB CÀNCER"

Cristina Cruz

Unitat de Fases I

Servei d'Oncologia

Hospital Vall d'Hebron

Biològ cs en càncer

biològics

1

La teràpia basada en biològics utilitza:

organismes vius,

Substàncies procedents d’organismes vius, o

versions sintètiques d’aquestes substàncies

biològics: 4ª modalitat de tractament del

càncer

2

Cirurgia

Radioteràpia

Quimioteràpia

Biològics

Alguns tipus de

teràpia biològica

ataquen

directament la

cèl.lula cancerosa

...

p.e. oncovirus

immunoteràpia

3

… Altres tipus de teràpia biològica exploten la capacitat

natural del sistema immune per atacar la cèl.lula

cancerosa

Vacunes

Cèl.lules

Bacteris

Citoquines: IL, IFN

Pèptids

Anticossos

immunoteràpia

4

Immune

checkpoints:

ANTI -CTLA-4

ANTI -PD-1 /

-PDL-1

Limfòcit T citotòxic

i complement Bloqueig dirigit de

receptors

immunomoduladors

5

Immune checkpoints:

CTLA-4 ( Cytotoxic T-lymphocyte–

associated antigen 4 )

6

PD- 1 (Programmed Death-1)

Ipilimumab

- anticòs monoclonal - Ig G1humana – anti-CTLA-4

(actua a fases inicials d’activació de la cèl.lula T)

- melanoma -> regressió (RR 10-15%)

- dosi ?

- freqüents efectes adversos (AE) relacionats amb la

immunitat

7

60% de pacients – algun AE immunològic (15% G2-3)

Pell > diarrea >>> endocrinopatia> hepatitis

4 patrons de resposta al tractament amb

Ipilimumab Response in

baseline lesions

Response in total tumor burden in the presence of new lesions

Response after initial increase in total tumor burden Slow, steady decline

in total tumor burden

3 months

PD

PR

CR

1.4 years

9 months

6 months 8 months 5 months

Ch

an

ge f

rom

baseli

ne (

%)

Relative day from randomization date

153

135

117

99

82

64

46

28

10

–8

–26

SP

D (m

m2)

977

863

749

635

521

407

293

179

65

–49

–163

SP

D (m

m2)

Ch

an

ge f

rom

baseli

ne (

%)

3737

3301

2865

2429

1993

1557

1121

685

249

–187

–623

SP

D (m

m2)

748

664

580

496

411

327

243

159

75

–9

–94

100

75

50

25

0

–25

–50

–75

–100

–125

2067

1826

1585

1344

1102

861

620

379

138

–103

–345

SP

D (m

m2)

SP

D (m

m2)

Ch

an

ge f

rom

baseli

ne (

%)

Relative day from randomization date Relative day from randomization date

Relative day from randomization date Relative day from randomization date Relative day from randomization date

Ch

an

ge f

rom

baselin

e (

%)

50

25

0

–25

–50

–75

–100

–125

Ch

an

ge f

rom

baselin

e (

%)

Ch

an

ge f

rom

baselin

e (

%)

SP

D (m

m2)

50

25

0

–25

–50

–75

–100

–125

50

25

0

–25

–50

–75

–100

–125

50

25

0

–25

–50

–75

–100

–125

50

25

0

–25

–50

–75

–100

–125

8528

7533

6538

5543

4548

3553

2558

1563

569

–426

–1421

9

Wk 20: Regression

Wk 36: Still Regressing

Screening

Wk 12: Progression

Pseudoprogressió

J.D. Wolchok, et al.“Guidelines for the evaluation of immune therapy activity in solid tumors:

immune-related response criteria.” Clin Cancer Res 2009;15(23):7412–20

The Immune-related Response Criteria (irRC) s

10

RECIST 1.1 irRC Target/index lesions

Up to 5 total (2/organ), unidimensional

up to 15 total (5/organ), bidimensional

New lesions Always represent PD Incorporated into TB if ≥5 x 5 mm

Non-target/index lesions

Contribute to define CR, PR, SD and PD

Contribute to define irCR

CR Disappearance of all known lesion(s); confirmed at 4 wk+

Disappearance of all known lesion(s); confirmed at 4 wk+

PR At least 30% decrease in SLD; confirmed at 4 wk+

At least 50% decrease in TB; confirmed at 4 wk+

SD Neither PR nor PD criteria met

Neither PR nor PD criteria met

PD 20% increase in SLD compared with nadir and/or unequivocal progression of non-target lesions and /or appearance of new lesions

At least 25% increase in TB compared with nadir in two consecutive observations at least 4 wk apart

RECIST 1.1 vs irRC

11

PD- 1 (Programmed Death-1)

12

PD- 1 (Programmed Death-1)

- T-cell coinhibitory receptor

- 2 known ligands: PD-L1 (B7-H1) & PD-L2 (B7-DC)

Via PD-1 / PDL-1

13

14

Anti PD-L1

15

ASCO 2013, estudi fase I MPDL3280A

Tumor Typea

Estimated PD-L1 Prevalence (non-

trial samples),b ≈ %

NSCLC (SCC) 50%

NSCLC (adeno) 45%

Colon 45%

Melanoma 40%

Head and neck SCC 25%

Renal 20%

Anti-PD-1 (BMS-936558, MDX-

1106)

Design 3+3 dose escalation (MEL, RCC, NSCLC, prostate, CRC)

Objectives Safety, MTD, PK, efficacy, biomarkers

Schedule IV infusion every 2w. Doses 0.1, 1.0, 3.0, or 10.0 mg/kg

Patients n=296 (CRC, CRPC, NSCLC-122 pt-, MEL-104-, RCC -34pt)

DLTS No DLTs (10mg/Kg).

Common AE Fatigue, rash, diarrhea, pruritus, decreased appetite, and nausea (similar across the dose levels tested). (irAE: pneumonitis, colitis, hepatitis, hypophysitis, thyroiditis, vitiligo)

MTD NO MTD.

PK Linear

PD PD-1–receptor occupancy by the antibody on circulating CD3+ T cells by FACS

16

Nivolumab

Frequent (>5%)

Special Interest (>3%)

17

Nivolumab:

AEs

Nivolumab:

Eficàcia

20

Biomarcador: PD-L1

Anti-PD-L1 antibody (BMS-

936559)

Design 3+3 dose escalation Advanced NSCLC, MEL, RCC, CRC, Gastric, Pancreatic, Ovarian, Breast

Objectives Safety, MTD, PK, efficacy, biomarkers

Schedule IV infusion every 2 w of each 6-week treatment cycle. 0.3 -1 – 3 - 10.0 mg /kg

Patients n=207

DLTS No DLTs (10mg/Kg).

Common AE Fatigue, infusion reactions, diarrhea, arthralgia, rash, nausea, pruritus and headache (similar across the dose levels tested). (irAE: rash, hypothyroidism, hepatitis; sarcoidosis (1), endophtalmitis (1), DM (1), myasthenia gravis (1))

MTD NO MTD.

PK half life: 15d; dose-dependent serum levels

PD/Biomarker

s

PD-L1 occupancy on CD3+ PBMC: >65% in 4 groups

Efficacy OR in NSCLC, MEL, RCC, ovarian (at all doses of 1mg/kg or higher). 21

22

BMS-936559:

AEs

23

24

Anti-PD-1 antibody

(MK-3475- Lambrolizumab)

Anti-PD-L1 antibody

(MPDL3280A)

PD-L1 Statusa

(n = 53)

RECIST 1.1

ORRb PD Ratec

IHC 3

(n = 6)

83%

(5/6)

17%

(1/6)

IHC 2 and 3

(n = 13)

46%

(6/13)

23%

(3/13)

IHC 1/2/3

(n = 26)

31%

(8/26)

38%

(10/26)

All patients

(IHC 0/1/2/3 and

7 patients with

diagnostic

unknown;

n = 53)

23%

(12/53)

40%

(21/53)

PD-L1 (Melanoma)

a Patient experiencing ongoing benefit per investigator. Patients first dosed at 1-20 mg/kg by Oct 1, 2012; data cutoff Apr 30, 2013.

Phase Ia: Duration of

Treatment in Responders - NSCLC

0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60 63 66 69 72 75 78 81 84

Time in Study (Weeks)

1 mg/kg IV q3wk

20 mg/kg IV q3wk

10 mg/kg IV q3wk

15 mg/kg IV q3wk

15 mg/kg IV q3wk

15 mg/kg IV q3wk

20 mg/kg IV q3wk

20 mg/kg IV q3wk

20 mg/kg IV q3wk

20 mg/kg IV q3wk

15 mg/kg IV q3wk

20 mg/kg IV q3wk

Figure 1. Duration of treatment and response for NSCLC patients with response

dosed by 1 October 2012 in Study PCD4989g

On study, on treatment

Treatment discontinued

First response

First PD

On study, post treatment

Ongoing response

NSCLC = Non-small cell lung cancer

On treatment = Last Dose + 3 weeks

Duration of Treatment and Response

Time (Weeks)

Histology IHC

Nonsquamous IHC 0

Squamous IHC 3

Nonsquamous IHC 0

Nonsquamous IHC 1

Nonsquamous IHC 0

Squamous IHC 2

Nonsquamous IHC 3

Squamous IHC 3

Nonsquamous IHC 3

Nonsquamous IHC 0

Nonsquamous IHC 3

Nonsquamous IHC 1

a

25

Anti-PD-L1 antibody

(MPDL3280A)

26

Futur desenvolupament de la

immunoteràpia…

Combinació amb altres fàrmacs:

Ipilimumab + Nivolumab

29

ASCO 2013

Totes les combinacions són segures?

30

Preguntes per un immunòleg…

Lawrence MS, et al. Nature. 2013.

Somatic mutation frequencies observed in exomes from 3083 tumor-normal pairs

- immunogenicitat?

- immunocompetència?

- coexistència de mecanismes inhibidors?

-PD1 / PDL1?

31

Walter John Urba MD, PhD

Gràcies