Retratamiento y pacientes refractarios a inmunoterapia

Delvys Rodríguez Abreu, MD

Medical Oncology Dept.

Hospital Universitario Insular de Gran Canaria. Spain

Re-treatment with IO is NOT approved in any line

Re-treatment with IO is NOT approved in any line

Planchard D, et al. Ann Oncol 2018

Some considerations Post-anti PD-1/L1 therapy

➢Type of progression FOCAL VS EXTENSIVE

➢Symptomatic versus Asymptomatic

➢Previous Response to IO. Primary or secondary resistance

➢End of treatment causes. Duration of treatment (2 years?)

➢No ongoing or serious toxic effects

Different scenarios Post-anti PD-1/L1 therapy

➢Treatment Beyond Progression

➢ In metastasic setting. After Monotherapy or Combo?

➢Post IO in Locally advance, Neoadjuvant or adjuvant setting

➢Type of Standard Chemotherapy +/- anti-angiogenic use

OS Post-PD in Atezolizumab Arm: By Post-PD Treatment

Gandara et al. ASCO 2017

Treatment beyond progression…

Nivolumab data

CheckMate 063CheckMate

017

CheckMate

057

TBP based on

investigator assesmentyes yes yes

irRECIST in protocol no no no

# of pts TBP13 out of 117

(11%)

28 out of 135

(21%)

71 out of 292

(24%)

Pts with benefit4 out of 117

(3%)

9 out of 135

(7%)

16 out of 292

(5%)

Benefit: Subsequent response or SD for 2 assessments (12 weeks) or 10% decrease if single

oligoprogressive lesion

Rizvi, Lancet 2015; Brahmer, N Engl J Med 2015; Borghaei, N Engl J Med 2015

Presented by: Solange Peters: ASCO 2017

Treatment Beyond Progression With Immune Checkpoint Inhibitors

Blumenthal GM et al. JAMA Oncol 2017

Recommendationsfrom FDA in USA

Beaver J, et al. Lancet Oncol 2018

Is anti PD1/L1 rechallenge effective?

• After Manteinance or Neo/Adjuvant therapy.

• Metastatic disease. First or Second Line.

Early Stage Locally advanced

No Data!!!

Rechallenge…KN 010: Pembrolizumab in previously treated advanced NSCLC

Herbst R, et al. ESMO 2018

▪ 79 patients completed 35 cycles or 2 years of pembrolizumab

▪ 95% patients had a complete response or partialresponse

▪ Response was ongoing in 64% of patients

14 pts received second course pembro43% PR and 36% SD

Bernard-Tessier A, et al. Eur J Cancer 2018

25% PR, 75% SD, PFS 2 12.9m (range 5- 35.4m)

Exploratory Analysis

• Improvement in PFS (HR 0.42), 1 year PFS:

65% vs40%

• Improvement in PFS independent from RR

• Trend in OS (HR 0.63)

• Some stabilizations by reexposure

A Signal – CheckMate 153

Spigel D et al, ESMO 2017; abstract 1297O

PET may be useful in predicting long term benefit?

Tan et al. Annals Oncoloy 2018, 29: 2115

PET can be an option for detecting activity of disease & may help guide discontinuation of therapy

SBRT+ IO

Luke et al. J Clin Oncol 2018

RETREATMENT?

NOT ALLOWED IN SPAIN!!

CHEMOTHERAPY AFTER IO: DOES IT WORK BETTER?

Some rationale:

• Selection of chemosensitive tumor cells under IO exposure

• IO can modify tumor micro-environment increasing sensitivity to chemo

• Chemotherapy can boost the immune response

• Chemotherapy can destroy some resistance mechanism of IO

• Still IO in blood at the same time with CT.

Aspeslagh S, et al. Eur J Cancer 2017

355 charts reviewed in 3 centers between 2011-2016RR 27%

Rothschild et al. ELCC 2017 Grigg C, et al. ASCO 2017

Schvartsman G, et al. Lung Cancer 2017

Curvas de Kaplan-Meier para supervivencia libre de progresión (PFS). Adaptado de Corral J, et al. Clin Transl Oncol. 2019 Feb 15.

Tiempo (meses) Tiempo (meses) Tiempo (meses)

Mediana de la PFS con IO Mediana de la PFS con

docetaxel + nintedanib

Mediana de la PFS

(IO seguido de docetaxel + nintedanib

)

Tiempo (meses) Tiempo (meses) Tiempo (meses)

mesesmesesmeses

rangorangorango

Adaptado de Corral J, et al. Clin Transl Oncol. 2019 Feb 15.

Supervivencia libre de progresión (SLP) obtenidas en cada paciente

con las diferentes terapias consecutivas .

La combinación de docetaxel + nintedanib tras 2L inmunoterapia en los pacientes

del programa de uso expandido (NPU) nacional produce un aumento de la ORR y

SLP independientemente del nivel de expresión de PD-L1

Efficacy of 2nd line chemo post IO?

mPFS2 on second-line therapy

21.5 (87.5% platinum-based)

versus 8.5 (94.4% IO)

Rina Hui et al, COSA 2017

0 3 6 9 1 2 1 5 1 8 2 1 2 4 2 7 3 0 3 3

0

1 0

2 0

3 0

4 0

5 0

6 0

7 0

8 0

9 0

1 0 0

T im e , m o n th sP

FS

2,

%

P e m b r o 1 5 4 1 3 4 1 1 7 1 0 8 9 6 8 0 7 3 6 4 3 8 1 2 3 0

C h e m o 1 5 1 1 2 2 1 0 0 6 4 5 7 4 2 3 5 2 5 1 3 7 2 0

N o . a t r is k

67.6%41.8%

49.7%19.0%

Events, n HR (95% CI)

Pembrolizumab 73 0.46 (0.34–0.62)

Chemotherapy 113

Median (95% CI)21.5 mo (14.8 mo–NR)8.5 mo (7.2–11.4 mo)

Keynote 024 progression after the next line of therapy (PFS2): THE SEQUENCE MATTERS…

INSIGNA: ECOG/SWOG Advanced Non-squamous Trial with Pembrolizumab

▪ Primary Endpoint: OS▪ Overall Objective: Determine which approach is of greatest

benefit in 1st line therapy of Non-Squamous NSCLC

Pembrolizumab

Induction Maintenance

2nd Line Treatment

Carbo/Pemetrexed/Pembrolizumab

Pembrolizumab

Pemetrexed/Pembrolizumab

Carbo/Pemetrexed/Pembrolizumab

Not Specified

Carbo/Pemetrexed≥1

% T

PS

po

siti

ve

Ran

do

miz

atio

n*

Arm B

1st Line Treatment

Post-Progression

Advanced Non-squamous

NSCLC

PIs: H. Borghaei (ECOG) and A. Chiang (SWOG)

REPLAY TRIAL SLCG

Multi-center exploratory phase II trial of Pembrolizumab (200 mg ) as second or further line withNSCLC who have failed to a prior treatment with anti-PDL1 drug

Primary:Overall Response Rate(ORR) per RECIST v1.1and irRC

Secondary:• Progression Free Survival (PFS) per

RECIST v1.1 and irRC• Overall Survival (OS) per RECIST v1.1

and irRC• Safety

Advanced/metasta

tic NSCLC ≥2nd

line who have

failed prior

PD1/PDL1

checkpoint

inhibitor

Response or Stable Disease

for at least > 16 weeks

Experience PD while on treatment

OR PD < 12 weeks after stopping

treatment

Stop treatment and PD > 12 weeks

after stopping treatment

Re-Treatment with

Pembrolizumab

Chemotherapy ≥ 4 cycles

(free election for the PI)

Re-Treatment with

Pembrolizumab

PD PD

PD

Cohort 2

Cohort 1

Bx

Bx110 patients.

Up to 2 y.

Up to 2 y.

Courtesy Dr. S Ponce

Why and where the treatment fails.?

Chen. Immunity 2013 39, 1-10

A new era in cancer care

3394 immunotherapy agents in development 2018

Tang et al. (doi:10.1038/nrd.2018.210)

CD 40 agonist

Ca

ncer

an

tig

en

pre

sen

tati

on

Phase 1b/2 of CD40 agonistic antibody APX005M in combination with nivolumab (nivo) in subjects with metastatic melanoma (M) or non-small cell lung cancer (NSCLC)

Harriet Kluger1,*, Sarah A. Weiss1,*, Anthony J. Olszanski2, Lynn Schuchter3, Gerald P. Linette3, Linda Garland4, Nicholas O. Iannotti5, Melissa Johnson6, Emin Avsar7, Minu K. Srivastava8, Ovid C. Trifan8, Martin J. Edelman2

Conclusions: APX005M + nivo demonstrated a good safety profile and promising antitumor activity in M subjects withPD while receiving anti-PD-1 therapy and potential activity in NSCLC. The study is currently enrolling subjects in the 2nd

stage of the Phase 2 M cohort and the 1st stage of the Phase 2 NSCLC cohort. Clinical trial information: NCT03123783.AACR-18

Pri

min

ga

nd

ac

tiv

ati

on

Mayes, Nat Rev Drug Discovery 2018

• M7824 (PD-L1 / TGFb trap)

• ALT-803 (nivolumab / IL15)

• NKT214 (nivolumab / IL2)

• Peglodecakin (PD-1 / IL10)

• CEA-IL2

New strategies specifically exploited in NSCLCCytokines

Infi

ltra

tio

n o

f T

ce

lls

in

to t

um

ors

• ORR overall patient population 21.3% (DCR 34.5%)• ORR 27.6% and 61.5% for PD-L1+ and PD-L1 high, respectively

Pretreated, IO naive

ALT-803, an IL-15 superagonist with nivolumab

• Interleukin-15 is critical for proliferation and activation of NK cells and CD8+ memory T cells

• IL-15 exhibits potent antitumor activities in animal models

• Limitating factors in the development of IL-15-based approaches weredifficulties in production and the short in vivo half-life of IL-15

• ALT-803, consists of an IL-15 mutant (IL-15N72D) with improved affinityfor CD122-expressing immune cells, bound to an IL-15 receptor α/IgG1 Fc fusion protein

Steel, et al. 2012

Infi

ltra

tio

n o

f T

cells in

to t

um

ors

Infi

ltra

tio

n o

f T

cell

s in

to t

um

ors

NTRK-214: IL-2 has pleiotropic immune stimulatoryeffects that may limit its anti-tumor activity

• NKTR-214 prodrug design with sustained signaling

• Preferentially activates effector T cells and NK cells over Tregs

• NKTR-214 increases proliferation of TILs and PD-1 expression on the surface of CD8+ T cells

NKTR-214 + nivolumab can convert PD-L1(-) tumors to PD-L1(+)

• Patients that were PD-L1(+) at baseline, or converted to PD-L1(+) after start of treatment showed greatest clinical benefit

Baseline:PD-L1 Negative

Week 3:PD-L1 Positive

Patient with Urothelial Carcinoma

Stage IV IO-Naïve 1-2L NSCLC Dose Escalation Cohort (N=5)

Best Overall Response by RECIST (2L): ORR=3/4 (75%); DCR=3/4 (75%)Best Overall Response by RECIST (1L and 2L): ORR=3/5 (60%); DCR=4/5 (80%)

SITC 2017 (Data Cut: Nov 2, 2017) ASCO 2018 (Data Cut: May 29, 2018)

- 1 0 0

- 8 0

- 6 0

- 4 0

- 2 0

0

2 0

4 0

Be

st %

Ch

an

ge

by

RE

CIS

T 1

.1

C R

- 1 0 0

- 8 0

- 6 0

- 4 0

- 2 0

0

2 0

4 0

Be

st %

Ch

an

ge

by

RE

CIS

T 1

.1

C R

u C R

Diab, ASCO 2018

NKTR-214 in combination with nivolumab showed encouraging anti-tumor activity with notable ORR in PD-L1 negative patients (42% melanoma, 53% RCC, 60% urothelial)

Pegilodecakin + Anti-PD-1 in NSCLC

P-STAT1P-STAT3

▪ IL-10 receptor is expressed on CD8 cells upon cancer cell recognition

▪ PEG-IL-10 (pegilodecakin) increases CD8 T cells cytotoxicity, proliferation and survival

▪ Pegilodecakin induced clonal T cell expansion in patients

Proliferation Survival

0 1 6 3 2 4 8 6 4 8 0 9 6 1 1 2 1 2 8

- 1 0 0

0

1 0 0

2 0 0

I H s p i d e r S C A N N S C L C ]

w e e k s

Ch

an

ge

in

Tu

mo

r B

urd

en

(ir

RC

%)

- 5 0 %

2 5 %

L e g e n d

Pegilodecakin might increase anti-PD-1 efficacy in IO naive

Disease

Treatment Combo(n=Evaluable Patients/

Enrolled Patients)

Prior Therapies

Median (Range)

DCR

(%)

ORR

(%)

mPFS

(Months)

mOS

(Months)

mFollow-up

(range)

Months

NSCLC

AM0010 (n=7/9)1 3 (1-7) 57% – 1.8 15.4

AM0010 + pembrolizumab (n=5/5)2 2 (0-5) 100% 2 (40%) 11 32.2 37.3 (35.9;39.1)

AM0010 + nivolumab (n=22/29) 2 (0-5) 82% 9 (41%)4 NR NR 23.2 (9.1;32.0)

AM0010 + anti-PD-1 (n=27/34) 2 (0-5) 85% 11 (41%) NR NR 24.7 (9.1;39.1)

Anti-PD-1 (Pembrolizumab)

(Garon NEJM 2015)1 41% 19.4% 3.06 9.35

(1) 5 of 5 patients tested are PD-L1 negative; (2) 4 of 4 patients tested are <1% PD-L1+; (3) Clinical trial in progress. Numbers as of May 1, 2018. Median follow-up as indicated; (4) Clinical trial in progress. Numbers as of May 1 2018. Median follow-up as indicated) (5) Garon et al NEJM 2015, previously treated patients; NR:Not reached

421

5- 0

00

2

08

- 00

37

10

- 00

01

09

- 00

11

08

- 00

27

01

- 00

25

08

- 00

22

03

- 00

23

15

- 00

05

01

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30

08

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28

15

- 00

04

01

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19

02

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80

03

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15

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01

10

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06

15

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06

11

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02

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05

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85

09

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- 1 0 0

- 5 0

0

5 0

1 0 0

2 0 0

3 0 0

2 5

Ch

an

ge

in

Tu

mo

r B

ur

de

n i

rR

C (

%)

P D - L 1 > 5 0 %

P D - L 1 < 1 %

P D - L 1 1 - 4 9 %

• Adenosine A2A receptor (CPI-444) / atezolizumab

• CD73 (BMS-986179) / nivolumab

• CD73 (MEDI 9447) / durvalumab

• Adenosine A2A receptor / CD73

New strategies specifically exploited in NSCLCAdenosine pathway

Infi

ltra

tio

n o

f T

cells in

to t

um

ors

Adenosine A2A receptor inhibitor CPI-444 +/- atezolizumab

Fong, ASCO 2017

Immune checkpoints

Chen L et alNature Reviews Immunology 13, 227-242 (April 2013)

Tum

or

ce

llki

llin

g

CheckpointsLAG-3 and T cell exhaustion: clinical scenario

• Negatively regulates T-cell activation and proliferation

• Interaction with MHC class II

• LAG-3 can mediate primary or acquired resistance

• Coexpression of severalinhibitory receptors withearly PD-1 and late LAG-3

TCR

T cell

PD-1

LAG-3

Tumorcell

PD-L1

MHC-II

TCR

T cellPD-1

TCR

T cell

PD-1

LAG-3

Tumorcell

PD-L1

MHC-II

αLAG-3 MAB αPD-1 MAB

I-O naive

αPD-1 escape

I-O naive

I-O refractoryPD-1blockade

Adapted from Ascierto, ESMO 2017

TCR

T cell

CD4 or CD8Effector T cell

Company Drug Study phase Cancer type Combination

BMS relatlimab

Phase 1,2, and 3Phase 1/2 NSCLC NCT01968109; NCT02750514

Solid tumorsHaematologicalmalignancies

NivolumabPhade 1/2 CA224-048 ipi+nivo+relatlimab 1L NCT03459222

Novartis LAG525 Phase 1, 2Solid tumorsHaematologicalmalignancies

spartalizumab

MSD MK4280 Phase 1 Solid tumors pembrolizumab

Regeneron/Sanofi REGN3767 Phase 1 Solid tumors cemiplimab (anti-PD-1)

Macrogenics MGD013 Phase 1Solid tumorsHaematologicalmalignancies

-

Tesaro TSR-033 Phase 1 Solid tumors Anti-PD-1

Boehringer/ Ingelheim - Sarah Cannon Research Institute

BI754111 preclinical - BI754091 (anti-PD-1)

Agenus/Incyte Not available preclinical - -

PRIMA IMP321 Phase 1,2 Solid tumorspembrolizumab, chemotherapy

Davar, SITC 2018

• TILs

• TILs / nivolumab

• TILs / durvalumab

• TCRs

New strategies specifically exploited in NSCLCAdoptive T cell therapy

TIL (tumor infiltrating lymphocytes) based adoptive cell transfer

Pre-TIL

3 0 6 0 9 0 1 2 0 1 5 0 1 8 0

- 8 0

- 7 0

- 6 0

- 5 0

- 4 0

- 3 0

- 2 0

- 1 0

0

1 0

2 0

3 0

4 0

5 0

6 0

7 0

8 0

% C

ha

ng

e in

T

um

or S

ize

vs

B

as

eli

ne

T i m e f r o m f i r s t n i v o l u m a b ( d a y s )

N i v o lu m a b

P R

P D

N iv o l u m a b o n g o i n g

T I L , I L 2

3 0 6 0 9 0 1 2 0 1 5 0 1 8 0 2 1 0

- 6 0

- 5 0

- 4 0

- 3 0

- 2 0

- 1 0

0

1 0

2 0

3 0

4 0

5 0

6 0

7 0

8 0

% C

ha

ng

e in

T

um

or S

ize

vs

p

re

-T

IL

T i m e f r o m T I L s t a r t ( d a y s )

T I L , I L 2 M a in t e n a n c e N iv o l u m a b

P R

P D

T r e a t m e n t o n g o in g

1 2

0 9

0 8

0 7

0 5

0 4

0 3

0 2

0 1

1 3

1 4

Teer J et al. WCLC 2018

Post-TIL

Anti PD1/L1 Clinical

Trials

▪ 1 in 2006

• 2,250 in Sept 2018

• 1716 in combination

• 339 with CTLA-4

• 283 with Chemo

254 Trials in

Lung

Cancer

All the

best is

yet to

come!!

THANK YOU!!

Dr. Delvys Rodríguez AbreuHospital Universitario Insular de Gran Canaria.

Spain@delvysra

drodabr@gobiernodecanarias.org