Immune checkpoint inhibitors in other thoracic malignancies

Mesothelioma and thymic malignancies

Enriqueta Felip

Vall d’Hebron University Hospital

and Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain

Madrid, 2-3 February 2017

Rare thoracic cancers

89 population-based cancer registries (1978-2002), followed until 31st Dec 2003

5-year OS

19 cases /million / year

1.3 cases /million / year

1.7 cases /million / year

Incidence

Siesling, Eur J Cancer 2012

Malignant pleural mesothelioma (MPM): outline

• Epidemiology, pathology

• Treatment

• Immunotherapy

Epidemiology

� MPM is a rare tumor with increasing incidence and poor prognosis

� Asbestos is the principal etiological agent of MPM (80%) (Wagner 1960, Elmes

1965)

� Long latency period (mean 20-40 yrs) after exposure (Stayner L, 2013)

� In Spain (López-Abente, 2013):

� incidence (2016-2020): 1,319 pleural cancer deaths (264 deaths/yr)

� Asbestos banned in 2001 but risk will increase until 2040

� Efficacy of a large scale screening, not yet established

Epithelioid

60%

Sarcomatoid

20%

Mixed (Biphasic)

20%

MPM classification (WHO 2004)

• Recommendations (ESMO 15):

– Recognition of tissue invasion is required for definitive diagnosis [IV, A]

– Surgical-type samples preferred for diagnosis [IV, A]

– Subtype diagnosis (epithelioid, biphasic, sarcomatoid) should be given in all cases

[IV, A]

ESMO, Baas, Ann Oncol 2015

Treatment

� Cis/pem, approved 1st line therapy, median OS of ≈13 mo

� No therapies approved for 2nd-line

� Options include combination therapy or monotherapy with

vinorelbine or gemcitabine, RR < 10%

VAT-PP (N=87)

Talc-pleurodesis (N=88)

Similar 1-y OS with VAT-PP higher surgical complications

1 year OS 52% vs 57% (p=0.83)

Rintoul, Lancet 2014

Antiangiogenic agents in MPM

MAPS Trial

Zalcman, Lancet 2015

N=448

PFS: 9.2 vs. 7.3, HR: 0.61, p<0.001

Nintedanib/pemetrexed/cis in patients with MPM: phase II

findings from placebo-controlled LUME-Meso trial

• ORR 59% vs 44% with nintedanib vs placebo

Grosso et al. J Thorac Oncol 2016; 11(suppl): abstr OA22.02

Nintedanib Placebo

Median PFS (95%CI), months

9.4 (6.7, 11.2)

5.7 (5.5, 7.0)

HR (95%CI); p-value 0.56 (0.34, 0.91); p=0.017

PF

S,

%

100

80

60

40

20

0

PFS

Time from randomisation, months

0

44

43

Patients at risk

2

38

38

4

35

32

6

27

16

8

22

9

10

15

4

12

12

3

14

4

2

16

2

2

18

2

1

20

1

1

22

0

1

24

0

26 28

Anti-mesothelin agents

• Mesothelin, tumor antigen highly expressed in many human

cancers, including malignant mesothelioma, pancreatic and

ovarian cancer

• Two anti-mesothelin agents currently in registration trials for

malignant mesothelioma

– Amatuximab (chimeric anti-mesothelin antibody) in 1st-line

– Anetumab ravtansine (mesothelin-directed antibody drug

conjugate) in 2nd-line

Phase II amatuximab

Amatuximab 5 mg/kg D1,8

Pemetrexed / Cisplatin

N=89

PFS: 6.1mo

OS: 14.8 mo

PR: 41%

Low vs. High (mo): 18.5 vs. 12.5

Ongoing Ph II: NCT02357147, n=560

Hassan, Clin Cancer Res 2014

Phase I anti-mesothelin antibody drug conjugate

anetumab ravtansine

Hassan. et al, WCLC 2015

38 at the MTD (6.5 mg/kg q3w): 16 mesothelioma

PR (31%)

SD (44%)

PD (25%)

On study > 2.5 years

Molecular characterization of MPM

(WES and expression)

• NF2 (17%) and BAP1 (25%), recurrent driver mutations in MPM

• Mutations in genes involved in chromatin modification

• Up-regulation of WNT and MAPK signaling

BRCA1-associated protein (BAP1)

Landanyi CCR 2012; Bott, Nat Genet 2011; Testa, Nat Genet 2011, Zauderer, JTO 2011

Mutations in BAP1 gene in 21%

No differences in OS by BAP1 status

Germline BAP1 mutations exist

Uveal MM, melanocityc nevi, RCC

New “undefined” syndrome

CAR-T cells

• T cells genetically engineered to express a chimeric antigen

receptor (CAR) have emerged as a promising therapeutic approach

for cancer treatment

• MSKCC Mesothelin-targeted CAR T-cell therapy (NCT02414269)

– A Phase I Clinical Trial of Malignant Pleural Disease Treated With

Autologous T Cells Genetically Engineered to Target the Cancer-

Cell Surface Antigen Mesothelin

CAR T cells for mesothelioma, the FAPME trialUniversity Hospital Zurich

FAP (fibroblast

activation protein):

expressed in about

90% of epithelial

cancers

FAP

T cell

Tumor cell

Targeting

element

Activation

FAP

Phase I study for the adoptive transfer of re-directed FAP-

specific T cells in the pleural effusion of patients with MPMUniversity Hospital Zurich; PI: A.Curioni-Fontecedro

Phase I trial for patients with MPM with pleural effusion testing the safety of a fixed

single dose of 1x10e6 adoptively transferred FAP-specific re-directed T cells given

directly in the pleural effusion. Lymphocytes will be taken 21 days before transfer from

peripheral blood. CD8 positive T cells will be isolated and re-programmed by retroviral

transfer of a chimeric antigen receptor (CAR) recognizing FAP which serves as target

structure in MPM

MPM, an immunogenic disease?

Shalapour, J Clin Invest 2015

Latency period

20-40 years

Chronic inflammation promotes tumor development

MPM, an immunogenic disease?

Lower mutational-load in MPM compared to 12 other cancer types

Rizvi, Science 2015; Bueno, Nat Genet 2016

In NSCLC, mutational-load & neoantigen correlates with efficacy

PD-L1 expression in MPM

Mansfield Cedres Alley Thapa

N 106 77 80 329

Epithelial 68 53 NR 203

Non-epithelial 38 24 NR 126

Antibody used5H1-A3-mouse

monoclonal

E1L3N-rabbit

IgG (cell

signaling)

22C3-mouse

monoclonal

E1L3N-rabbit

IgG (cell

signaling)

Criteria of

positivity

>5%

membranous

and/or

cytoplasmic

staging

>1%

membranous

and/or

cytoplasmic

staging

>1%

membranous

staging

>5%

membranous

staging

% of PDL1

positivity40 20.7 45.2 41.7

Prognosis worse worse NR worse

Mansfield, JTO 2014; Cedrés, PLos One 2015; Alley, WCLC 2015; Thapa, ASCO 2016

MPM, an immunogenic disease?

High PDL1 positive >50% by E1L3N

Only 10% of MPM has high PDL1 expression associated with strong

immune cell infiltrate

Thapa – ASCO 2016 (Abstract 8518)

Non-inflamed Inflamed

Anti-CTLA-4 in MPM: phase II

Calabró, Lancet Oncol 2013; Calabró, Lancet Resp Med 2015

MESO-TREM 2008 MESO-TREM 2012

DoseTremelimumab 15 mg/kg Q90d

until PD

Tremelimumab 10 mg/kg Q4w

x 6, then Q12w until PD

N 29 29

End-Point ORR of 17% by mRECIST % of immune-related RR

RR / DCR By RECIST 6.8% / 37.9%By RECIST: 3.4 % / 38%

By irRC: 13.8% / 65.5 %

PFS (mo) 6.2 6.2

OS (mo) 10.7 11.3 (15.8 in biphasic)

1-yr OS (%) 48% 48.3%

G 3-4 AEs 14% 7%

DETERMINE, tremelimumab phase IIb trial

Kindler – ASCO 2016 (A 8502)

DETERMINE, tremelimumab phase IIb trial

Kindler, ASCO 2016 (A 8502)

No survival benefit in any pre-specified subgroup of patients

• mPFS at 24 wks, not different by PDL1 status (39.2% vs 40.7% for PDL1+ vs PDL1-)

Avelumab in pts with advanced unresectable mesothelioma from

the JAVELIN solid tumor phase Ib trial

Hassan et al. J Clin Oncol 2016; 34 (suppl): abstr 8503

Best overall response by RECIST 1.1 n=53

CR, n (%) 0

PR, n (%) 5 (9.4)

SD, n (%) 25 (47.2)

PD n (%) 18 (34.0)

Non-evaluable, n (%) 5 (9.4)

ORR, % (95%CI) 9.4 (3.1, 20.7)

Disease control rate, % (95%CI) 56.6 (42.3, 70.2)

ORR according to PD-L1 expression level

Staining cut-off level (n=39) PD-L1+ PD-L1-

≥1% tumor cells 2/20 (10.0) 2/19 (10.5)

≥5% tumor cells 2/14 (14.3) 2/25 (8.0)

≥25% tumor cells 0/7 (0.0) 4/32 (12.5)

≥10% tumor-infiltrating immune cells 0/6 (0.0) 4/33 (12.1)

Long-term OS for patients with MPM

on pembrolizumab enrolled in KEYNOTE-028

aPatients could have received ≥1 type of prior therapy.

Data cutoff date: June 20, 2016.

6165 – EW Alley

Characteristic, n (%) N = 25

Age, median (range), years 65.0 (32-86)

Male 17 (68.0)

Race

White

Asian

Not specified

21 (84.0)

2 (8.0)

2 (8.0)

ECOG performance status

0

1

9 (36.0)

16 (64.0)

Prior lines of therapy

0

1

≥2

2 (8.0)

15 (60.0)

8 (32.0)

Characteristic, n (%) N = 25

HistologyEpithelioidSarcomatoidBiphasicNot specified

18 (72.0)2 (8.0)2 (8.0)

3 (12.0)

Prior therapiesCisplatin/carboplatinPemetrexedGemcitabineVinorelbine

22 (88.0)21 (84.0)

4 (16)1 (4)

•Positivity: membranous PDL1 expression in

≥1% of tumor, associated

inflammatory cells or positive staining in

stroma

•MPM: of 80 evaluable samples, 38 PDL1+

(45.2%)

Confirmed Objective Response Rate (RECIST v1.1, investigator review)

Best Overall Response n % 95% CI

Complete response 0 0 0-13.7

Partial response 5 20.0 6.8-40.7

Stable disease 13 52.0 31.3-72.2

Progressive disease 4 16.0 4.5-36.1

No assessment/not evaluable 3 12.0

Duration of response, median (range), months 12.0 (3.7-20.5+)

Objective response rate: 20.0% (95% CI, 6.8%-40.7%)

Clinical benefit rate (CR + PR + SD ≥6 months): 40% (95% CI, 21.1%-61.3%)

6165 – EW Alley

Progression-Free Survival

(investigator review)

PFS N = 25

Events, n (%) 21 (84.0)

PFS, median (95% CI),

months5.4 (3.4-7.5)

6165 – EW Alley

Overall Survival

OS N = 25

Events, n (%) 14 (56.0)

OS, median (95% CI),

months

18.0

(9.4-not

reached)

6165 – EW Alley

Phase II trial of pembrolizumab in patients with

malignant mesothelioma

• 1-2 prior regimens

• No patient selection based on PDL1 expression

• 34 patients included, 74% epithelioid

• 21% PR, 56% SD, 6.2 months PFS

• RR according to PDL1 expression:

– 17 patients, PDL1 negative, 2 PR (12% RR)

– 15 patients, PDL1 > 1%, 4 PR (27% RR)

Kindler WCLC 2016

Phase II study of nivolumab in MPM (NivoMes)

• 1-2 prior regimens

• 34 patients included, 28 epithelioid

• PDL1 expression 0% 20 patients vs 1-5% 4 patients vs 25-50% 3

patients vs > 50% 3 patients

• 15% PR / 35% SD; 33% disease control at 24 weeks

• Response seen in all groups irrespective of PDL1 expression

• 110 days median PFS

Baas WCLC 2016

Trial

Keynote-028

Pembrolizumab

Alley WCLC

2016

NivoMes

Nivolumab

Baas WCLC

2016

Pembrolizumab

Alley WCLC

2016

Avelumab

Hassan ASCO

2016

Nº pts25

PDL1+

34

unselected

34

unselected

53

unselected

PR 20% 15% 21% 9.4%

SD 52% 35% 59% 47.2%

DCR 72% 50% 80% 56.6%

PD 16% 50% 20% 34

DOR12.0 mo

(3.7 -20.5+)n.a. not reached n.a.

Anti-PD1 & anti-PDL1 in MPM

Efficacy of immunotherapy as 2nd line better than historic controls

PROMISE-ME

Multicenter randomized phase III study comparing pembrolizumab vs standard

chemotherapy for advanced pre-treated MPM patientsTrial Chair: A.Curioni-Fontecedro (CH) and S. Popat (UK)

Malignant pleural mesotheliomaafter/on previous chemotherapy

1 : 1R

Pembrolizumab 200mg fixed dose i.v. day 1 of each 3-week cycle

Chemotherapy by institutional choiceGemcitabine 1000 mg/m2 d1/d8, q3w i.v. orVinorelbine 30 mg/m2 d1/d8, q3w i.v. orVinorelbine 60/80 mg/m2 d1/d8 q3w p.o.

• • •

CTCT

3Week 6 9 18 270≤-4 39

• • •

until PD by RECIST 1.1for max 2 years*

Blood

FFPE

BloodBlood

CT CT CT CT

Progression of

disease

(FFPE)

Progression of

disease

• • •

* continuation beyond PD in case of clinical benefit

Primary Endpoint: Progression-free survival

MAPS 2: phase II trial in mesothelioma

Recruitment expected in ~18 months, real: 4 months!!!

Malignant MesotheliomaReceived 1 or 2

chemotherapy regimensPS 0-1

Nivolumab 3mg/kgQ2W

Nivolumab 3 mg/kg Q2W+

Ipilimumab 1mg/kg Q6WEnd point: DCR

NCT02588131: NIBIT-MESO-1 phase II trial, tremelimumab and durvalumab

N=114

Immunotherapy as 1st line

Advanced NSCLC PDL1> 50%

KEYNOTE-024 Trial

Reck, NEJM 2016

HR 0.60; 95% (0.41-0.89)

P = 0.005

Advanced MPM PDL1> 1%

KEYNOTE-028 Trial

No relationship between

PDL1 expression and RR

Alley, WCLC 2016

NCT02784171: Cis/pem vs. cis/pem/pembrolizumab vs. pembrolizumab

NCT02899299: CheckMate743, PhIII, nivolumab + ipililumab vs. cis/pem

NCT02899195: Durvalumab concurrent vs. sequential to cis/pem

Immune checkpoint inhibitors in MPM: summary

• CTLA-4 inhibitors as single agent, unlikely to be active

• Single agent PD1/PDL1 inhibitors have shown promise

� Safety signals consistent with other settings

• Combination of immune-studies are eagerly awaited

� Combining anti-PD1/PDL1 with CT

o Pem/cis +/- durvalumab

� Combining anti-PD1/PDL1 with CTLA-4 inhibitors

o Nivo+/- ipilimumab

• Ongoing randomized trials in 1st and 2nd line

Thymic epithelial tumors (TEP): outline

• Epidemiology, pathology

• Treatment

• Immunotherapy

• TETs, a heterogeneous group of rare thoracic malignancies

• Mean age at diagnosis, 50-60 yrs

• Genetic risk factors, such as multiple endocrine neoplasia I (MEN1), may

influence the development of TETs

• One-third of patients with thymoma present with autoimmune disease,

mainly myasthenia gravis

Neuromuscular

Myasthenia gravis

Peripheral neuropathy

Polymyositis

Dermatomyositis

Encephalitis

Optical myelitis

Haematologic disorders

Red cell aplasia

Pernicious anaemia

Erythrocytosis

Pancytopoenia

Haemolytic anaemia

Leukaemia

Multiple myeloma

Collagen and

auto-immune disorders

Systemic lupus erythematosus

Rheumatoid arthritis

Sjogren’s syndrome

Scleroderma

Endocrine disorders

Multiple endocrine neoplasia

Cushing’s syndrome

Thyrotoxicosis

Pneumonitis

Dermatologic disorders

Pemphigus

Lichen planus

Chronic mucosal candidiasis

Alopecia areata

Miscellaneous

Giant cell myocarditis

Nephrotic syndrome

Ulcerative collitis

Hypertrophic arthropathy

Interstitial pneumonitis

Immune deficiency

Hypogammaglobulinaemia

T-cell deficiency syndrome

Autoimmune disorders associated with thymomas

• WHO 2015

A AB B1 B2 B3

“Médullary” Mixed “Cortical”

Histo-pathologic classification

SCC

Thymoma Carcinoma

• Surgery remains the mainstay

• RT and CT have also been applied widely as

adjuvant and palliative procedures

• Recurrence of TETs (10-15% of all-stage

resected tumors) should be managed

according to the same strategy as newly

diagnosed tumors

• Several consecutive lines of CT may be

administered when the patient presents

progression

Treatment of TETs

TIMER

Reference Study

population

Study treatment ORR OS

Bonomi et al 1993 21 patients Cisplatin 50 mg/m2/3 wks 10% 76 w

Highley et al 1999 15 patients Ifosfamide 1.5 g/m2 × 5 dd/3 wks 46.2% 5y OS 57%

Loeher et al 2006 27 patients (11

CT)

Pemetrexed 500 mg/m2/3 wks 17% NR

Reference Study

population

Study treatment ORR OS

Fornasiero et al.,

1991

37patients cisplatin, doxorubicin, vincristina and

cyclophosphamide;

92 15

Loehrer et al 1994 30 patients cisplatin, doxorubicin, cyclophosphamide; 50 38

Kim et al 2004 22 patients cisplatin, doxorubicin, cyclophosphamide,

prednisone

77 NR

Giaccone et al 1996 16 patients cisplatin, etoposide 56 4.3 y

Loehrer et al 2001 28 patients cisplatin, etoposide, ifosfamide; 32 31.6 m

Lemma et al 2011 46 patients Carboplatin, paclitaxel 42.9 20 m

Hirai et al 2015 40 patients Carboplatin, paclitaxel 36 7.5 m

Chemotherapy in TET

Lancet Oncol 2015; 16: 177

Thymic carcinomaPFS: 7.6 mo

ThymomaPFS: 8.5 mo

KIT wild-type tumors

TETs: PDL1 expression

Techniques Thymoma Thymic

carcinoma

Antibody Cohort

(n)

PDL1

positive

(n, %)

PDL1

negative

(n, %)

Cohort

(n)

PDL1

positive

(n, %)

PDL1

negative

(n, %)Katsuya,

Lung Cancer 15clone E1L3 101 22 (23%) 79 (77%) 38 26 (70%) 12 (30%)

Padda,

JTO 15clone 5H1 65 44 (68%) 21 (32%) 4 3 (75%) 1 (25%)

Yokoyama

Ann Thorac Sur

16

clone

EPR1161

82 44 (54%) 38 (46%) - - -

• Lymphocyte agglomerates mainly observed in type AB, B1 and B2

thymomas, less frequent in B3 thymomas and thymic carcinomas

• In TET lymphocytic infiltration & evidence of PDL1 expression support

immune-checkpoint inhibition strategies

Phase II study of pembrolizumab in patients with

recurrent thymic carcinoma

• Ongoing phase 2 study in patients with thymic carcinomas who had progressed

after ≥1 CT; patients treated with pembrolizumab 200 mg q3w for up to 2 yrs

• Key results

– 30 patients included

– RR 24% (1 CR, 5 PR, 10 SD, 9 PD)

– mPFS 36 weeks

– G 3- 4 toxicities reported in 4 patients;

one with severe myositis/miocarditis

requiring pacemaker placement and the

other having emergence of type 1 diabetes

• Conclusion

– Encouraging activity of pembrolizumab in thymic carcinoma

Giaccone et al. J Clin Oncol 2016; 34 (suppl): abstr 8517

Safety and clinical activity of avelumab (anti-PDL1) in

patients with advanced TETs

Rajan et al. J Thorac Oncol 2016; 11(suppl): abstr OA18.03

Primary endpoint

• ORR by RECIST 1.1

Secondary endpoints• Evaluation of tumour cell PD-L1 expression

• Peripheral blood immune subset analysis

Avelumab

10 mg/kg q2w

(n=5)a

PD / toxicity

Key patient inclusion criteria

• Thymoma or thymic carcinoma

• Previously treated with ≥1

standard therapies

• No prior immune checkpoint

inhibitors

• No history of autoimmune

disease

(n=8)

Avelumab

20 mg/kg q2w

(n=3)b

PD / toxicity

a4 patients with thymoma and 1 patient with thymic carcinomabAll thymoma

Safety and clinical activity of avelumab (anti-PD-L1) in

patients with advanced TETs

Conclusions

�Avelumab is active in patients with recurrent TETs

�Strategies to be developed to lessen the risk of development of

irAEs in response to immune checkpoint inhibitor therapy

• 4 / 8 patients with PR

• G3-4 irAEs observed in 5 cases

Targeting immune checkpoints: PDL1

EORTC-ETOP NIVOTHYM

Primary endpoint: PFS rate at 6 months

Secondary endpoints:

- ORR and DCR, Duration of response

- OS

- QOL

- Safety

Eligible patients Nivolumab 240 mg IV q2 weeks

Primary objective:

To detect activity of nivolumab as single agent as second line treatment

for type B3 thymoma and thymic carcinoma

Biomarkers: SPECTA

PD-L1

Cytokines

Molecular profiling

PIs: N. Girard, S. Peters

Three phase II studies to evaluate pembrolizumab in TETs are ongoing or

will soon enroll patients

Immune checkpoint inhibitors in TETs:

Summary

• Clinical evaluation of immune checkpoint inhibition in TETs

justified

• Extreme vigilance will be required during treatment given

– Autoimmune disorders in thymomas

– Documented toxicity profiles of PD1/PDL1 and CTLA-4 blockers, mainly

represented by autoimmune disorders

– More irAE noted in the few patients treated so far

• Difficult to perform phase III trials

Thanks!!

efelip@vhebron.net

efelip@vhio.net