7-. dr. enrriqueta felip · 2016 nivomes nivolumab baas wclc 2016 pembrolizumab alley wclc 2016...
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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