thymic tumors update on treatment strategies · thymic tumors update on treatment strategies...

THYMIC TUMORS

UPDATE ON TREATMENT STRATEGIES

Nicolas Girard

Institut du Thorax Curie Montsouris, Institut Curie, Paris, France

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DISCLOSURE

- Personal financial interests: Astra-Zeneca, Boehringer-Ingelheim, Bristol Myers

Squibb, Hoffmann La Roche, Lilly, Merck Sharp Dohme, Novartis, Pfizer, Takeda

- Institutional financial interests: Astra-Zeneca, Boehringer-Ingelheim, Bristol Myers

Squibb, Hoffmann La Roche, Lilly, Merck Sharp Dohme, Novartis, Pfizer, Takeda

- Non-financial interests: Former VP of International Thymic Malignancy Interest

Group, Executive board of French Thoracic Cancer Intergroup, Secretary of the

Oncology Group of the French Speaking Respiratory Medicine Society, Associated

coordinator of RYTHMIC

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THYMIC TUMORS:

SYSTEMIC TREATMENT

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THYMIC TUMORS:

SYSTEMIC TREATMENT

KEY FACTORS TO CONSIDER

BEFORE TREATING PATIENTS

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#1 MAKE SURE OF THE DIAGNOSIS

World Health Organization 2015

A AB B1 B2 B3

“Médullary” Mixed “Cortical” SCC

Thymoma Carcinoma

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#1 MAKE SURE OF THE DIAGNOSIS

ASCO 2016

Pathological review

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THYMIC TUMORS:

SYSTEMIC TREATMENT



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#2 STAGING IS COMPLEX

MASAOKA-KOGA TO TNM

8th TNM staging

system

Masaoka-Koga : I, IIA, IIB, III

Masaoka-Koga : III

Masaoka-Koga : III

Masaoka-Koga : IVB

Detterbeck et al. J Thorac

Oncol 2014;S65-72Do not d

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#2 STAGE, HISTOLOGY, OTHERS

u The most significant prognostic factor in thymic malignancies is the completion of surgical resection, whatever classification is used.

Rossi et al. Histopathology 2008;53:483

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THYMIC TUMORS:

SYSTEMIC TREATMENT



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#3 LEVELS OF EVIDENCE ARE LIMITED:

ROOM FOR MULTIDISCIPLINARY DISCUSSION

0%

20%

40%

60%

80%

100%

NSCLC Mesothelioma Thymic tumors

V

IV

III

II

I

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Coordinator:B. BesseGustave

Roussy

RYTHMIC network

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EURACAN network

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THYMIC TUMORS:

SYSTEMIC TREATMENT



SURGERY UPFRONT IN

RESECTABLE TUMORS

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u Median sternotomy is the standard approachu Complete exploration of the pleural cavities

u Mediastinal nodes sampling/resection (stage III tumor/thymic carcinoma)

u Complete thymectomy, including tumor, normal thymus, and mediastinal fatu en bloc resection of involved structures:

- lung, vessels, pleural implants, phrenic nerves

- surgical clips in areas of concern

u Frozen section not recommended for margins assessment

SURGERY PRINCIPLES

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Orientation and marking in the operative room

YESNO

D. Gossot, Montsouris Institute

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J Thorac Oncol 10.1016/j.jtho.2016.08.131

TOWARDS MINIMALLY-INVASIVE SURGERY?

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THYMIC TUMORS:

SYSTEMIC TREATMENT



SURGERY UPFRONT IN

RESECTABLE TUMORS

POST-OPERATIVE

DECISION-MAKING

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68/143

20/37

0

20

40

60

80

100

0 5 10 15 20 25

Stage I/II

Stage III

Stage IVA

Stage IVB

%

Years

Events/n 10-year recurrence % (IC95)

121/3 097

140/654

64/109

17/38

8 (7-8)

29 (27-31)

71 (34-100)

57 (24-90)

0

20

40

60

80

100

0 5 10 15 20

Stage I/II

Stage III

Stage IVA

Stage IVB

%

Years

28/112

19/26

25 (22-29)

59 (44-76)

76 (58-100)

54 (37-67)

Thymomas

(n = 7 005)

Thymic carcinomas

(n = 977)

Cumulative incidence of recurrences in Masaoka-Koga groups

ITMIG retrospective database

Detterbeck et al. WCLC 2013, abstr. MS16.2

Recurrence rates: stage

Events/n 10-year recurrence % (IC95)

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POSTOPERATIVE RADIOTHERAPY GUIDELINES

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THYMIC TUMORS:

SYSTEMIC TREATMENT



SURGERY UPFRONT IN

RESECTABLE TUMORS

POST-OPERATIVE

DECISION-MAKING

STRATEGIES

FOR SYSTEMIC THERAPY

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KEY QUESTION IS:WHAT IS THE INTENT OF THE SYSTEMIC TREATMENT?

PRIMARY

CHEMOTHERAPY

EXCLUSIVE

CHEMOTHERAPY

SYSTEMIC

THERAPIES FOR

RECURRENCES

J Thorac Oncol 2011;6(7 Suppl 3):S1749

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PRIMARY CHEMOTHERAPY:

CASE REPORT

27-year old male, chest pain, no myasthenia

MTB: Is upfront complete resection achievable?

Re: « Not sure »

Biopsy: thymoma, type B3

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CLINICAL EVIDENCE

Administered regimens

n=91

CAP

76%

Paclitaxel +

Carboplati…

Etoposide

+/- Platin

8%

Others

6%

2%

17%

77%

4%

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

Primary

42%

44%Progression

Stable

Partial

responseComplete

response

Tumor response

Historical data

Girard N. Eur Respir Rev 2013;22:75Merveilleux du Vignaux et al. J Thorac Oncol 2018; online first

RYTHMIC data

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CASE REPORT

27-year old male, chest pain, no myasthenia

Then surgery !

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ADVANCED TUMORS: MULTIMODAL TREATMENT

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u Limited data in the literature…no consensus

- Sequential approach:

- 23 patients, stage III-IV unresectable thymoma

- induction with CAP (4 cycles), then radiotherapy

- 5-year PFS: 54%

- 5-year OS: 53%

- Concurrent approach:

Loehrer et al. J Clin Oncol 1997;15:3093

Korst et al. J Thorac Cardiovasc Surg 2014;147:36

CHEMO-RADIATION FOR THYMIC TUMORS

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PRIMARY

CHEMOTHERAPY

EXCLUSIVE

CHEMOTHERAPY

SYSTEMIC

THERAPIES FOR

RECURRENCES


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EXCLUSIVE CHEMOTHERAPY:

CASE REPORT

67-year old male, lombalgia, hypercalcemia

Biopsy: thymic carcinoma, CD117+, CD5+

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CLINICAL EVIDENCE

Administered regimens

n=41

CAP

66%

Paclitaxel +

Carboplatin

20%

Etoposide

+/- Platin

12%

Others

2%

42%

44%Progression

Stable

Partial

responseComplete

response

28%

36%

36%

Exclusive

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

Tumor response

Historical data

Girard N. Eur Respir Rev 2013;22:75Merveilleux du Vignaux et al. J Thorac Oncol 2018; online first

RYTHMIC data

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BETTER RESPONSE WITH ANTHRACYCLINS?

Thymoma: yes Thymic carcinoma: not sure

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PRIMARY

CHEMOTHERAPY

EXCLUSIVE

CHEMOTHERAPY

SYSTEMIC

THERAPIES FOR

RECURRENCES


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RECURRENCES:

CASE REPORT

32 year-old male, Morvan syndrome

2011

chemo and resection for thymoma, type B2-B3

2014

Resection of implant 2016

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RECURRENCES:

CLINICAL EVIDENCE FOR SYSTEMIC TREATMENT

Paclitaxel

+/-

Carboplatin

44%

Etoposide

+ Platin

16%Etoposide

4%

CAP

13%

Sunitinib/Lu…

Pemetrexed

3%

Milciclib

3%

Others

6%

First recurrence

n=79

Sunitinib/

other

VEGFR …

Paclitaxel

+/-

Carbopla…

Etopos

ide

12%

Pemetr…

Others

16%

Recurrence 2

n=54

Recurrence 3

n=29

Recurrence 4

n=13

Sunitinib

/other

VEGFR

TKIs…

Paclitaxel

+/- Platin

17%

Pemetre

xed…

Everoli

mus

7%

Others

28%

Everolimus

23%

Sunitinib

16%Etoposi

de +

Platin…

Pemetrexed

15%

Others

31%

Merveilleux du Vignaux et al. J Thorac Oncol 2018; online first

RYTHMIC data

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2%

28% 31%42%

25%15%17%

36%42%

44%71%

54%

77%

36% 19%

13%4%

31%

4% 7%

0%

20%

40%

60%

80%

100%

Primary Exclusive Recurrence

1

Recurrence

2

Recurrence

3

Recurrence

4

RECURRENCES:



RYTHMIC data

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RECURRENCES:



RYTHMIC data

20,7

6,2 7,6 6,2 6,98,7

0

5

10

15

20

25

Primary Exclusive Recurrence

1

Recurrence

2

Recurrence

3

Recurrence

4

PFS

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THYMIC TUMORS:

SYSTEMIC TREATMENT



SURGERY UPFRONT IN

RESECTABLE TUMORS

POST-OPERATIVE

DECISION-MAKING

STRATEGIES


PRECISION MEDICINE

APPROACHES?

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Ross et al. ESMO 2017

Squamous Cell

Patients 69

Median Age (y) 57

Gender (% Female) 34%

Avg GA/tumor 4.1

Avg CRGA/tumor 1.0

Significant Genomic

Alterations

KIT

FGFR3

PIK3CA

TMB >10 mutations/Mb 9%

TMB >20 mutations/Mb 9%

0%

5%

10%

15%

20%

25%

30%

35%

40%

45%

50%

CDKN2A

TP53

CDKN2B

CYLD

KIT

SETD2

ARID1A

KDM6A

EP300

BAP1

KRAS

MLL2

TET2

PBRM1

STK11

MEN1

FGFR3

SPEN

FOXP1

HRAS

ASXL1

SPTA1

PTPRD

ZNF703

PIK3CA

PIK3CG

MAGI2

FGFR1

BRCA2

CCND2

PTEN

FAT1

CDKN1B

MLL3

CHD4

TNKS2

FGF6

FGF23

CREBBP

ATM

EZH2

BRAF

Perc

ent S

am

ple

s

Mutation Frequency by Gene

THYMIC CARCINOMAS

FOUNDATION MEDICINE PANEL

Thymic squamous cell carcinomas

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Adeno. BasaloidLymphoepi-

theliomatous

Neuro-

endocrineNOS Squamous Cell Sarcomatoid

Patients 7 5 5 30 54 69 4

Median Age (y) 48 58 50 48 57 57 61

Gender (% Female) 43% 60% 20% 37% 24% 34% 50%

Avg GA/tumor 4.0 2.8 1.0 3.3 4.1 4.1 4.8

Avg CRGA/tumor 0.9 0.3 -- 0.9 0.8 1.0 1.0

Significant Genomic

Alterations

PDGFRA

FGFR3

KIT

MET

PTCH1

CDKN2A

FBXW7

CDKN2A

MEN1

KIT

BRCA2

IDH1

ERBB2

ERBB3

KIT

PTEN

PIK3CA

KIT

FGFR3

PIK3CA

ERBB2

IDH1

KIT

TMB >10 mutations/Mb 14% -- -- 3% 5% 9% --

TMB >20 mutations/Mb 0% -- -- 3% 5% 9% --

Ross et al. ESMO 2017

THYMIC CARCINOMAS

FOUNDATION MEDICINE PANEL

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WHICH PATHWAYS FOR PRECISION MEDICINE

APPROACHES?

ensuringpatientsanequalaccesstohighlyspecialized

management ensuringpatientsanequalaccesstohighly

specializedmanagement

ensuringpatientsan

equalaccesstohighly

specialized

management ensuring

patientsanequal

accesstohighly

specialized

management

ensuringpatientsan

equalaccesstohighly

specialized

management ensuring

patientsanequal

accesstohighly

specialized

managementensuringpatientsan

equalaccesstohighly

specialized

management ensuring

patientsanequal

accesstohighly

specialized

management

ensuringpatientsanequalaccesstohighlyspecialized

management ensuringpatientsanequalaccesstohighly

specializedmanagement

ensuringpatients

equalaccesstohighl

specializedmanageme

ensuringpatients

equalaccesstohighl

specializedmanagem

ensuringpat

equalaccess

specializedma

ensuringpat

equalaccess

specializedmanag

ensuringpatientsan

equalaccesstohighl

specialized

management ensur

patientsanequal

accesstohighly

specialized

management

KITinhibitors

KIT

activating

mutations

Cyclin-dependent

kinaseinhibitors

VEGFRs inhibitors

VEGFRs

overexpression

Immune

checkpoints

inhibitors

PD-L1

expression

Loss of

CDKN2A/B

IGF-1R

overexpression

PI3K

subunits

mutations

BCL2

gains

PI3Kinhibitors

Proapoptotic

agents

IGF-1Rinhibitors

Histone

deacetylase

inhibitors

Mutated

epigenetic

regulatory genes

Girard et al. J Thorac Oncol 2016;11:1197

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Ann Oncol 2012;23:2409

KIT INHIBITORS FOR KIT MUTATIONS

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Lancet Oncol 2015; 16:177

KIT INHIBITORS

CONFOUNDING EFFECT OF ANGIOGENESIS INHIBITION

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OTHER STRATEGIES: MESOTHELIN INHIBITION

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OTHER STRATEGIES: SELINEXOR

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THYMIC TUMORS:

SYSTEMIC TREATMENT



SURGERY UPFRONT IN

RESECTABLE TUMORS

POST-OPERATIVE

DECISION-MAKING

STRATEGIES


PRECISION MEDICINE

APPROACHES?

IMMUNE CHECKPOINT

INHIBITORS

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IMMUNOTHERAPY FOR THYMIC TUMORS

RATIONALE

Low tumor mutation burdenExpression of PD-L1

Sakane et al. Oncotarget 2018;9:6993 Radovich et al. Cancer Cell 2018;33:244

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AUTO-IMMUNE DISORDERS

J Thorac Oncol 2017;13:436

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AUTO-IMMUNE DISORDERS

THYMOMA VS. THYMIC CARCINOMA

Thymomas: loss of AIRE Thymic carcinomas: shared antigens

Mathis et al. Annu Rev Immunol 2009;27:287

Darnell et al. NEJM 2003;349:1543

Cellule dendritique

Apoptose

Délétion

clonale

Délétion

clonale

Auto-immunityPas de délétion

clonaleNo apoptosis

Apoptosis

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Lancet Oncol 2015; 16:177

AUTO-IMMUNE DISORDERS MAY BE EXACERBATED

BY TREATMENT

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SAFETY IS THE FIRST CONCERN

Major risk of immune-related toxicity in thymomas

J Thorac Oncol 2016;11:e147

Waterfall plot. Three PRs were observed with a single dose of avelumab (*).

OA18.03: Safety and Clinical Activity of Avelumab (MSB0010718C; Anti-PD-L1) in Patients with Advanced Thymic Epithelial Tumors (TETs)

– Arun Rajan

Duration of Treatment and Response

Rajan et al. WCLC 2016

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PHASE II TRIALS

Response rate: 23%

Median DOR: 22 months

Severe irAE: 15%

Lancet Oncol 2018;19:347

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PHASE II TRIALS

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IMMUNOTHERAPY FOR THYMIC TUMORSNOT A STANDARD, ADDITIONAL TRIALS NEEDED

EORTC-ETOPNIVOTHYM

Primaryendpoint:PFSrateat6months

Secondaryendpoints:

- ORR andDCR,Durationofresponse

- OS

- QOL

- Safety

Eligiblepatients Nivolumab 240mgIVq2weeks

Primaryobjective:

Todetectactivityofnivolumab assingleagentassecondlinetreatment

fortypeB3thymoma andthymic carcinoma

Biomarkers:SPECTA

PD-L1

Cytokines

Molecular profiling

PIs:N.Girard,S.Peters

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THYMIC TUMORS:

SYSTEMIC TREATMENT



SURGERY UPFRONT IN

RESECTABLE TUMORS

POST-OPERATIVE

DECISION-MAKING

STRATEGIES


PRECISION MEDICINE

APPROACHES?

IMMUNE CHECKPOINT

INHIBITORS

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TEAM IS THE KEY!

Contact: [email protected]

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thymic tumors update on treatment strategies · thymic tumors update on treatment strategies...

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