terapie innovative dei tumori tiroide rossella elisei, md · thyroid tumor cell endotelial cell the...

TERAPIE INNOVATIVE DEI TUMORI TIROIDE

Rossella Elisei, MD

Associate Professor of EndocrinologyDepartment of Endocrinology

University of Pisa, Italy

FoRiSIE Winter School in Clinical Endocrinology8-11 Gennaio, 2020

GOOD TUMORS

90% OF WD-PTC70% OF WD-FTC50% OF MTC

CURABLE

15-20% OF WD-DTCLOOSING

THE WD FEATURES

INTERMEDIATE

BAD TUMORS

80% OF PDTC100% OF ATC30% OF MTC

LETHAL

THYROID CARCINOMAHAVE DIFFERENT

BIOLOGICAL BEHAVIOURS

For many years: No systemic therapies for bad and ugly thyroid cancer

TYROSINE KINASE INHIBITORS!

The majority of TKIs are small molecules competing for ATP binding site

ATP binding site

TK receptor

TK receptor

TK receptor

TKI

PLCg

P P

RET EGFRMET

P

P

p21ras

PI3KGRB2 SOS

AKT

MEK

PTEN

VEGFR

VEGFR

VEGF

THYROID TUMOR CELL

ENDOTELIAL CELL

The TKI cross-talking

Modified from Kondo T, et al.Nat Rev Cancer. 2006

Genetic alteration PTC FTC ATC MTC

RET rearrangement

13-43% ⎯ ⎯ ⎯

RET mutation ⎯ ⎯ ⎯

30-50% (sporadic)

(MEN2: 100%)

NTRK1 rearrangement

5-13% ⎯ ⎯ ⎯

BRAF mutation 29-69% ⎯ 10-35% ⎯

RAS mutation 0-21% 40-53% 20-60%20-25% in sporadic

PPARrearrangement

⎯ 25-63% ⎯ ⎯

P53 mutation ⎯ ⎯ 67-88% ⎯

Genetic alterations in thyroid cancer are targets of TKI

PROFILE OF TKI IN DEVELOPMENT FOR THE TREATMENT

OF RAI REFRACTORY THYROID CANCER

AND ADVANCED MEDULLARY THYROID CANCER

ACTIONS OF TKI ASSOCIATED WITH

DIFFERENT TARGETS

SORAFENIB2005 2007

• Locally advanced or

metastatic,

RAI-refractory DTC

• Radiologic progression

(RECIST) within the

previous 14 months

• No prior chemotherapy,

targeted therapy, or

thalidomide

417 patients randomized from Oct 2009

to July 2011

DECISION study design: phase III

• Stratified by:

– geographical region (North America or Europe or Asia)

– age (<60 or ≥60 years)

• Progression assessed by independent central review

every 8 weeks

• At progression:

– patients on placebo allowed to cross over at the investigator’s discretion

– patients on sorafenib allowed to continue on open-label sorafenib at the investigator’s

discretion

* Progression-free survival (PFS) – Time from the date of randomization until the date of

radiological progression or death (if death occurs before progression).

Sorafenib400 mg orally twice daily

Placebo orally twice daily

Randomization 1:1Primary endpoint

Secondary endpoints

Overall survival

Response rate

Safety

Time to progression

Disease control rate

Duration of response

Sorafenib exposure (AUC0–12)

• Progression-free survival*

n

Median PFS,

days (months)

Sorafenib

Placebo

207 329 (10.8)

210 175 (5.8)

100 200 300 400 500 600

Days from randomization

0 700 800

100

90

80

70

60

50

40

30

20

10

0

HR: 0.587; 95% CI: 0.454–0.758;

p<0.0001

Full analysis set.CI, confidence interval; HR, hazard ratio; PFS, progression-free survival

Primary Objective: comparison of the progression free survivals of the two groups according to RECIST

PROGRESSION F

REE S

URVIVAL%

PFS in predefined subgroups

Variable n HR (95% CI)Region Europe 249

North America 72

Asia 96Age group <60 years 161

≥60 years 256Histology (central review) Papillary 235

Hürthle cell 74

Follicular 31

Poorly differentiated 38Lung metastases only No 347

Yes 70Bone metastases only No 304

Yes 113FDG uptake Negative 29

Positive 320No. target or non-target lesions <Median 163

≥Median 254Target lesion size <Median 208

≥Median 209Gender Male 199

Female 218Cumulative RAI ≥600 mCi No 264

Yes 1330.0 0.5 1.0 1.5 2.0

Favors sorafenib

Favors placebo

A CASE OF POORLY DIFFERENTIATED THYROID CANCER TREATED WITH SORAFENIB

Before therapy

After 10 days

After 20 days

Other secondary efficacy endpoints

Sorafenib

n (%)

Placebo

n (%)p value

Total evaluable patients 196 201

Response rate 24 (12.2) 1 (0.5) <0.0001

Complete response 0 0 –

Partial response 24 (12.2) 1 (0.5) –

Stable disease for ≥6 months 82 (41.8) 67 (33.2) –

Disease control rate (CR + PR

+ SD ≥6 months)106 (54.1) 68 (33.8) <0.0001

Median duration of response

(PRs) months (range)

10.2 (7.4–

16.6)NA –

CR, complete response; PR, partial response;

SD, stable disease; NA, not assessed

Maximum reduction in target lesion size(by independent central review)

Maxim

um

red

ucti

on

in

targ

et

lesio

n s

ize (

%)

–70

–50

–40

–20

0

20

60

–30

–10

10

30

50

40

–60

Sorafenib Placebo

27% of patients73% of patients

Overall survivalS

urv

iva

l p

rob

ab

ilit

y (

%)

Days from randomization

0

10

20

40

60

80

100

30

50

70

90

0 100 200 300 400 500 600 700 800 900 1000

At progression:

• 150 patients on placebo (71%) received open-label sorafenib

• 55 patients on sorafenib (27%) received open-label sorafenib

Median OS

Sorafenib Not reached

Placebo Not reached

HR: 0.802; 95% CI: 0.539–1.194

p=0.138, one-sided

SELECT Study 303: Study Schema

1818

Patients with DTC (N = 392)

•IRR evidence of progression within previous 13 months

•131I-refractory disease

•Measurable disease

•Up to 1 prior VEGF or VEGFR-targeted therapy

Placebo (n=131)24 mg daily PO

Lenvatinib (n=261)24 mg daily PO

Treatment until

disease progression

confirmed by IRR

(RECIST v1.1)

Lenvatinib

(Optional, open-label)

Rand

omization

2:1

International, randomized, double-blind, phase 3 trial

Primary endpoint

• PFS

Secondary endpoints

• ORR

• OS

• Safety

Primary Endpoint:Kaplan-Meier Estimate of PFS

CI, confidence interval; HR, hazard ratio; NR, not reached.

Median PFS, months (95% CI)

Lenvatinib 18.3 (15.1–NR)

Placebo 3.6 (2.2–3.7)

HR (99% CI): 0.21 (0.14–0.31)

Log-rank test: P < 0.0001

Progression

events, 41%

Progression

events, 86%

Reprinted with permission. © 2014 American Society of Clinical Oncology. All rights reserved

PFS by Previous VEGF-TKI

Time (months)

Time (months)

Pro

gre

ss

ion

-Fre

e

Su

rviv

al

1.00.90.80.70.60.50.40.30.20.10.0

0 2 4 6 8 10 12 14 16 18 20 22 24 26

Median (months) (95% CI)


Placebo 3.6 (2.1–5.3)

HR (95% CI): 0.20 (0.14–0.27)

Log-rank Test: P < 0.0001

No Previous TKI (n = 299)

Pro

gre

ss

ion

-Fre

e

Su

rviv

al

1.00.90.80.70.60.50.40.30.20.10.0

0 2 4 6 8 10 12 14 16 18 20 22 24 26

Median (months) (95% CI)


Placebo 3.6 (1.9–3.7)

HR (95% CI): 0.22 (0.12–0.41)

Log-rank Test: P < 0.0001

Previous TKI (1 line) (n = 93)

Lenvatinib 195 167 148 135 123 116 108 72 52 34 20 11 3 0

Placebo 104 56 36 25 17 12 10 4 3 1 1 1 0 0

Number of subjects at risk:

Lenvatinib 66 58 50 41 36 32 28 20 14 10 4 0 0 0

Placebo 27 15 7 4 2 1 1 1 1 1 1 1 0 0



PFS Subgroup Analyses

CI, confidence interval; HR, hazard ratio; NR, not reached; PFS, progression-free survival.

Events/N Median (Months)

Lenvatinib

14/65

31/72

31/63

31/61

61/141

14/28

32/92

60/157

47/104

17/35

90/226

Placebo

21/28

31/32

31/34

30/37

60/71

18/19

35/41

74/83

39/48

7/7

106/124

Baseline Tumor

Burden (mm)

≤35

35−60

60−92

>92

Histology

Papillary

Poorly differentiated

Follicular

Bone Metastasis

No

Yes

Lung Metastasis

No

Yes

Lenvatinib

NR

16.4

14.8

13.9

16.6

14.8

NR

20.2

14.8

14.8

18.7

Placebo

5.6

3.7

3.6

2.4

3.5

2.1

3.7

3.7

2.1

2.4

3.6

HR (95% CI)

0.14 ( 0.06, 0.33)

0.19 ( 0.10, 0.36)

0.24 ( 0.13, 0.43)

0.21 ( 0.11, 0.42)

0.30 ( 0.20, 0.44)

0.21 ( 0.08, 0.56)

0.10 ( 0.05, 0.19)

0.18 (0.12, 0.27)

0.26 (0.16, 0.42)

0.24 ( 0.08, 0.77)

0.21 ( 0.15, 0.29)

Favors PlaceboFavors Lenvatinib

HR and 95% CI

1010.10.01

Events/N


Response Rates

n (%) Lenvatinib (n = 261) Placebo (n = 131)

ORR 169 (65%) 2 (2%)

95% CI 59.0–70.5 0.0–3.6

P-value <0.0001

Complete response 4 (2%) 0

Partial response 165 (63%) 2 (2%)

Stable disease ≥ 23 weeks 40 (15%) 39 (30%)

Progressive disease 18 (7%) 52 (40%)

Median time to objective

response, months (95% CI)a 2.0 (1.9–3.5) –

Duration of response, months,

median (95% CI)NR (16.8–NR) –

a Non-responders were not included in the median time

to response assessment.


Best Tumor Response

CR, complete response; PD, progressive disease; PR, partial response; SD, stable disease.

Median tumor

shrinkage for

responders (range):

-52%

(-100%, -30%)

Median tumor

shrinkage for all

patients (range):

+2%

(-53%, +54%)


June, 2011 December, 2011

30x30 mm

20x21 mm

upper right paratracheal mediastinum

(19 MONTHS)

CHANGE IN TUMOR SIZE OVER TIME (data from SELECT)

June 2016

PARENCHIMAL CAVITY OF THE

SUPERIOR RIGHT LUNG LOBE

(63MM )

Stability of the other lesions

Stability of neoplastic disease fromSeptember 2015 to June 2016…Side effects … appearance of severedyspnea

Clinical case

RISK OF FISTULAE

❖LOCAL INFILTRATION : TRACHEA, CAROTID, BIG VESSELS, ESOPHAGUS

❖LUNG INFILTRATION: BRONCHI, VESSELS

❖GASTROINTESTINAL: BOWEL ULCERATION OR DIVERTICULITIS

❖ETC…

SEVERE ADVERSE EVENT RISK OF DEATH

WHICH STARTING DOSE?

March 2016

September 2016

April 2016

July 2016

60 x 42 mm 36 x 26 mm

CT scan

… after 6 months…

CT scan after 12 months (on March 29, 2017)

60 x 42 mm 24 x 11 mm

September 2016…

No therapy

After 1 month After 2 monthsAfter 45 days

No therapy

After 4 months After 7 months

Overall Survival, ITT population


Lenvatinib 261 248 239 230 219 211 203 169 114 78 55 22 10 3 0

Placebo 131 126 126 118 108 103 96 78 53 39 23 8 2 1 0

Overa

ll S

urv

ival

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.00 2 4 6 8 10 12 14 16 18 20 22 24 26

1.0

28

Time (months)

Median OS, months (95% CI)

Lenvatinib NR (22.0–NR)

Placebo NR (20.3–NR)

HR (95% CI): 0.73 (0.50–1.07)

Log-rank test: P = 0.1032

ITT, intent-to-treat; RPSFT, rank-preserving structural failure time.

Significant difference was

observed in the RPSFT-adjusted

OS, which was used to correct for

a potential cross-over effect in the

placebo arm.


Overall Survival by Histology:(Unadjusted for Crossover)

Median months (95% CI)

Lenvatinib 22.0 (21.0–NE)

Placebo NR (16.3–NE)

HR (95% CI): 0.92 (0.60–1.41)

Log-rank test: P = 0.708

Median months (95% CI)

Lenvatinib NR (NE–NE)

Placebo NR (20.3–NE)

HR (95% CI): 0.41 (0.18-0.97)

Log-rank test: P < 0.035

Papillary Thyroid Cancer Follicular Thyroid Cancer


Lenvatinib 169 158 153 145 134 127 120 105 71 47 32 13 5 1

Placebo 90 85 85 81 74 71 66 53 35 26 13 5 2 1


Lenvatinib 92 90 86 85 85 84 83 64 43 31 23 9 5 2

Placebo 41 41 41 37 34 32 30 25 18 13 10 3 0

OVERALL SURVIVAL

<65 YRS >65 YRS

▪ Vandetanib

▪ Approved in the USA (2011) and EU (2012) for symptomatic or

progressive, unresectable locally advanced or metastatic MTC, both

in children and adults

▪ Based on a Phase 3 study (ZETA) demonstrating improved PFS

compared to placebo

▪ Subjects had to have either progressive disease or symptomatic

disease

▪ Cabozantinib

▪ Approved in the USA (2012) and EU (2014) for the treatment of adult

patients with progressive unresectable locally advanced ormetastatic MTC

▪ Based on a Phase 3 study (EXAM) demonstrating improved PFS

compared to placebo

▪ Subjects had to have progressive disease

THE NOVEL DRUGS IN USE IN MTC (2011-2012)

Vandetanib in patients with locally advanced or metastatic medullary thyroid cancer:

a randomized, double-blind phase III trial (ZETA)Samuel A Wells,1 Bruce G Robinson,2 Robert F Gagel,3 Henning Dralle,4

James A Fagin,5 Massimo Santoro,6 Eric Baudin,7 Rossella Elisei,8

Barbara Jarzab,9 James Vasselli,10 Jessica Read,11 Peter Langmuir10

Anderson J Ryan12 and Martin Schlumberger7, for the ZETA investigators*

1

Time (months)

0

Pro

gres

sio

n-f

re

e s

urviv

al

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

6 12 18 24 30 36

Number of patients

231 196 169 140 40 1 0

100 71 57 45 13 0 0

Vandetanib 300 mg

Placebo

Vandetanib 300 mg

Placebo

FIGURE 1

Significant increase of progression free survival

Wells S. et al, J Clin Oncol, 2011

Patient n 018: 2 months of Vandetanib

May 2007 September 2007

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22

Months

Pro

bab

ilit

y

219 121 78 55 31 12 2 1

111 35 11 6 3 2 0 0

Cabozantinib

Placebo

p<0.0001

Progression Free Survival by IRC(Primary Endpoint)

Cabozantinib Placebo

Median PFS(months) 11.2 4.0

1 year PFS 47.3% 7.2%

HR (95% CI) 0.28 (0.19, 0.40)

p < 0.0001

Elisei R et al, JCO, 2013

PRECabozantinib

Post (6 months)Cabozantinb

Vandetanib in Children and Adolescents with Multiple Endocrine Neoplasia Type 2B Associated Medullary Thyroid Carcinoma

Fox E et al; Clin Cancer Res; 2013

CABOZANTINIB PLACEBO

KNOWN RECEIPT OF PRIOR CAPRELSA: N=34

N 25 9

ORR 7(28%)* 0

PFS median, months 12.8

(11.2 in the entire group)

2.8

HR=0.07; p=0.0001

*6 of 7 patients reporting tumor response after treatment with cabozantinib actually stopped vandetanib treatment due to disease progression,

Cabozantinib is active after vandetanib(second line)


THE SIDE EFFECTS

and their impact on

the patients’ QofL

Sorafenib: Most common side effects

AE*, % Sorafenib (n=207) Placebo (n=209)

Any grade Grade 3/4 Any grade Grade 3/4

Hand–foot skin reaction 76.3 20.3 9.6 0

Diarrhea 68.6 5.8 15.3 1.0

Alopecia 67.1 0 7.7 0

Rash/desquamation 50.2 4.8 11.5 0

Fatigue 49.8 5.8 25.4 1.4

Weight loss 46.9 5.8 13.9 1.0

Hypertension 40.6 9.7 12.4 2.4

Metabolic – lab (other) 35.7 0 16.7 0

Anorexia 31.9 2.4 4.8 0

Oral mucositis 23.2 1.0 3.3 0

Pruritus 21.3 1.0 10.5 0

Nausea 20.8 0 11.5 0

Hypocalcemia 18.8 9.2 4.8 1.4

*National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 3.0

Adverse Event, %

Lenvatinib (n = 261) Placebo (n = 131)

Any

Grade Grade ≥ 3

Any

GradeGrade ≥ 3

Hypertension 68 42 9 2

Diarrhea 60 8 8 0

Fatigue / asthenia 59 9 28 2

Decreased appetite 50 5 12 0

Nausea / vomiting 46 3 15 1

Decreased weight 46 10 9 0

Stomatitis 36 4 4 0

Palmar-plantar

erythrodysesthesia

syndrome

32 3 1 0

Proteinuria 31 10 2 0

Headache 28 3 6 0

Dysphonia 24 1 3 0


Lenvatinib: Most common side effects

>30% of patients:DiarrheaRashNauseaHypertension

ECG QT prolongation 14%

VANDETANIB ADVERSE EVENT

Grade 3, more frequent:DiarrheaHypertensionQT prolongation

Wells S. et al, J Clin Oncol, 2011

a Worst Grade AE during the treatment period is reportedb Sponsor defined grouping of preferred terms

Cabozantinib (N=214) Placebo (N=109)

Median Duration of Exposure

6.7 months 3.4 months

Adverse Eventa All Grades n (%)

Grade ≥ 3 n (%)

All Grades n (%)

Grade ≥ 3 n

(%)Diarrhea 135 (63) 34 (16) 36 (33) 2 (2)

Hand foot skin reaction 107 (50) 27 (13) 2 (2) -

Decreased weight 102 (48) 10 (5) 11 (10) -

Decreased appetite 98 (46) 10 (5) 17 (16) 1 (0.9)

Nausea 92 (43) 3 (1) 23 (21) -

Fatigue 87 (41) 20 (9) 31 (28) 3 (3)

Dysgeusia 73 (34) 1 (0.5) 6 (6) -

Hair color changes 72 (34) 1 (0.5) 1 (0.9) -

Hypertensionb 70 (33) 18 (8) 5 (5) 1 (0.9)

Most Frequent Adverse Events(>30% Incidence)


TKI side effects

UNPREDICTABLE…

EACH PATIENT HAS HIS/HER OWN RISK…

When to start the TKI?

RAI-refractory DTC: definition and identification

Schlumberger M, Brose M, Elisei R et al. Definition and management of radioactive iodine-refractory differentiated thyroid cancer. Lancet Diabetes Endocrinol. 2014

1. Local disease or distant metastases unable to take up

131I: negative post-therapeutic WBS (all lesions or

some of them)

2. Local disease or distant metastases able to take up 131I

but with progression during 12–18 months after the last

131I treatment

3. Persistence of disease after administration of cumulative

activity of 600 mCi 131I without any evidence of clinical

benefit

Response Evaluation Criteria in Solid Tumors

(RECIST)

PROGRESSIVE DISEASE (PD)

Increase 20% from baseline of the targetlesions or the appearance of new lesions

Eisenhauer et al. Europ J Cancer, 2009

• Surgery (especially for isolated lesions or when thedisease is confined to the neck)

• External radiotherapy (palliative, pain control for bonelesions)

• Whole brain irradiation (for stabilization of multiplemetastases)

• Intra-arterial embolization (especially for liver metastases)

• Radiofrequency ablation (lung, bone, liver, local disease)

• Pamidronate IV (multiple bone lesions)

• Endobronchial laser ablation (to maintain vital functions)

Local treatments

A B

THERMOABLATION

Before After

LIV

ER

C D

PAR

AT

RA

CH

EA

L

RE

CU

RR

EN

CE

stable valueImaging: stable disease

Wait and see

Imaging: progression of the disease at multiple sites

Time to treat

Increasing values

More frequent imaging controls (every 3 months)

When to treat ?

Serum Tg or CT

dabrafenib (BRAF inhibitor) and trametinib (MEK inhibitor)

Subbiah V1

Subbiah V et al, JCO 2018

https://www.ncbi.nlm.nih.gov/pubmed/?term=Subbiah%20V%5BAuthor%5D&cauthor=true&cauthor_uid=29072975

20 monthsvs 6 mths

19% vs 47% by Landa et al

FOR THE NEXT FUTURE

Tyrosine kinase selective drugs: monotarget

Loxo 292 (RET inhibitor)

Blue 669 (RET inhibitor)

Larotrectinib (TRK inhibitor)

Entrectinib (TRK, ROS e ALK fusions inhibitor)

L Wirth, ATA 2018

Larotectinib is a specific TRK inhibitor

CONCLUSIONS 1

A not negligible % of thyroid cancer patients have anadvanced disease that requires systemic therapy

For the treatment of de-DTC and PDTC two drugs havealready been approved (sorafenib and lenvatinib)

Several and important side effects have been reportedand only advanced and progressive cases, according toRECIST, should be treated with TKI

At the moment there are no evidence of a positiveimpact on the overall survival with the exception oflenvatinib in FTC and in older patients.

Side effects mut be known by doctors, early identifiedand declared by patients to immediately counteregulatewith adequate procedures.

THANK YOU FOR YOUR ATTENTION

AIT 3-5 DICEMBRE 2020

terapie innovative dei tumori tiroide rossella elisei, md · thyroid tumor cell endotelial cell the...

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