Developments in the management of cancer-associated ......Cancer-Associated Thrombosis (CAT) Prevalence and Burden •VTE is a major complication of cancer and a leading cause of death

Developments in the management of cancer-associated thrombosis

Andrés J. Muñoz Martín MD, PhD

Medical Oncology Department

Hospital General Universitario Gregorio Marañón, Madrid

Universidad Complutense, Madrid, Spain

Cancer & Thrombosis Workig Group, Spanish Society of Medical Oncology (SEOM)

Tel Aviv, 16 May 2019

My disclosures

Consultant or advisory role

• Daiichi Sankyo, Leo Pharma, Pfizer-BMS, Sanofi

Research funding

• Leo Pharma, Sanofi, Rovi

Speakers’ bureau

• Daiichi Sankyo, Leo Pharma, Rovi, Sanofi

Inventor

• TiC Onco (with José Manuel Soria)

Summary

• New drugs in Oncology and VTE risk

• Primary thromboprophylaxis in ambulatory setting

• New risk assessment models and molecular risk factors

• DOACs & CAT treatment (ready for prime time?)

Cancer-Associated Thrombosis (CAT)Prevalence and Burden

• VTE is a major complication of cancer and a leading cause of death among cancer patients

• Approximately 20% of all VTE cases occur in patients with cancer

• VTE affects up to 20% of patients with cancer before death and has been reported in up to 50% of cancer patients at the time of postmortem examination

• CAT has important clinical and economic consequences, including

– Increased morbidity resulting from hospitalization and anticoagulation use

– Bleeding complications

– Increased risk of recurrent VTE

– Cancer treatment delays and stop

– Finally increased costs

Lyman GH. Cancer. 2011;117:1334-1349

ImmunotherapyA new strategy to treat cancer in many tumors…much more than chemo

The 2016 & 2017 Clinical Cancer Advance of the Year

New toxicity: inflammation…it’s related to thrombosis 5

Roopkumar & Khorana et al . Blood 2018: single institution 522 patients, 30.3% VTE incidenceIbrahimi et al. Blood 2017: single institution (Oklahoma), similar incidence to other systemic therapiesTESEO registry first analysis February 2019: 4% (13/330)

Cyclin-Dependent Kinase Inhibitor–Associated Thromboembolism

• Palbociclib, ribociclib and abemacilcib: initial treatment of advanced, hormone receptor–positive breast cáncer (oral drug for long time in combination with HT)

• Class effect of CDK inhibition?

• Or pharmacodynamic and/or pharmacokinetic differences?

– Unknown physiopathology

– Variable off-target effects may also play a role in VTE risk

• Primary thromboprophylaxis?

Olson et al. JAMA Oncology 2019

EGFR monoclonal antibodies

• Cetuximab/panitumumab meta-analysis (Petrelli et al. Ann Oncol. 2012)

– VTE: MoAbs RR 1.34; p=0.01

– However no increased VTE with TKIs: RR 1.16; p=0.65 (?)

• Necitumumab (ASCO 2016 abstract e20534)

• Class effect of anti-EGFR moAb? But not with TKI…

Primary thromboprophylaxis outpatient setting

Thromboprophylaxis really works!

• LMWH: SAVE ONCO, PROTECHT, CONKO-004 & FRAGEM-UK

• DOACs: AVERT, CASSINI (intermediate/high-risk based on KS)

But only occasionally used in routine clinical practice

9

PROTECHT and SAVE-ONCO: Efficacy of LMWH in VTE preventionPrimary thromboprophylaxis really works!

a. Agnelli G, et al. Lancet Oncol. 2009;10:943-949; b. Agnelli G, et al. N Engl J Med. 2012;366:601-609.

PROTECHT[a]

0

0.5

1

1.5

2

2.5

3

3.5

4

4.5

Nadroparin Placebon = 769 n = 381

Pat

ien

ts W

ith

VTE

Eve

nts

, %

2.0

3.9P = .02

0

0.5

1

1.5

2

2.5

3

3.5

4

Semuloparin Placebon = 1608 n = 1604

Pat

ien

ts W

ith

VTE

Eve

nts

, %

1.2

3.4P < .001

SAVE-ONCO[b]

Incidence of thromboembolic events in ambulatory patients with metastatic or locally advanced cancer receiving chemotherapy can be reduced with LMWH thromoboprophylaxis without a significant increased bleeding risk

No impact in OS + Low event rates in the placebo arm (high NNT)

Cochrane ReviewEfficacy/Safety of LMWH for VTE Prevention

Di Nisio M, et al. Cochrane Database Syst Rev. 2016;12:CD008500.

• Based on pooled estimates from 8 RCTs in ambulatory patientsreceiving chemotherapy

Risk of Symptomatic VTE

Risk of Major Bleeding

LMWH Inactive Control

Pooled Events Total Events TotalRisk Ratio

Random, 95% CI

Total (95% CI) 1829 14170.53

[0.38, 0.75]

Total events 50 82

Test for Overall effect: Z = 3.58 ( P = .0003)

LMWH Inactive Control

Pooled Events Total Events TotalRisk Ratio

Random, 95% CI

Total (95% CI) 2207 18111.30

[0.75, 2.23]

Total events 53 39

Test for Overall effect: Z = 0.94 ( P = .35)

0.01 0.1 10 100

Favors LMWH Favors Control

0.01 0.1 10 100

Favors LMWH Favors Control

CASSINI vs AVERTSimilarities/Differences in Study Design

Tromboprophylaxis really works (again) with DOACs

*Includes symptomatic or asymptomatic VTE and VTE-related death.a. Khorana AA, et al. Thromb Haemost. 2017;117:2135-2145. b. Kimpton M, et al. Thromb Res. 2018;164:S124-S129.

Ambulatory patients with solid tumors at high risk of VTE (Khorana score of ≥ 2)

Patient population

CASSINI[a] AVERT[b]

Entry criterion Thrombosis free by CUS

Treatment duration 180 days

Primary efficacy

Time to first occurrence of objectively confirmed VTE*

Primary analysis

ITT mITT

CUS not performed

Supportive analysis

On-treatment period

AVERTEfficacy/Safety Outcome

Carrier M, et al. N Engl J Med. 2019;380:711-719.

Cumulative Incidence Apixaban Placebo HR (95% CI) P Value NNT/NNH

VTE (mITT), % 4.2 10.2 0.41 (0.26, 0.65) < .001 NNT =17

Major bleeding (mITT), % 3.5 1.8 2.00 (1.01, 3.95) .046 NNH = 59

Major bleeding (on

treatment), %2.1 1.1 1.89 (0.39, 9.24) NS NNH = 100

CASSINIEfficacy/Safety Outcome

From N Engl J Med, Khorana AA, et al., Rivaroxaban for Thromboprophylaxis in High-Risk Ambulatory Patients with Cancer, 380, 720-728, Copyright © 2019. Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

Cumulative Incidence Rivaroxaban Placebo HR (95% CI) P Value

VTE, n, % (ITT) 25/420, 6.0 37/421, 8.8 0.66 (0.40, 1.09) .10

VTE, n, % (during treatment) 11/420, 2.6 27/421, 6.4 0.40 (0.20, 0.80) -

Major bleeding (ITT), n, % 8/405, 2.0 4/404, 1.0 1.96 (0.59, 6.49) .26

Cumulative analysis of the CASSINI & AVERT trial

KS2 68.5% KS2 67.1%

Ben-Aharon Meta-analysisLung & Pancreas Cancer

Primary thrombo-prophylaxis in solid malignancies – a meta-analysis 1235

cancer LM WH reduced the RR for VT E even fur-

ther [0.28 (95% CI 0.16 – 0.49) for pancreatic can-

cer] and [0.43 (95% CI 0.26 – 0.71) for lung cancer] .

LM WH had no effect on survival in meta-analysis

of all tr ials.

Based on our meta-analysis the NNT to prevent

one symptomatic VT E is 50 (95% CI 33 – 100).

Among lung cancer patients the NNT to prevent one

VT E is 33 (95% CI 25 – 100) and in pancreatic cancer

the NNT to prevent one VT E is 10 patients (95% CI

7 – 16), indicating a substantial benefi t for LM WH in

this subpopulation. T he rate of serious adverse events

was low, with the number needed to harm (NNH)

being 100 (95% CI 50 – very large number) for clini-

cally relevant bleeding. T he RR for major bleeding

events was not greater compared with the control arm

and neither the rate of thrombocytopenia. We could

not infer based upon the analysis whether a specifi c

LM WH exhibit superior results compared with other

agents of this group, it is therefore probably safe to

assume there is a class effect.

T he rationale for primary thromboprophylaxis

in cancer patients arises from the marked risk of can-

cer-associated VT E. Population-based case-control

studies indicate a two-year cumulative incidence of

0.6 – 7.8%, depending on the population studied

[28,29]. T he risk for VT E depends profoundly on the

primary site of cancer, whereas pancreatic, gastric and

lung cancers confer the highest risk to develop VT E

[30]. Lung and cardiac comorbidities which are

frequent in lung cancer patients increase the risk of

VTE by 20% [31,32]. Former studies indicate that the

incidence of VTE is highest within the fi rst six months

of commencing the anti-cancer treatment [2].

Our meta-analysis did not show a survival advan-

tage. Several studies have indicated that selected pop-

ulations may gain a survival advantage from LM WH

prophylaxis, whereas the LM WH benefi t was most

apparent among patients with a better prognosis. Some

other considerations that may impact survival analysis

include the short length of follow-up: in some of the

studies in a subgroup analysis, the good-prognosis

group of patients experienced a superior survival with

LM WH [18,19]. Another determinant is the effect of

LM WH in different tumor types and disease stages.

T he majority of studies included in the meta-analysis

encompass a variety of tumor types whereas the bio-

logical role of LM WH may differ in distinctive cancers.

Due to the main role of coagulation pathways in pan-

creatic and lung cancer, the potential benefi t of con-

comitant administration of LM WH may be enhanced

in these cancers, as we have shown in this meta-anal-

ysis in terms of VTE reduction in these entities.

Several limitations of this analysis must be acknowl-

edged. The heterogeneity of cancer types and disease

stages in some of the studies may attenuate the impact

phylaxis to cancer patients concomitantly with

standard chemotherapy signifi cantly reduces the risk

for symptomatic VT E, any VT E and PE, while the

risk for major bleeding is not signifi cantly increased.

In a subgroup analysis of pancreatic cancer and lung

Study or Subgroup

1.10.1 nadroparin

Agnelli 2009 (PROTECHT)

Subtotal (95% CI)

Total events

Heterogeneity: Not applicable

Test for overall effect: Z = 1.76 (p = 0.08)

1.10.2 semuloparin

Agnelli 2012 (SAVE ONCO)

Subtotal (95% CI)

Total events



1.10.3 certoparin

Haas 2012 (TOPIC 2)

Subtotal (95% CI)

Total events



1.10.4 dalteparin

Altinbas 2004

Subtotal (95% CI)

Total events



Total (95% CI)

Total events

Heterogeneity: Tau² = 0.00; c² = 1.74, df = 3 (p = 0.63); I ² = 0%


Test for subgroup differences: c² = 1.74, df = 3 (p = 0.63), I ² = 0%

Events

7

7

9

9

5

5

1

1

22

Total

199

199

591

591

268

268

42

42

1100

Events

7

7

25

25

10

10

0

0

42

Total

80

80

589

589

264

264

42

42

975

Weight

26.1%

26.1%

47.3%

47.3%

23.9%

23.9%

2.7%

2.7%

100.0%

M-H, Random, 95% CI

0.40 [0.15, 1.11]

0.40 [0.15, 1.11]

0.36 [0.17, 0.76]

0.36 [0.17, 0.76]

0.49 [0.17, 1.42]

0.49 [0.17, 1.42]

3.00 [0.13, 71.61]

3.00 [0.13, 71.61]

0.42 [0.25, 0.71]

M-H, Random, 95% CI

0.01 0.1 1 10 100

Favours LMWHFavours control

Study or Subgroup

1.14.1 nadroparin


Subtotal (95% CI)

Total events



1.14.2 semuloparin


Subtotal (95% CI)

Total events



1.14.3 dalteparin

Marvayas 2012

Subtotal (95% CI)

Total events



1.14.4 enoxaparin

Riess 2010 (CONKO004)

Subtotal (95% CI)

Total events



Total (95% CI)

Total events

Heterogeneity: Tau ² = 0.00; c² = 2.88, df = 3 (p = 0.41); I ² = 0%

Test for overall effect: Z = 4.01 (p < 0.0001)


Events

3

3

3

3

7

7

2

2

15

Total

36

36

126

126

59

59

160

160

381

Events

3

3

14

14

17

17

15

15

49

Total

17

17

128

128

62

62

152

152

359

Weight

14.3%

14.3%

21.4%

21.4%

49.3%

49.3%

15.0%

15.0%

100.0%

M-H, Random, 95% CI

0.47 [0.11, 2.10]

0.47 [0.11, 2.10]

0.22 [0.06, 0.74]

0.22 [0.06, 0.74]

0.43 [0.19, 0.97]

0.43 [0.19, 0.97]

0.13 [0.03, 0.54]

0.13 [0.03, 0.54]

0.31 [0.18, 0.55]

LMWH Control Risk ratio Risk ratio


M-H, Random, 95% CI

0.01 0.1 1 10 100

Favours LMWHFavours [control]

(A)

(B)

Figure 3. Forest plot of risk ratios (RRs) comparing (A) venous

thromboembolism (VT E) in lung cancer patients and (B) in

pancreatic cancer patients who received LM WH in addition to

standard therapy versus those who received standard therapy only.

Risk ratios for each trial are represented by the squares , the size

of the square represents the weight of the trial in the meta-analysis,

and the hor izontal line crossing the square represents the 95%

confi dence interval (CI). T he diamonds represent the estimated

overall effect based on the meta-analysis random effects of all

trials.

Act

a O

nco

l D

ow

nlo

aded

fro

m i

nfo

rmah

ealt

hca

re.c

om

by

Sano

fi S

yn

thel

abo

on

01

/23

/15

Fo

r p

erso

nal

use

on

ly.

Primary thrombo-prophylaxis in solid malignancies – a meta-analysis 1235

cancer LM WH reduced the RR for VT E even fur-

ther [0.28 (95% CI 0.16 – 0.49) for pancreatic can-

cer] and [0.43 (95% CI 0.26 – 0.71) for lung cancer] .

LM WH had no effect on survival in meta-analysis

of all tr ials.

Based on our meta-analysis the NNT to prevent

one symptomatic VT E is 50 (95% CI 33 – 100).

Among lung cancer patients the NNT to prevent one

VT E is 33 (95% CI 25 – 100) and in pancreatic cancer

the NNT to prevent one VT E is 10 patients (95% CI

7 – 16), indicating a substantial benefi t for LM WH in

this subpopulation. T he rate of serious adverse events

was low, with the number needed to harm (NNH)

being 100 (95% CI 50 – very large number) for clini-

cally relevant bleeding. T he RR for major bleeding

events was not greater compared with the control arm

and neither the rate of thrombocytopenia. We could

not infer based upon the analysis whether a specifi c

LM WH exhibit superior results compared with other

agents of this group, it is therefore probably safe to

assume there is a class effect.

T he rationale for primary thromboprophylaxis

in cancer patients arises from the marked risk of can-

cer-associated VT E. Population-based case-control

studies indicate a two-year cumulative incidence of

0.6 – 7.8%, depending on the population studied

[28,29]. T he risk for VT E depends profoundly on the

primary site of cancer, whereas pancreatic, gastric and

lung cancers confer the highest risk to develop VT E

[30]. Lung and cardiac comorbidities which are

frequent in lung cancer patients increase the risk of

VTE by 20% [31,32]. Former studies indicate that the

incidence of VTE is highest within the fi rst six months

of commencing the anti-cancer treatment [2].

Our meta-analysis did not show a survival advan-

tage. Several studies have indicated that selected pop-

ulations may gain a survival advantage from LM WH

prophylaxis, whereas the LM WH benefi t was most

apparent among patients with a better prognosis. Some

other considerations that may impact survival analysis

include the short length of follow-up: in some of the

studies in a subgroup analysis, the good-prognosis

group of patients experienced a superior survival with

LM WH [18,19]. Another determinant is the effect of

LM WH in different tumor types and disease stages.

The majority of studies included in the meta-analysis

encompass a variety of tumor types whereas the bio-

logical role of LM WH may differ in distinctive cancers.

Due to the main role of coagulation pathways in pan-

creatic and lung cancer, the potential benefi t of con-

comitant administration of LM WH may be enhanced

in these cancers, as we have shown in this meta-anal-

ysis in terms of VTE reduction in these entities.

Several limitations of this analysis must be acknowl-

edged. The heterogeneity of cancer types and disease

stages in some of the studies may attenuate the impact

phylaxis to cancer patients concomitantly with

standard chemotherapy signifi cantly reduces the risk

for symptomatic VT E, any VT E and PE, while the

risk for major bleeding is not signifi cantly increased.

In a subgroup analysis of pancreatic cancer and lung

Study or Subgroup

1.10.1 nadroparin


Subtotal (95% CI)

Total events



1.10.2 semuloparin


Subtotal (95% CI)

Total events



1.10.3 certoparin

Haas 2012 (TOPIC 2)

Subtotal (95% CI)

Total events



1.10.4 dalteparin

Altinbas 2004

Subtotal (95% CI)

Total events



Total (95% CI)

Total events




Events

7

7

9

9

5

5

1

1

22

Total

199

199

591

591

268

268

42

42

1100

Events

7

7

25

25

10

10

0

0

42

Total

80

80

589

589

264

264

42

42

975

Weight

26.1%

26.1%

47.3%

47.3%

23.9%

23.9%

2.7%

2.7%

100.0%

M-H, Random, 95% CI

0.40 [0.15, 1.11]

0.40 [0.15, 1.11]

0.36 [0.17, 0.76]

0.36 [0.17, 0.76]

0.49 [0.17, 1.42]

0.49 [0.17, 1.42]

3.00 [0.13, 71.61]

3.00 [0.13, 71.61]

0.42 [0.25, 0.71]

M-H, Random, 95% CI

0.01 0.1 1 10 100

Favours LMWHFavours control

Study or Subgroup

1.14.1 nadroparin


Subtotal (95% CI)

Total events



1.14.2 semuloparin


Subtotal (95% CI)

Total events



1.14.3 dalteparin

Marvayas 2012

Subtotal (95% CI)

Total events



1.14.4 enoxaparin

Riess 2010 (CONKO004)

Subtotal (95% CI)

Total events



Total (95% CI)

Total events


Test for overall effect: Z = 4.01 (p < 0.0001)


Events

3

3

3

3

7

7

2

2

15

Total

36

36

126

126

59

59

160

160

381

Events

3

3

14

14

17

17

15

15

49

Total

17

17

128

128

62

62

152

152

359

Weight

14.3%

14.3%

21.4%

21.4%

49.3%

49.3%

15.0%

15.0%

100.0%

M-H, Random, 95% CI

0.47 [0.11, 2.10]

0.47 [0.11, 2.10]

0.22 [0.06, 0.74]

0.22 [0.06, 0.74]

0.43 [0.19, 0.97]

0.43 [0.19, 0.97]

0.13 [0.03, 0.54]

0.13 [0.03, 0.54]

0.31 [0.18, 0.55]



M-H, Random, 95% CI

0.01 0.1 1 10 100

Favours LMWHFavours [control]

(A)

(B)

Figure 3. Forest plot of risk ratios (RRs) comparing (A) venous

thromboembolism (VT E) in lung cancer patients and (B) in

pancreatic cancer patients who received LM WH in addition to

standard therapy versus those who received standard therapy only.

Risk ratios for each trial are represented by the squares , the size

of the square represents the weight of the trial in the meta-analysis,

and the hor izontal line crossing the square represents the 95%

confi dence interval (CI). T he diamonds represent the estimated

overall effect based on the meta-analysis random effects of all

trials.

Act

a O

nco

l D

ow

nlo

aded

fro

m i

nfo

rmah

ealt

hca

re.c

om

by

Sano

fi S

yn

thel

abo o

n 0

1/2

3/1

5F

or

per

son

al u

se o

nly

.

LUNG CANCER

RR 0.42PANCREATIC CANCER

RR 0.31

Ben-Aharon et al. Acta Oncol. 2014;53(9):1230-7

Primary thromboprophylaxis outpatient setting

Limitations to expand ambulatory primary thromboprophylaxis:

No impact in OS

Low event rate in control arm (<10%) & high NNT with &without KS

No QoL analysis

High cost (cost effectiveness analysis )

To expand thromboprophylaxis, definitely we have to improve STRATIFICATION:

• Selection of patients (control arm VTE incidence <10%): better RAM, > KS

• Clinical detection of high-risk of bleeding: lack of RAM of bleeding

17

Khoran score (KS) & New RAMs

• Is KS the right tool/risk assessment model to identify cancer patients for primary thromboprophylaxis in ambulatory setting?

2008 2010 2012 2013 2016 2017 2018 2019

Khorana score

ViennaCATS

PROTECHTscore

CONKOscore

ONKO TEVscore

TiC Oncoscore

COMPASS CATscore

Simplified Vienna CATscore

THROLY score(lymphomas only)

Next generation to KS: Simplicity vs Complexity

Khorana A. presented @ ICTHIC congress Bergamo 2018 & Lancet Hematology 2018

Select Risk Tools

Innovation/Modification Improves predictionEfficacy

Validated

Vienna CATS Adds D-dimer and soluble P-selectin YesPPV 35% in score 5 or higher

No

PROTECHT Removes body-mass index and adds chemotherapy (cisplatin, carboplatin and gemcitabine)

UnclearAUC/NNT similar in original report

No

ONKOTEV Adds metastatic disease, previous VTE, and compression

YesImproved AUC

No, validation on going

COMPASS-CAT Only for use in breast, colorectal, lung and ovarian cancer

YesImproved AUC

Lung only, further validation on going

New- Vienna Adds D-dimer and removes all other variables except tumor site

YesImproved PPV

Yes

TiC Onco Adds genetic risk factors (genomic risk score)

YesImproved AUC & PPV

No, validation on going (ISTH 2019)

“Perhaps we can heed the advice of the aphorism attributed to many sources, including Albert Einstein: everythingshould be made as simple as possible, but not any simpler. This, too, is more complicated than it seems. »

Score Validation Program 2019

• Retrospective validation in Vienna CAT cohort (ISTH 2019)

• Prospective validation adding D-dimer (multicentre study, ongoing):– Cancer & Thrombosis Working Group Spanish Society of Medical Oncology (SEOM)

• Validation in a single cancer (completed):– NSCLC

• Pilot study adding circulating tumor cells (CTCs) + D-dimer + genomics in pancreatic cancer (ongoing)

• AIRTOP study (starting September 2019), panel of biomarkers: genomics + D-dimer + miRNA + NETS

Applying Risk Assessment

Emerging applications for risk assessment need to be clinically integrated

Angelini D & Khorana AA. Semin Thromb Hemost. 2017;43(5):469-478

Genomics of the neoplasm

DIFFERENTIAL GENE EXPRESSION IN LUNG CANCER PATIENTS WITH AND WITHOUT VTE

5151

Genes under-expressed in patients with VTE

Genes over-expressed in patients with VTE

Normalized counts

log2

fold

chan

ge

Sussman et al. Blood 2017; 130:554

NSCLC ALK+ and VTE

• Zugazagoitia, Muñoz & Manzano et al. European Respiratory Journal 2018

– 241 ALK-rearranged NSCLC patients

– 73 patients (30 %) developed thromboembolic disease

– 74% in the first 6 months from cancer diagnosis

– 16% recurrent VTE

– Liver mets: significant risk factor

– mOS VTE+ 20 months vs VTE- 36 months (p=0.036)

– mOS VTE at baseline 15 m

– mOS recurrent VTE 10 m

• Toronto IASCL 2018: METROS trial ROS1-rearranged NSCLC VTE+ 42%

Zugazagoitia, Muñoz, Manzano. Eur Respir J. 2018;51(5) NSCLC: None Small-Cell Lung CancerALK: Anaplastic lymphoma kinase

23

• Podoplanin was associated with a high risk of VTE

• While mutant IDH-1-R12H was associated with a very low risk for VTE

• IDH-1-R132H mutation is only detected in tumors, which are podoplanin negative– Subhazard ratio (SHR) for podoplanin positive plus IDH-1-R132H wt tumors, compared to

podoplanin negative plus IDH-1-R132H mutant tumors: 4.69, 95%CI: 1.28- 17.17; p=0.020).

24Rield J et al. XXVI Congress of the International Society on Thrombosis and Haemostasis and 63rd Annual Scientific and Standardization Committee (SSC) Meeting 2017

PROTECTIVE FACTOR!IDH mutation

Variability of the VTE-Risk: VTE-Risk ModifiersMultiple Risk (Clinical) Factors XX Century

Patient-related factors– Older age– Gender– Race

• Higher in African Americans• Lower in Asians

– Patient comorbidities– History of VTE

Treatment-related factors– Major surgery– Hospitalization– Chemotherapy– Central venous catheters– Hormonal therapy– Antiangiogenic agents– ESAs– Transfusions

Cancer-related factors– Site of cancer– Stage– Initial period after diagnosis

Variability of the VTE-Risk: VTE-Risk modifiersMultiple Risk (Clinical & Molecular) Factors XXI Century

Patient-related factors– Older age– Gender– Race

• Higher in African Americans• Lower in Asians

– Patient comorbidities– History of VTE

Treatment-related factors– Major surgery– Hospitalization– Chemotherapy– Central venous catheters– Hormonal therapy– Antiangiogenic agents– ESAs– Transfusions

Cancer-related factors– Site of cancer– Stage– Initial period after diagnosis

Cancer-related factors– Genomics– Other molecular

biomarkersPatient-related factors

– Genomics

This is a QUALIFIED report. This specimen failed to meet minimum performance standards following sequencing

due to factors such as low tumor content or sub-standard sequence coverage. We can confirm the presence of the

genomic alterations detailed in this report, but we cannot confirm the absence of other alterations.

GENE ALTERATION

Partner Name

Partner Study ID

FMI Study ID

Site

Patient Sex

Patient Date of Birth

Accession Number

Diagnosis

Received Date

Visit Type

Date Collected

Sample Type

Report Date Subject ID FMI Sample ID

06MAY2019 15003-289 TRF405174

Next Generation Sequencing: Mainly the Risk is Driven By the Tumor

• Clinical practice: NGS (Foundation Medicine, etc.), liquid biopsy

An another opportunity

• Big Data + Machine Learning + Natural Language Processing

• Integrate:

– Genomics of the patient

– Genomics of the tumor

– Clinical risk factors (type of chemotherapy, etc.)

Report Date Subject ID FMI Sample ID

06MAY2019 15003-289 TRF405174

TESEOM Registry

• Specific VTE Cancer Registry (complement RIETE)

• Cancer & Thrombosis Working Group, Spanish Society of Medical Oncology (SEOM)

• Started: July 2018

• International registry– Spain 40 centers

– Portugal 2 centers

– 500 patients May 2019

– Extension to other countries

– Next future: add a sample of the tumor [email protected]

Hokusai VTE cancer: Edoxaban vs LMWH1

1. Van Es N et al. Thromb Haemost 2015;114:1268–76;2. Raskob GE et al. N Engl J Med 2018;378:615–24

R 1:1

Objectively-confirmed VTE and cancer

(active or diagnosed in previous 2 years)

N=10502

LMWH* sc

Day 5 12 months

Dalteparin200 IU/kg OD

Edoxaban60 mg OD†

Day 30

Dalteparin150 IU/kg OD

Day 0

*≥5 days of LMWH. Choice of LMWH type and lead-in duration were left to treating physician†Edoxaban 30 mg OD for patients requiring dose adjustment for CrCl 30–50 mL/min, body weight ≤60 kg and/or concomitant P–gp inhibitor use

CrCl: creatinine clearance; LMWH: low-molecular-weight heparin; OD: once daily; P-gp: P-glycoprotein; PROBE: Prospective Randomised Open Blinded End-Point; sc: subcutaneous; VTE: venous thromboembolism

Primary endpoint: Composite of recurrent VTE or major bleeding

Key secondary endpoints: Recurrent VTE, major bleeding

0

2

4

6

8

10

12

14

16

1. Raskob GE et al. N Engl J Med 2018;378:615–24

• No significant interactions between subgroups and treatment, with the exception of GI cancer at randomisation

Primary outcome(Recurrent VTE or major bleeding)

*Secondary outcomesCI: confidence interval; GI: gastrointestinal; HR: hazard ratio

HR: 0.97 (95% CI 0.70–1.36)p=0.006 for non-inferiority

p=0.87 for superiority

Eve

nt

rate

(%

)

n=71n=67 n=59n=41 n=21n=36

Edoxaban (n=522)

Dalteparin (n=524)

0

2

4

6

8

10

12

14

16

Eve

nt

rate

(%

)

HR: 0.71(95% CI 0.48–1.06)

p=0.09

HR: 1.77(95% CI 1.03–3.04)

p=0.04

Recurrent VTE* Major bleeding*

Hokusai VTE cancer: Safety and efficacy outcomes1

12.8 13.5

7.9

11.3

6.9

4.0

First recurrent VTE or major bleeding event

1. Raskob GE et al. N Engl J Med 2018;378:615–24 (supplementary appendix); 2. Kraaijpoel N et al. Thromb Haemost 2018;118:1439–49

Edoxaban (n=522) Dalteparin (n=524)

Characteristics of primary outcome: Recurrent VTE,1 n (%) 34 (6.5%) 54 (10.3%)

Confirmed fatal 0 0

DVT only 13 30

Symptomatic 22 40

Characteristics of primary outcome: Major bleeding,1 n (%) 33 (6.3%) 17 (3.2%)

Fatal 0 2

Intracranial 2 4

Upper GI 17 3

Lower GI 3 3

Major bleeding by cancer type,2 n/N (%)

GI cancer 21/165 (12.7%)* 5/140 (3.6%)

Other cancers 18/357 (5.0%) 19/384 (4.9%)

DVT: deep vein thrombosis

*HR (edoxaban vs dalteparin): 4.0 (95% CI 1.5–10.6); p=0.005

Select-D: Rivaroxaban vs LMWH1

1. Young AM et al. J Clin Oncol 2018;36:2017–23

Prospective, randomised, open-label, multicentre pilot phase III study

R

Rivaroxaban15 mg BID for 21 days

then 20 mg OD*

RPE index event or RVT positive after ~5 months

Active cancer with symptomatic DVT

and/or PE

N=406Dalteparin200 IU/kg OD

for first 30 daysthen 150 IU/kg OD

Rivaroxaban20 mg OD

Placebo

6 months 12 months

Follo

w-u

p

*Dose reduction or discontinuation specified for different levels of renal impairment. If a patient’s platelet counts falls to <50,000/mm3, rivaroxaban should be discontinued until the platelet count recovers to above 50,000/mm3

BID: twice daily; CRNM: clinically-relevant nonmajor; PE: pulmonary embolism; RVT: residual vein thrombosis

Efficacy (primary): Rate of VTE recurrence (symptomatic and incidental PE) Secondary: Rate of major bleeding and CRNM bleeding (also assess survival, health economics)

Select-D: Safety and efficacy outcomes1

4

11

0

2

4

6

8

10

12

14

1. Young AM et al. J Clin Oncol 2018;36:2017–23

HR: 0.43(95% CI 0.19–0.99)

HR: 1.83(95% CI 0.68–4.96)

HR: 3.76(95% CI 1.63–8.69)

Cu

mu

lati

ve e

ven

t ra

te

at 6

mo

nth

s (%

)

• 54% of patients completed 6 months of trial treatment

• Most major bleeding events were GI bleeds also GU bleeds were more common (9 vs 1 patient)

• Patients with oesophageal or gastro-oesophageal cancer tended to experience more major bleeds with rivaroxaban than with dalteparin (4 of 11 [36%] vs 1 of 19 [11%]): stop recruitment

6

13

4 4

0

2

4

6

8

10

12

14

Recurrent VTE Major bleeding CRNM bleeding

Rivaroxaban (n=203)

Dalteparin (n=203)C

um

ula

tive

eve

nt

rate

at

6 m

on

ths

(%)

Recurrent events

Raskob et al. N Engl J Med. 2018; Young et al. J Clin Oncol. 2018

HOKUSAI SELECT-D

Major bleedings

HOKUSAI SELECT-D

Pathogenesis of DOAC-Related GI Bleeding

Cheung KS, et al. World J Gastroenterol. 2017;23:1954-1963.

Mucosa

GI tract

Topical effect on the mucosa

NOAC

Topical effect

Systemic anticoagulant effect from NOAC

Incomplete absorption(topical anticoagulant

effect)

Direct caustic effect(eg, tartaric acid in

dabigatran)

Inhibition of mucosal healing

© Medscape, LLC

Raskob et al. N Engl J Med. 2018

1 in 7 patients1 in 25 patients

Persistence with anticoagulation for CAT

Khorana AA, et al. Res Pract Thromb Haemost. 2017;1:14-22.

ADAM trialClinical outcomes during treatment period

11/1/2018 Paper: Apixaban, Dalteparin, in Active Cancer Associated Venous Thromboembolism, the ADAM VTE Trial

https://ash.confex.com/ash/2018/webprogram/Paper118808.html 2/2

outcome measures compared to parenteral dalteparin in the treatment of cancer associated VTE. These data support the clinical utility of apixaban for the

acute treatment of VTE in this patient population.

No relevant conflicts of interest to declare.

See more of: 332. Antithrombotic Therapy: Management of Challenging Patients and Scenarios See more of: Oral and Poster Abstracts

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McBane et al. ASH 2018

Guidelines ISTH 2018NCCN 2019

Initial LMWH followed by edoxaban (category 1) Rivaroxaban monotherapy (category 2A)

Version 1.2019, 02/28/19 © 2019 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.

NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®)

Cancer-Associated

Venous Thromboembolic

Disease

Version 1.2019 — February 28, 2019

Continue

NCCN.org

Final treatment recommendation should be made after shared decision making with patients regarding a potential reduction in recurrence

but higher bleeding rates with specific NOACs, incorporating patient preferences and values

Anticoagulant Therapy Suggest Use of

Specific NOACs

(edoxaban or rivaroxaban)

In patients with low risk of bleeding and no drug-drug

interactions with current systemic therapy

LMWH

In patients with high risk of bleeding, including

Patients with luminal GI cancers with an intact primary

Patients with cancers at risk of bleeding from the GU

tract, bladder, or nephrostomy tubes

Patients with active GI mucosal abnormalities such as

duodenal ulcers, gastritis, esophagitis, or colitis

Diminishing recurrent VTE rates in cancer patients with anticoagulant therapy

a. Wang TF, et al. Res Pract Thromb Haemost. 2018;2:429-438; b. Raskob GE, et al. N Engl J Med. 2018;378:615-624;c. Young AM, et al. J Clin Oncol. 2018;36:2017-2023.

Warfarin[a]

10% to 16%

LMWH[a]

6% to 9%

DOACs[b,c]

4% to 8%

Improving the efficacy…but paying a price? Or is a question of LMWH?dosification

DOACs in the recurrence setting?

Ongoing trials in patients with cancer and VTE: Study overview

Study Study design DOAC ComparatorPrimary outcome

Treatment duration

Sample size (N)

Initial and intermediate treatment

CASTA-DIVA1 Randomised, open, non-inferiority, PROBE

Rivaroxaban Dalteparin Recurrent VTE 3 months 200

ADAM-VTE2 Randomised, open label, superiority

Apixaban Dalteparin Major bleeding 6 months 315

CANVAS3

Randomised, open label,

non-inferiorityAny DOAC

LMWH or fondaparinux (alone or followed by VKA)

VTE recurrence 6 months

940

CARAVAGGIO4 IIS, randomised, open label, PROBE

Apixaban Dalteparin VTE recurrence 6 months 1168

Extended treatment

EVE5 Randomised, open label

Apixaban lower dose BID

Apixaban higher dose BID

Major & CRNM 6 months 370

1. Clinicaltrials.gov: NCT02746185; 2. McBane R et al. Thromb Haemost 2017;117:1952–61; 3. Clinicaltrials.gov: NCT02744092; 4. Agnelli G et al. Thromb Haemost 2018; DOI: 10.1055/s-0038-1668523; 5. Clinicaltrials.gov: NCT03080883

DOACs: New treatment option but, maybe not the right drug for all cancer patients…my thoughts

• High-risk bleeding

– Mucosa involvement or primary tumor in place (not resected)

– Concomitant treatment with antiangiogenics (antiangiogenic therapy increase the risk of bleeding: bevacizumab, aflibercept, etc.)

– Tumor invading great vessels (lung cancer and vena cava/aorta/pulmonary artery…)

– Thrombocytopenia, etc.

• Concomitant treatment with other drugs (interactions, clinically relevant?)

• Impaired oral intake: obstructive tumors, nauseas&vomiting, etc.

• Malabsorption: extensive GI resection (cytoreductive surgery), etc.

• Liver impairment: extensive liver mets, etc.

• Mucositis (treatment toxicity) & benign diseases of the GI mucosa

Documents

Developments in the management of cancer-associated ......Cancer-Associated Thrombosis (CAT) Prevalence and Burden •VTE is a major complication of cancer and a leading cause of death