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
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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
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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)
• 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
“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%
• 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
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
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
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
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.
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)
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