javier sastre - simposio científico hitos oncológicos · javier sastre servicioi de oncología...
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![Page 1: Javier Sastre - Simposio científico Hitos Oncológicos · Javier Sastre Servicioi de Oncología Médica HC San Carlos de Madrid jsastrev@salud.madrid.org. 2008 SORAFENIB 1ªL 2ªL](https://reader031.vdocuments.pub/reader031/viewer/2022041011/5ebaee7d2c82607890704d15/html5/thumbnails/1.jpg)
¿Qué ha ocurrido con el hepatocarcinoma?
Javier SastreServicioi de Oncología Médica
HC San Carlos de Madrid
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2008
SORAFENIB
1ªL
2ªL
2017
REGORAFENIB
2018
LENVATINIB
CABOZANTINIB
RAMUCIRUMAB
PEMBROLIZUMAB + LENVATINIBATEZOLIZUMAB + BEVACIZUMAB
NIVOLUMAB
PEMBROLIZUMAB
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Phase III REFLECT Trial design
Advanced
HCC 1:1
Sorafenib 400 mg/12h
Lenvatinib 12 mg/day
(8mg in < 60Kg)
Treatment until disease
Progression or
unaceptable toxicity
Stratification factors:
1. Region (Pacific Asia vs Non Pacific Asia)
2. Vascular invasion or extrahepatic disease
3. ECOG (0 vs 1)
4. Weight (< 60Kg vs > 60 Kg)
Primary objective:
Overall survival
Secondary objectives:
PFS
Response rate
Toxicity and Quality of Live
Lenvatinib pharmacokinetics
940 ptes
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REFLECT: Assessments and Statistical analysis
• The primary end-point of OS was first tested for noninferiority then for superiority.– The required number of events for the primary analysis was 700 deaths.
• The HR and its 95% CI were estimated from a Cox proportional hazard model, withtreatment group as a factor and the analysis stratified according to randomizationfactors:
– The noninfeiority margin was set at 1.08 based on previous phase 3 trials of sorafenib.
– Noninferiority would be declared if the upper limit of the 2-sided 95% CI for HR was < 1.08.
• A fixed-sequence procidure was followed to control the overall type I error rate of analysis for efficacy endpoints at a = 0.05 (2-sided).
• After noninferiority was declared, secondary efficacy endpoints were tested:– Differences in PFS and TTP were tested using stratified log-rank test with randomization stratification factors
and the associated HR and its 95% CI were evaluated
– A difference in ORR was tested using the Cochran-Mantel-Haenszel chi-square test with randomizationstratification factors as strata, and the associated odds ratio and its 95% CI were evaluated.
• To assess futility, 2 interim analyses were performed using Bayesian predicitveprobability in a noninferiority design.
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REFLECT: Primary end-point (OS)
Kuso M. Lancet 2018 Published online February 9, 2018 http://dx.doi.org/10.1016/S0140-6736(18)30207-1
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REFLECT: Secondary objective (PFS)
Kuso M. Lancet 2018 Published online February 9, 2018 http://dx.doi.org/10.1016/S0140-6736(18)30207-1
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Presented By Ann-Lii Cheng at 2017 ASCO Annual Meeting
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Presented By Ann-Lii Cheng at 2017 ASCO Annual Meeting
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RESOURCE: Primary and Secondary end-points
10.6m vs 7.8m
3.1m vs 1.5m
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RESOURCE: Subgroup analysis
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Bruix et al. Lancet Oncol. 2016
Reducción de dosis: 54% (vs. 10% pbo.)
Interrupción tto: 10% (vs. 4% pbo.)
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Presented By Ghassan Abou-Alfa at 2018 Gastrointestinal Cancers Symposium
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Presented By Ghassan Abou-Alfa at 2018 Gastrointestinal Cancers Symposium
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No. at Risk
Cabozantinib 470 382 281 206 159 116 93 63 44 31 22 12 4 1 0
Placebo 237 190 117 82 57 37 25 20 15 10 7 5 3 0 0
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42
0.0
0.2
0.4
0.6
0.8
1.0
Pro
babilit
y o
f O
S
Time (months)
Abou-Alfa GK, et al. ASCO GI 2018;Poster presentation 207 (Board A4)
Median OS
mo (95% CI)
No. of
deaths
Cabozantinib (n=470) 10.2 (9.1-12.0) 317
Placebo (n=237) 8.0 (6.8-9.4) 167
HR=0.76 (95% CI 0.63–0.92), p=0.0049*
CELESTIAL: OS
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Median PFSmo (95% CI)
No. ofevents
Cabozantinib(N=470)
5.2 (4.0–5.5) 349
Placebo (N=237) 1.9 (1.9–1.9) 205
Progression-free survival assessed per RECIST 1.1
0 3 6 9 12 15 18 21 24
0.0
0.2
0.4
0.6
0.8
1.0
Pro
babilit
y o
f PFS
Time (months)
No. at RiskCabozantinib
Placebo
470
237
266
70
131
21
80
13
39
5
15
2
10
2
3
2
3
1
HR=0.44 (95% CI 0.36–0.52), P<0.0001
Abou-Alfa GK, et al. ASCO GI 2018;Poster presentation 207 (Board A4)
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Presented By Ghassan Abou-Alfa at 2018 Gastrointestinal Cancers Symposium
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Presented By Ghassan Abou-Alfa at 2018 Gastrointestinal Cancers Symposium
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REACH 2: Study Design
R
A
N
D
O
M
I
Z
E
2:1
Stratification factors
• Macrovascular invasion
(yes vs. no)
• ECOG PS (0 vs. 1)
• Geographic region
• Americas, Europe,
Israel and Australia
• Asia (except Japan)
• Japan
Primary endpoint: Overall survival
Secondary endpoints:
• PFS, TTP, ORR
• Time to deterioration in FACT
Hepatobiliary Symptom Index-8
(FHSI-8)
• Time to deterioration in ECOG PS
• Safety, PK, Immunogenicity
• Baseline AFP ≥400
ng/mL
• BCLC stage B/C
• Child Pugh A
• ECOG PS 0/1
• Prior sorafenibPlacebo + BSC
Q2W
Ramucirumab + BSC
8 mg/kg IV Q2W
Statistical assumptions and analysis
• 80% power, alpha 0.05
• HR 0.67
• mOS 6.7 months ramucirumab vs. 4.5 months placebo
• N=279 (2:1 randomization, ramucirumab vs placebo)
• 221 events
ClinicalTrials.gov NCT02435433
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REACH 2: Overall Survival
Ramucirumab Placebo Difference P-value
Patients / Events 197/147 95/74
Median, months 8.5 7.3 1.2
HR (95% CI) 0.710 (0.531, 0.949) 0.0199
Survival rate (%)
12 months 36.8 30.3 6.5 0.2930
18 months 24.5 11.3 13.2 0.0187
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Adverse EventsRamucirumab Placebo
n (%) n=197 n = 95
Discontinuation due to treatment-related AEa 21 (10.7) 3 (3.2)
Dose adjustmentb due to AE 68 (34.5) 13 (13.7)
Deaths due to treatment-related AEa 3 (1.5)
TEAEs in ≥ 15% Patients in Ramucirumab arm Any Grade Grade ≥3 Any Grade Grade ≥3
Patients with ≥ 1 TEAE 191 (97.0) 116 (58.9) 82 (86.3) 42 (44.2)
Fatigue 54 (27.4) 7 (3.6) 16 (16.8) 3 (3.2)
Peripheral edema 50 (25.4) 3 (1.5) 13 (13.7) 0
Hypertension 48 (24.4) 24 (12.2) 12 (12.6) 5 (5.3)
Decreased appetite 46 (23.4) 3 (1.5) 19 (20.0) 1 (1.1)
Proteinuria 40 (20.3) 4 (2.0) 4 (4.2) 0
Abdominal pain 39 (19.8) 3 (1.5) 12 (12.6) 2 (2.1)
Nausea 37 (18.8) 0 11 (11.6) 0
Ascites 35 (17.8) 8 (4.1) 7 (7.4) 2 (2.1)
Diarrhea 32 (16.2) 0 14 (14.7) 1 (1.1)
AE = Adverse Events aRelated per investigator judgement; bDose adjustment = dose delay, dose reduction and dose omission
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• There are a number of approaches to immunotherapy for HCC:1,2
1. Feun LG et al. Hepatoma Res 2017;3:43–51.2. Greten TF, et al. Clin Cancer Res. 2013;19:6678–6685.
Antibody
CTL mediated lysisTumor cell
death
Peptides
Cytokines
Enhanced
T-cell function
Foxp3+ Treg
IL-10, TGF-β
MDSC
T-cell
activation
T-cell
T-cell activation
& priming
Antibody
Oncolytic
virusTumor
ablation
Checkpoint
blockadeCytokines (GM-
CSF,
IL-2, IFN-y, etc)
Dendritic
cells
Cancer Vaccines
Elimination of
suppressor cells
Blockade of
immunosuppressive
cytokines
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There are a number of ongoing checkpoint inhibitor studies in HCC
Tumour entity Investigated regimen Trial identifier
HCC Nivolumab (anti PD-1 Ab) NCT02576509
HCC Nivolumab (anti PD-1 Ab) plus CC-122 (immunostimulatorypathway modifier)
NCT02859324
HCC Nivolumab (anti PD-1 Ab) plus LRT (Yttrium 90Y glass microspheres)
NCT02837029
HCC Nivolumab (anti PD-1 Ab) plus ipilimumab (anti CTLA-4 Ab) NCT01658878
HCC PDR001 (anti PD-1 Ab) plus INC280 (c-Met inhibitor) NCT02795429
HCC Pembrolizumab (anti PD-1 Ab) NCT02702401
HCC Pembrolizumab (anti PD-1 Ab) NCT02940496
HCC Pembrolizumab (anti PD-1 Ab) plus dendritic cells, cytokine-induced killer cells
NCT02886897
HCC Atezolizumab + bevacizumab vs sorafenib
HCC Tremelimumab (anti CTLA-4 Ab) NCT01853618
HCC Tremelimumab (anti CTLA-4 Ab) plus durvalumab (anti PD-1L Ab) NCT02519348
HCC Tremelimumab (anti CTLA-4 Ab), durvalumab (anti PD-1L Ab) plus LRT
NCT02821754
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Phase 1/2 Study of Nivolumab ± Other Agents in HCC (CheckMate040)1
1. CheckMate 040 (NCT01658878). Available at: https://clinicaltrials.gov/ct2/show/NCT01658878?term=checkmate+040&rank=1 (Accessed January 2018).
2. El-Khoueiry AB et al. The Lancet 2017:389:2492–2502.
Cabo, cabozantinib; Ipi, ipilimumab; Nivo, nivolumab.
Cohort 1: NivoDose
EscalationUninfected HCC
HCV-infected HCCHBV-infected HCC
Patients with advanced HCC (N=620)
Inclusion criteria (cohort non-specific*):1
• Advanced HCC ineligible for, or progressive disease after, surgical and/or locoregionaltherapies
• ECOG PS 0 or 1
Exclusion criteria (cohort non-specific*):
• Prior or current clinically significant ascites
• History of hepatic encephalopathy
• Prior anti-PD-1/PD-L1/PD-L2 or other antibody therapy2
Cohort 3: 1L Nivo vs Sorafenib
Cohort 4: Nivo + Ipi
Cohort 6: Nivo + Cabo vs Nivo + Cabo + Ipi
Study Endpoints
• Primary:
• Safety, tolerability
• ORR
• Secondary:
• CR
• DCR
• DOR
• TTR
• TTP
• PFS
• OS
Enrollment is ongoing
Cohort 2: Nivo
Dose ExpansionUninfected sorafenib
naïve/intolerantUninfected sorafenib
progressorsHCV-infected HCCHBV-infected HCC
Cohort 5: Nivo in Child-Pugh B7 to B8
*Cohort specific inclusion/exclusion criteria not listed here
Data
available2
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CheckMate 040: Overall survival
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Study Design
Presented By Andrew Zhu at 2018 Gastrointestinal Cancers Symposium
KEYNOTE-224: Pembrolizumab in HCC previouslytreated with Sorafenib
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Presented By Andrew Zhu at 2018 Gastrointestinal Cancers Symposium
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Slide 6
Presented By Andrew Zhu at 2018 Gastrointestinal Cancers Symposium
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Ikeda et al. @ASCO 2018
A Phase 1b Trial of Lenvatinib (LEN) Plus Pembrolizumab
in Patients With Unresectable HCC
ORR: 42%
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2008
SORAFENIB
1ªL
2ªL
2017
REGORAFENIB
2018
LENVATINIB
CABOZANTINIB
RAMUCIRUMAB
PEMBROLIZUMAB + LENVATINIBATEZOLIZUMAB + BEVACIZUMAB
NIVOLUMAB
PEMBROLIZUMAB
Conclusiones