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Emerging Immunotherapy and Future Directionsin Unresectable HCC
Bruno SangroClínica Universidad de Navarra. IdISNA. CIBERehd.
Pamplona, Spain
Conflicts of Interest
Personal financial interests
• Consulting or advisory role: Adaptimmune, Astra Zeneca, Bayer, BMS, BTG, Ipsen, Lilly, Merck, Onxeo, Novartis, Roche, Sirtex Medical
• Lectures: AstraZeneca, Bayer, BMS, Sirtex Medical, Terumo
• Research grants: BMS, Onxeo, Sirtex
Non-financial interests
• Investigator for clinical trials sponsored by Adaptimmune, Astra Zeneca, Bayer, BMS, Novartis, Ipsen, Roche, Sirtex Medical
Therapeutic Potential of Immunotherapy
• Targets tumor heterogeneity
• Ability to adapt to resistance mechanisms
• Multiple targets that can be synergistic
• Potential synergy with locoregional and targeted therapies
– Immunogenic cell death
– Enhanced transcription of relevant epitopes
Greten and Sangro. J Hepatol 2017.
Improving the Effect of PD-1/PD-L1 Blockade
Combination Therapies Based on PD-1/PD-L1 Blockade
IpilimumabTremelimumab
Bevacizumab
Abemaciclib(CDK4 & 6)
Y90-TARE
SF-1126(PI3K – mTOR)
Pexa-Vec(VPV-GM-CSF)IRX-2
(cytokines)
SBRT
Galunisertib(TGFb)
IRE
Lenvatinib
Copanlisib(PI3K)
Tadalafil + Vancomycin
CBT-501(c-met)
BMS 986205(IDO-1)
Sorafenib
CC-122(ubiquitination)
TACE
Vorolanib
FT2102(IDH1-R132 mut)
RFA/MW
Bavituximab(phosphatidilserine)
Voyager 1(VSV-IFN-NIS)
T-Vec(HSV-GM-CSF)
Regorafenib
DPX-Survivin
P53-MVA
Epacanostat(IDO-1)
ALT-803(IL-15 superagonist)
Cabozantinib
Guadecitabine(DNA demetilation)
Ramucirumab
KY1044(ICOS)
Axitinib
Immune StimulationOncolytic and
Non-Oncolytic VirusLocoregional Therapies
Other Targeted TherapiesMulti-TKIs
Anti-Angiogenics
Anti-CTLA-4 Anti-PD-1 / PD-L1Nivolumab
PembrolizumabDurvalumab
AtezolizumabAvelumab
Hepa 129 tumors have infiltrating Tregs expressing CTLA-4.
Belinostat Potentiates Checkpoint Inhibition in HCC
Therapeutic effect is associated with • decrease in splenic Tregs and PD-1+ CD4
T cells• enhanced antitumor T cell response
Llopiz D, et al. Presented at AACR 2017. Poster #1059
Phase 3 Trials with Combinations with IO Agents in HCCAdvanced Stage
Trial Population n Control Arm Inv. Agent
HIMALAYA Advanced 1L 1200 SorafenibDurvalumab orDurvalumab + Tremelimumab
CheckMate 9DW Advanced 1L 1084Sorafenib orLenvatinib
Nivolumab + Ipilimumab
Imbrave 150 Advanced 1L 480 SorafenibAtezolizumab + Bevacizumab
COSMIC-312 Advanced 1L 640 SorafenibAtezolizumab + Cabozantinib
LEAP-002 Advanced 1L 750 LenvatinibPembrolizumab + Lenvatinib
NCT02702401; NCT02576509; NCT03298451; NCT03434379; NCT03412773
VEG
FC
TLA
-4M
ult
i-TK
I
Imbrave 150 Atezolizumab + Bevacizumab vs. Sorafenib Safety Summary
Cheng AL, et al. Presented at ESMO Asia 2019
Atezo + Bev(n = 329)
Sorafenib(n = 156)
Treatment duration, median, mo Atezo = 7.4; Bev = 6.9 2.8
All-Grade AEs, any cause, n (%) 323 (98) 154 (99)
Treatment-related all-Grade AEs 276 (84) 147 (94)
Grade 3-4 AE , n (%)b 186 (57) 86 (55)
Treatment-related Grade 3-4 AEb 117 (36) 71 (46)
Serious adverse event, n (%) 125 (38) 48 (31)
Treatment-related SAE 56 (17) 24 (15)
Grade 5 AE, n (%) 15 (5) 9 (6)
Treatment-related Grade 5 AE 6 (2) 1 (< 1)
AE leading to withdrawal from any component, n (%) 51 (16) 16 (10)
AE leading to withdrawal from both components 23 (7) 16 (10)
AE leading to dose interruption of any study treatment, n (%) 163 (50) 64 (41)
a Safety-evaluable population. b Highest grade experienced. c No dose modification allowed for Atezo + Bev arm.
Combination Systemic Therapy of HCCMulti-TKI + Anti-PD-1
• N=30
• ORR 53.3% by RECIST 1.1 IIR
• Median DOR 8.3 months
• Median PFS 9.69 months
• Grade ≥ 3 TEAE 73%
• SAE 50%, 13% fatal (1 SBP, 1 ARDS, 1 perforation)
• Expansion cohort underway
Ikeda M, et al. Presented at AACR 2019
Pembrolizumab 200 mg IV d1 + Lenvatinib 12 or 8 mg daily PO, q3wk
Targeting Checkpoints In Cancer Therapy
* These agents arget PD-L1. CTLA-4=cytotoxic T-lymphocyte antigen-4; GITR=glucocorticoid-induced TNFR family related gene; KIR=killer-cell immunoglobulin-like receptor; LAG-3=lymphocyte-activation gene-3; NK=natural killer; PD-1=programmed death-1; PD-L1=programmed death ligand-1.
1. Pardoll DM. Nat Rev Cancer. 2012;12:252-264. 2. Mellman I et al. Nature. 2011;480:480-489.
Adapted from Mellman et al and Pardoll et al.1,2
TremelimumabIpilimumab
Several checkpoint-targeted agents are under investigation for cancer
Nivolumab PembrolizumabDurvalumab*Atezolizumab*
PD-1
TIM-3
BTLA
VISTALAG-3HVEM
CD27
CD137
GITR
OX40
CD28
T cell
B7-1
CTLA-4
BMS-986016
MOXR0916
TRX518
Urelumab
Varlilumab
Agents Targeting T Cells
(Adaptive Immunity)
Agents Targeting NK Cells
(Innate Immunity)
KIR
Adapted from Pardoll et al.1
Lirilumab
Blocking agents Stimulating agents
Greten and Sangro. J Hepatol 2017
Codrituzumab(anti-GP3)
AFP SPEAR T cells
HEPAVAC (multipeptide + RNAadj)
TremelimumabIpilimumab
NivolumabPembrolizumab
DurvalumabAtezolizumab
Immune-Based Therapies for HCC
CAR-GPC3 T cells
CIK cells
Immunotherapy for HCCCell Therapy
Prieto, Melero, Sangro. Nat Rev Gastroenterol Hepatol 2015;12:681-700
Peripheral or Tumor-infiltrating Immune Cells
• Leukapheresis or Tumor Harvesting
• Cell sorting
• Cell expansion and maturation
• IFN-γ, IL-1, IL-2 and anti-CD3
• Cell engineering
• TCRs, CAR-T
• Reinfusion
CytokinesViral vectors
Adjuvant Immunotherapy With Autologous CIK Cells for HCC
Injection of activated cytokine-induced killer cells
• CD3+/CD56+ T cells
• CD3+/CD56– T cells
• CD3–/CD56+ natural killer cells
Randomized Phase III open-label trial
230 patients with HCC after resection, RFA, or ethanol injection
Primary Endpoint: Recurrence-free survival
0.00
0.60
0.80
1.00
0
RFS
(P
rob
abili
ty)
0.40
0.20
3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54Time (months)
114 106 98 93 89 87 85 82 79 76 59 52 47 40 29 18 8 2
112 98 87 76 67 60 54 52 51 46 40 32 27 23 18 12 10 1ImmunotherapyControl
No. at risk
0.80
1.00
0
OS
(Pro
bab
ility
)
0.60
3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54Time (months)
114 109 109 109 109 109 108 108 107 100 84 74 70 64 47 35 21 6
112 102 100 99 97 96 93 92 90 80 70 59 56 53 42 30 21 4ImmunotherapyControl
No. at risk
Immunotherapy
Control
Immunotherapy
Control
Lee JH et al. Gastroenterology. 2015;148:1383
Engineered TCRs and Chimeric Antigen Receptors
Sharpe M and Mount N. Dis. Model. Mech. 2015;8:337-350
AFP-targeted TCRs
Cytotoxic activity of AFP SPEARTM T-cells towards AFP-expressing HepG2-GFP 3D microtissues
Gerry A, et al. Presented at ILCA 2016; Goyal L, et al. Presented at AACR 2019
HCC Antigenicity
Deregulation of oncofetal and cancer/testis proteins
Shared tumor-associated antigens (TAAs):• Alpha-fetoprotein (AFP)• Glypican-3 (GPC-3)• NY-esophageal squamous carcinoma-1 (NY-ESO-1)• Melanoma-associated gene-1 (MAGE-A1)• Synovial sarcoma X chromosome breakpoint (SSX-2)• human telomerase-reverse transcriptase (hTERT)
Genetic & Epigenetic Changes
Non-synonymous somatic mutations
Private tumor-specific antigens
Vaccines
Agent Trial Design Sample size, Population
Primary Endpoint Relevant Findings
Glypican-3 peptides
ProspectiveSingle arm
33, advanced HCC Safety No relevant toxicity
Telomerase derived peptide
ProspectiveSingle arm
40, advanced HCC RR at 6 monthsRR at 6 months: 0 PR; 18 SD
Prieto, Melero, Sangro. Nat Rev Gastroenterol Hepatol 2015;12:681-700; http:\\www.clinicaltrials.gov
AgentTrial
Ph Agent(s) Immunogenic mechanism N CountryComple-
ted
AlloStim + AllovaxNCT02409524
IITumor-derivedchaperone-rich cell lysate(CRCL) + adjuvant
CRCL provides both a source of tumor antigens and danger signals triggering
antigen presenting cell activation.30
Korea / Taiwan
Jun 2016
TelomelysinNCT02293850 I/II
Oncolytic adenovirus carrying the hTERT promotor
Virus-induced oncolysis releases tumor epitopes and provides costimulatory
danger signals. 33 Thailand Dec 2017
Peptide Vaccines
Agent Trial Design Sample size, Population Primary Endpoint Relevant Findings
Glypican-3 peptides
Prospective.Single arm. 33, advanced HCC Safety No relevant toxicity.
Telomerase derived peptide
Prospective.Single arm. 40, advanced HCC RR at 6 months RR at 6 months: 0 PR; 18 SD
HEPAVAC clinical trial (multicenter, randomized, international)
– Feasibility– Safety– Biological efficacy (immunomonitoring)– Signs of efficacy (PFS, OS and QoL)
Prieto, Melero, Sangro. Nat Rev Gastroenterol Hepatol 2015;12:681-700
Future Directions
BCLC 0–A BCLC B BCLC C
Resection
LTX [III, A]
Ablation
[III, A]
TACE [I, B]
SBRT
Brachytherapy
SIRT [III, C]Systemic
therapy
[I, A]
SIRT
[III, C]
Sorafenib
Lenvatinib
[I, A]
Regorafenib
Cabozantinib†
Ramucirumab*‡
[I, A]
Nivolumab*
Pembrolizumab*
[III, B]
Resection
LTX [III,
A]
TACE
[I, A]
TACE failure/
refractoriness
TACE/RFA as and Adjunct to CTLA-4 InhibitionTremelimumab
• 19 patients evaluable
• 26 % response rate
• 76% disease control rate
• 7.4 months median TTP
Duffy AG, et al. J Hepatol 2017, 66:545
HCC population– All etiologies, Child-Pugh A/B7, BCLC
Stage C, post-sorafenib
Treatment and follow-up– 2 dose levels until progression (irRECIST).
– Subtotal TACE (8 pts) or RFA (10 pts) performed during week 6
ICPIs in Combination with IA TherapiesEMERALD-1 Clinical Trial
NCT03778957
Patient population• Confirmed HCC• Unsuitable for curative
therapy• No prior TACE• No extrahepatic disease• Child-Pugh A-B7• ECOG 0 or 1• Exclude Vp3 and Vp4• No prior systemic therapy
ARM ATACE + DurvalumabFollowed by Durvalumab + Placebo
ARM BTACE + DurvalumabFollowed by Durvalumab + Bevacizumab
ARM CTACE + PlaceboFollowed by Placebos
R1:1:1
Potential Synergy Between Radiation and ICPIs
• 53 M1 HNSCC patients with ≥2 RECIST 1.1 measurable lesions randomized to Nivolumab or Nivolumab + SBRT to one lesion (lung metastasis in 59%).
Nivolumab Nivolumab + SBRT p
Overall Response Rate 26.9% 22.2% 0.94
1-year Overall Survival 64% 53% 0.79
Progression-Free Survival 1.9 months 2.4 months 0.8
McBride AM, et al. Presented at ASCO 2018
• Multiple case reports of abscopal effect of radiation
• Adjuvant pembrolizumab in 97 patients with metastatic NSCLC.
– Patients with any prior radiotherapy had significantly longer PFS (HR 0.56, p=0.019) and OS (post-hoc analysis)
Immune Activation in SIRT-treated HCC
Chew V, et al. Gut 2018
Tumor tissue and blood samples from 41 HCC patients• TILs from 14 resected patients• PBMCs from 31 patients (4 also resected)
Phase 2 Clinical Trials with IO Agents in HCCCombination with SIRT
Investigational Therapy n Control Arm Primary Endpoint
SIRT + Nivolumab 40 -- Safety & tolerability
SIRT + Nivolumab 40 -- ORR
SIRT + Nivolumab 35 -- Nivolumab MTD
SIRT + Pembrolizumab 30 -- PFS
NCT03380130; NCT03099564; NCT03033446; NCT02837029
PFS: progression-free survival. ORR: overall response rate; MTD: maximal tolerated dose
A Study of the Safety and Antitumoral Efficacy of Nivolumab After SIRT for the Treatment of Patients With HCC That Are Candidates for Locoregional Therapies
NASIR-HCC
NCT02416466
PRIMARY OBJECTIVES• Rate and type of adverse events, liver
decompensation, and transient and permanent drug discontinuations due to toxicity.
SECONDARY OBJECTIVES• Response rate and DCR• Duration of response• TTP and PFS• Overall survival• Pattern of progression
SIRTSingle Session
Nivolumab 240 mgq2 wk
ProgressionToxicity24 doses
3 wk
STUDY POPULATION
• Child-Pugh A and ECOG 0-1
• Not suitable for resection, transplantation, or ablation
• Candidates for LRT based on absence of EHD.
• Not optimal candidates for TACE because of
– Single tumors > 5 cm *.
– Multiple tumors that cannot be targeted superselectively and are in the BCLC-B2 substage *.
– Unilobar tumors with segmental or lobar portal vein invasion.
• Adequate organ function and measurable disease.
* according to local practice at site de la Torre M, et al. Presented at ILCA 2019
Changes in grade (baseline-maximumgrade according to CTCAE) ALBI
gradeChild-Pugh
scoreY90 activity
(GBq)
Liver volumen
(ml)Target liver(% of total)
TreatmentDesignAST ALT T Bilirubin
G0-G0 G0-G0 G0-G0 1 5 1,00 1765 0,34 BilobarG0-G0 G0-G0 G0-G0 2 6 1,80 2558 0,79 RightG1-G1 G0-G0 G0-G0 1 5 1,50 1705 0,49 LeftG1-G1 G0-G0 G0-G0 2 5 1,40 2522 0,72 RightG1-G1 G1-G2 G0-G0 1 5 1,40 1548 1,00 BilobarG1-G1 G0-G1 G0-G0 1 5 1,00 1860 0,09 RightG0-G1 G0-G1 G0-G0 1 5 2,00 1775 0,57 BilobarG0-G1 G0-G1 G0-G0 1 5 1,80 2104 1,00 BilobarG1-G2 G0-G1 G0-G0 2 6 2,10 2671 1,00 BilobarG0-G0 G0-G0 G0-G1 2 5 1,50 1879 0,49 RightG2-G3 G3-G2 G0-G1 1 5 1,20 2150 0,55 RightG0-G0 G0-G0 G1-G2 5 1,00 1776 0,53 BilobarG1-G1 G0-G1 G1-G2 1 5 1,50 1450 0,53 RightG0-G1 G0-G0 G1-G2 2 6 0,80 1240 0,78 RightG1-G2 G1-G1 G1-G2 2 5 0,90 1572 0,73 RightG1-G2 G0-G1 G0-G2 2 5 0,80 1156 0,72 BilobarG1-G1 G1-G1 G1-G3 2 6 0,90 1205 0,58 RightG1-G2 G1-G1 G0-G3 2 5 1,00 2406 0,61 RightG1-G3 G0-G2 G0-G3 2 6 2,10 1487 0,68 Left
• Intense (≥ 2-grade) changes in liver tests occurred only in patients with ALBI grade 2 despite of Child-Pugh score; and morefrequently in patients with liver volume < 1500 ml.
Changes In Liver Tests, Patient
And TreatmentCharacteristics
No change
1-grade increase
2-grade increase
3-grade increase
Results
de la Torre M, et al. Presented at ILCA 2019
Neoadjuvant Dual CTLA-4/PD-1 Blockade in HCC
Kaseb AO, et al. Presented at ASCO GI 2019
Resection
N N N N N N N N N N
I I I I
Up to 2 years
Nivolumab240 mg
Ipilimumab1 mg/kg
Blood sample
Tumor sample
Clinical Trials with IO Agents in HCCEarly Stage
Trial n Control Arm Investigational Agent
Checkmate 9DX 530 Placebo Nivolumab
EMERALD-2 888 PlaceboTACE + Durvalumab
TACE + Durvalumab + Bevacizumab
Keynote-937 950 Placebo Pembrolizumab
NCT03778957. NCT03383458