emerging immunotherapy and future directions in ...€¦ · 230 patients with hcc after resection,...

30
Emerging Immunotherapy and Future Directions in Unresectable HCC Bruno Sangro Clínica Universidad de Navarra. IdISNA. CIBERehd. Pamplona, Spain

Upload: others

Post on 07-Aug-2020

2 views

Category:

Documents


0 download

TRANSCRIPT

Page 1: Emerging Immunotherapy and Future Directions in ...€¦ · 230 patients with HCC after resection, RFA, or ethanol injection Primary Endpoint: Recurrence-free survival 0.00 0.60 0.80

Emerging Immunotherapy and Future Directionsin Unresectable HCC

Bruno SangroClínica Universidad de Navarra. IdISNA. CIBERehd.

Pamplona, Spain

Page 2: Emerging Immunotherapy and Future Directions in ...€¦ · 230 patients with HCC after resection, RFA, or ethanol injection Primary Endpoint: Recurrence-free survival 0.00 0.60 0.80

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

Page 3: Emerging Immunotherapy and Future Directions in ...€¦ · 230 patients with HCC after resection, RFA, or ethanol injection Primary Endpoint: Recurrence-free survival 0.00 0.60 0.80

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

Page 4: Emerging Immunotherapy and Future Directions in ...€¦ · 230 patients with HCC after resection, RFA, or ethanol injection Primary Endpoint: Recurrence-free survival 0.00 0.60 0.80

Greten and Sangro. J Hepatol 2017.

Improving the Effect of PD-1/PD-L1 Blockade

Page 5: Emerging Immunotherapy and Future Directions in ...€¦ · 230 patients with HCC after resection, RFA, or ethanol injection Primary Endpoint: Recurrence-free survival 0.00 0.60 0.80

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

Page 6: Emerging Immunotherapy and Future Directions in ...€¦ · 230 patients with HCC after resection, RFA, or ethanol injection Primary Endpoint: Recurrence-free survival 0.00 0.60 0.80

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

Page 7: Emerging Immunotherapy and Future Directions in ...€¦ · 230 patients with HCC after resection, RFA, or ethanol injection Primary Endpoint: Recurrence-free survival 0.00 0.60 0.80

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

Page 8: Emerging Immunotherapy and Future Directions in ...€¦ · 230 patients with HCC after resection, RFA, or ethanol injection Primary Endpoint: Recurrence-free survival 0.00 0.60 0.80

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.

Page 9: Emerging Immunotherapy and Future Directions in ...€¦ · 230 patients with HCC after resection, RFA, or ethanol injection Primary Endpoint: Recurrence-free survival 0.00 0.60 0.80

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

Page 10: Emerging Immunotherapy and Future Directions in ...€¦ · 230 patients with HCC after resection, RFA, or ethanol injection Primary Endpoint: Recurrence-free survival 0.00 0.60 0.80

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

Page 11: Emerging Immunotherapy and Future Directions in ...€¦ · 230 patients with HCC after resection, RFA, or ethanol injection Primary Endpoint: Recurrence-free survival 0.00 0.60 0.80

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

Page 12: Emerging Immunotherapy and Future Directions in ...€¦ · 230 patients with HCC after resection, RFA, or ethanol injection Primary Endpoint: Recurrence-free survival 0.00 0.60 0.80

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

Page 13: Emerging Immunotherapy and Future Directions in ...€¦ · 230 patients with HCC after resection, RFA, or ethanol injection Primary Endpoint: Recurrence-free survival 0.00 0.60 0.80

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

Page 14: Emerging Immunotherapy and Future Directions in ...€¦ · 230 patients with HCC after resection, RFA, or ethanol injection Primary Endpoint: Recurrence-free survival 0.00 0.60 0.80

Engineered TCRs and Chimeric Antigen Receptors

Sharpe M and Mount N. Dis. Model. Mech. 2015;8:337-350

Page 15: Emerging Immunotherapy and Future Directions in ...€¦ · 230 patients with HCC after resection, RFA, or ethanol injection Primary Endpoint: Recurrence-free survival 0.00 0.60 0.80

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

Page 16: Emerging Immunotherapy and Future Directions in ...€¦ · 230 patients with HCC after resection, RFA, or ethanol injection Primary Endpoint: Recurrence-free survival 0.00 0.60 0.80

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

Page 17: Emerging Immunotherapy and Future Directions in ...€¦ · 230 patients with HCC after resection, RFA, or ethanol injection Primary Endpoint: Recurrence-free survival 0.00 0.60 0.80

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

Page 18: Emerging Immunotherapy and Future Directions in ...€¦ · 230 patients with HCC after resection, RFA, or ethanol injection Primary Endpoint: Recurrence-free survival 0.00 0.60 0.80

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

Page 19: Emerging Immunotherapy and Future Directions in ...€¦ · 230 patients with HCC after resection, RFA, or ethanol injection Primary Endpoint: Recurrence-free survival 0.00 0.60 0.80

Future Directions

Page 20: Emerging Immunotherapy and Future Directions in ...€¦ · 230 patients with HCC after resection, RFA, or ethanol injection Primary Endpoint: Recurrence-free survival 0.00 0.60 0.80

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

Page 21: Emerging Immunotherapy and Future Directions in ...€¦ · 230 patients with HCC after resection, RFA, or ethanol injection Primary Endpoint: Recurrence-free survival 0.00 0.60 0.80

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

Page 22: Emerging Immunotherapy and Future Directions in ...€¦ · 230 patients with HCC after resection, RFA, or ethanol injection Primary Endpoint: Recurrence-free survival 0.00 0.60 0.80

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

Page 23: Emerging Immunotherapy and Future Directions in ...€¦ · 230 patients with HCC after resection, RFA, or ethanol injection Primary Endpoint: Recurrence-free survival 0.00 0.60 0.80

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)

Page 24: Emerging Immunotherapy and Future Directions in ...€¦ · 230 patients with HCC after resection, RFA, or ethanol injection Primary Endpoint: Recurrence-free survival 0.00 0.60 0.80

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)

Page 25: Emerging Immunotherapy and Future Directions in ...€¦ · 230 patients with HCC after resection, RFA, or ethanol injection Primary Endpoint: Recurrence-free survival 0.00 0.60 0.80

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

Page 26: Emerging Immunotherapy and Future Directions in ...€¦ · 230 patients with HCC after resection, RFA, or ethanol injection Primary Endpoint: Recurrence-free survival 0.00 0.60 0.80

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

Page 27: Emerging Immunotherapy and Future Directions in ...€¦ · 230 patients with HCC after resection, RFA, or ethanol injection Primary Endpoint: Recurrence-free survival 0.00 0.60 0.80

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

Page 28: Emerging Immunotherapy and Future Directions in ...€¦ · 230 patients with HCC after resection, RFA, or ethanol injection Primary Endpoint: Recurrence-free survival 0.00 0.60 0.80

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

Page 29: Emerging Immunotherapy and Future Directions in ...€¦ · 230 patients with HCC after resection, RFA, or ethanol injection Primary Endpoint: Recurrence-free survival 0.00 0.60 0.80

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

Page 30: Emerging Immunotherapy and Future Directions in ...€¦ · 230 patients with HCC after resection, RFA, or ethanol injection Primary Endpoint: Recurrence-free survival 0.00 0.60 0.80