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Clinical Trial
. 2021 Sep 20;39(27):2991-3001.
doi: 10.1200/JCO.20.03555. Epub 2021 Jul 22.

Safety, Efficacy, and Pharmacodynamics of Tremelimumab Plus Durvalumab for Patients With Unresectable Hepatocellular Carcinoma: Randomized Expansion of a Phase I/II Study

Robin Kate Kelley  1 , Bruno Sangro  2 , William Harris  3 , Masafumi Ikeda  4 , Takuji Okusaka  5 , Yoon-Koo Kang  6 , Shukui Qin  7 , David W-M Tai  8 , Ho Yeong Lim  9 , Thomas Yau  10 , Wei-Peng Yong  11 , Ann-Lii Cheng  12 , Antonio Gasbarrini  13 , Silvia Damian  14 , Jordi Bruix  15 , Mitesh Borad  16 , Johanna Bendell  17 , Tae-You Kim  18 , Nathan Standifer  19 , Philip He  20 , Mallory Makowsky  20 , Alejandra Negro  20 , Masatoshi Kudo  21 , Ghassan K Abou-Alfa  22   23
Affiliations
Clinical Trial

Safety, Efficacy, and Pharmacodynamics of Tremelimumab Plus Durvalumab for Patients With Unresectable Hepatocellular Carcinoma: Randomized Expansion of a Phase I/II Study

Robin Kate Kelley et al. J Clin Oncol. .

Abstract

Purpose: This phase I/II study evaluated tremelimumab (anticytotoxic T-lymphocyte-associated antigen-4 monoclonal antibody) and durvalumab (antiprogrammed death ligand-1 monoclonal antibody) as monotherapies and in combination for patients with unresectable hepatocellular carcinoma (HCC), including a novel regimen featuring a single, priming dose of tremelimumab (ClinicalTrials.gov identifier: NCT02519348).

Patients and methods: Patients with HCC who had progressed on, were intolerant to, or refused sorafenib were randomly assigned to receive T300 + D (tremelimumab 300 mg plus durvalumab 1,500 mg [one dose each during the first cycle] followed by durvalumab 1,500 mg once every 4 weeks), durvalumab monotherapy (1,500 mg once every 4 weeks), tremelimumab monotherapy (750 mg once every 4 weeks [seven doses] and then once every 12 weeks), or T75 + D (tremelimumab 75 mg once every 4 weeks plus durvalumab 1,500 mg once every 4 weeks [four doses] followed by durvalumab 1,500 mg once every 4 weeks). Safety was the primary end point. Secondary end points included objective response rate (ORR) by Response Evaluation Criteria in Solid Tumors v1.1 and overall survival; exploratory end points included circulating lymphocyte profiles.

Results: A total of 332 patients were enrolled (T300 + D, n = 75; durvalumab, n = 104; tremelimumab, n = 69; and T75 + D, n = 84). Tolerability was acceptable across arms, with grade ≥ 3 treatment-related adverse events occurring in 37.8%, 20.8%, 43.5%, and 24.4%, respectively. Confirmed ORRs (95% CI) were 24.0% (14.9 to 35.3), 10.6% (5.4 to 18.1), 7.2% (2.4 to 16.1), and 9.5% (4.2 to 17.9), respectively. An early expansion of CD8+ lymphocytes was associated with response across arms, with highest proliferating CD8+ lymphocyte levels occurring in the T300 + D arm. The median (95% CI) overall survival was 18.7 (10.8 to 27.3), 13.6 (8.7 to 17.6), 15.1 (11.3 to 20.5), and 11.3 (8.4 to 15.0) months in the T300 + D, durvalumab, tremelimumab, and T75 + D arms, respectively.

Conclusion: All regimens were found to be tolerable and clinically active; however, the T300 + D regimen demonstrated the most encouraging benefit-risk profile. The unique pharmacodynamic activity and association with ORR of the T300 + D regimen further support its continued evaluation in HCC.

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Conflict of interest statement

Robin Kate KelleyConsulting or Advisory Role: Agios, AstraZeneca, Bristol Myers Squibb, Genentech/Roche, Merck, Gilead Sciences, Exact SciencesResearch Funding: Lilly, Exelixis, Novartis, Bristol Myers Squibb, MedImmune, Merck Sharp & Dohme, Agios, AstraZeneca, Adaptimmune, Taiho Pharmaceutical, Bayer, QED Therapeutics, EMD Serono, Partner Therapeutics, Genentech/RocheTravel, Accommodations, Expenses: Ipsen Bruno SangroConsulting or Advisory Role: Bristol Myers Squibb, AstraZeneca, Bayer, Adaptimmune, Sirtex Medical, BTG, Merck, H3 Biomedicine, Ipsen, Lilly, Roche/Genentech, Eisai, IncyteSpeakers' Bureau: Bristol Myers Squibb, Bayer, Sirtex Medical, Ipsen, Lilly, AstraZeneca, Eisai, Incyte, RocheResearch Funding: Bristol Myers Squibb, Sirtex MedicalTravel, Accommodations, Expenses: AstraZeneca, Bristol Myers Squibb, Sirtex Medical, BayerOther Relationship: Medscape, Target Pharmasolutions William HarrisConsulting or Advisory Role: Neo Therma, Eisai, Exelixis, Bristol Myers Squibb, QED Therapeutics, ZymeworksResearch Funding: ArQule, Exelixis, Halozyme, Bristol Myers Squibb, MedImmune, Agios, Bayer, Merck, BTGTravel, Accommodations, Expenses: Eisai Masafumi IkedaHonoraria: Taiho Pharmaceutical, Bayer Yakuhin, Eisai, Lilly Japan, Dainippon Sumitomo Pharma, Teijin Pharma, EA Pharma, MSD, Mylan, Otsuka, Yakult Pharmaceutical, Servier, Astellas Pharma, Chugai Pharma, Takeda, AstraZeneca, Novartis, Bristol Myers SquibbConsulting or Advisory Role: Bayer Yakuhin, Eisai, Novartis, Lilly Japan, Chugai Pharma, Micron, Ono Pharmaceutical, AstraZeneca, Servier, Takeda, GlaxoSmithKline, EMD SeronoResearch Funding: Bayer Yakuhin, Yakult Pharmaceutical, Lilly Japan, Ono Pharmaceutical, Eisai, AstraZeneca, Chugai Pharma, Bristol Myers Squibb, ASLAN Pharmaceuticals, Novartis, MSD, J-Pharma, Takeda, Pfizer, Nobelpharma, Merck, Delta-Fly Pharma, Chiome Bioscience, Merus NV Takuji OkusakaHonoraria: Eisai, Ono Pharmaceutical, Taiho Pharmaceutical, Lilly, AstraZeneca, Chugai Pharma, Yakut Honsha, Daiichi SankyoConsulting or Advisory Role: Taiho Pharmaceutical, Dainippon Sumitomo Pharma, Bristol Myers Squibb, AstraZeneca, Eisai, Nihon ServierResearch Funding: Novartis, Eisai, Dainippon Sumitomo Pharma, Baxter, Lilly, Taiho Pharmaceutical, AstraZeneca, Chugai Pharma, Bristol Myers Squibb, MSD Yoon-Koo KangConsulting or Advisory Role: DAE HWA Pharmaceutical, Bristol Myers Squibb, Zymeworks, ALX Oncology, Amgen, Novartis, Macrogenics, Surface Oncology, Blueprint Medicines David W.-M. TaiHonoraria: Bristol Myers Squibb, EisaiConsulting or Advisory Role: Bristol Myers Squibb, EisaiSpeakers' Bureau: Ipsen, Bristol Myers Squibb, Eisai, RocheResearch Funding: Bristol Myers Squibb, Sirtex Medical, Novartis Ho Yeong LimHonoraria: Bayer, Eisai, MSD Oncology, Bristol Myers Squibb/Medarex, AstraZenecaConsulting or Advisory Role: Bayer, Eisai, Bristol Myers Squibb, AstraZenecaSpeakers' Bureau: Bayer Thomas YauHonoraria: Bristol Myers Squibb, MSD Oncology, AstraZenecaConsulting or Advisory Role: Bristol Myers Squibb Wei-Peng YongConsulting or Advisory Role: AbbVie/Genentech, Amgen, Bristol Myers Squibb, Ipsen, Novartis, AstraZenecaSpeakers' Bureau: Lilly, Sanofi/Aventis, Taiho Pharmaceutical, Eisai, Bayer, MSD OncologyTravel, Accommodations, Expenses: Pfizer Ann-Lii ChengHonoraria: Bayer Yakuhin, AstraZeneca, Eisai, Genentech/RocheConsulting or Advisory Role: Bristol Myers Squibb, Bayer Schering Pharma, Eisai, Ono Pharmaceutical, AstraZeneca, Genentech/Roche, MSD, BeiGene, IQVIA, Ipsen, F. Hoffmann-La Roche Ltd Antonio GasbarriniHonoraria: AbbVie, Actial, Alfasigma, Eisai, Gilead Sciences, MSD, Sandoz, Sanofi, TakedaConsulting or Advisory Role: Alfasigma, Actial, MSD, Gilead Sciences, Takeda, AbbVieSpeakers' Bureau: AbbVieExpert Testimony: AbbVie, Alfasigma, Actial, Sanofi, MSD, Gilead Sciences, Eisai Silvia DamianResearch Funding: Basilea Pharmaceutical Jordi BruixConsulting or Advisory Role: Bayer Schering Pharma, Sirtex Medical, Novartis, Bristol Myers Squibb, Eisai, BTG, Roche, Arqule, BasileaSpeakers' Bureau: Bayer Schering PharmaResearch Funding: Bayer Schering Pharma, IpsenTravel, Accommodations, Expenses: Ipsen, AstraZeneca Mitesh BoradStock and Other Ownership Interests: Gilead Sciences, AVEO, Intercept Pharmaceuticals, Spectrum PharmaceuticalsConsulting or Advisory Role: G1 Therapeutics, Fujifilm, Agios, Insys Therapeutics, Novartis, ArQule, Celgene, Inspyr Therapeutics, Halozyme, Pieris Pharmaceuticals, Taiho Pharmaceutical, Immunovative Therapies, Exelixis, Lynx Group, Genentech, Western Oncolytics, Klus Pharma, De Novo Pharmaceuticals, Merck, ImvaxResearch Funding: Boston Biomedical, miRNA Therapeutics, Senhwa Biosciences, MedImmune, BiolineRx, Agios, Halozyme, Celgene, Threshold Pharmaceuticals, Toray Industries, Dicerna, Sillajen, Eisai, Taiho Pharmaceutical, EMD Serono, Isis Pharmaceuticals, Incyte, Sun Biopharma, ARIAD, ImClone Systems, QED Therapeutics, Puma Biotechnology, Adaptimmune, Merck Serono, RedHill Biopharma, BasileaTravel, Accommodations, Expenses: ArQule, Celgene, AstraZeneca Johanna BendellConsulting or Advisory Role: Gilead Sciences, Genentech/Roche, Bristol Myers Squibb, Five Prime Therapeutics, Lilly, Merck, MedImmune, Celgene, EMD Serono, Taiho Pharmaceutical, Macrogenics, GlaxoSmithKline, Novartis, OncoMed, Leap Therapeutics, TG Therapeutics, AstraZeneca, Boehringer Ingelheim, Daiichi Sankyo, Bayer, Incyte, Apexigen, Array BioPharma, Sanofi, ARMO BioSciences, Ipsen, Merrimack, Oncogenex, FORMA Therapeutics, Arch Oncology, Prelude Therapeutics, Phoenix Biotech, Cyteir, Molecular Partners, Innate Pharma, Torque, Tizona Therapeutics Inc, Janssen, Tolero Pharmaceuticals, TD2, Amgen, Seattle Genetics, Moderna Therapeutics, Tanabe Research, Beigene, Continuum Clinical, Cerulean Pharma, Kyn Therapeutics, Bicycle Therapeutics, Relay Therapeutics, Evelo Therapeutics, Fusion PharmaceuticalsResearch Funding: Lilly, Genentech/Roche, Incyte, Gilead Sciences, Bristol Myers Squibb, Leap Therapeutics, AstraZeneca/MedImmune, Boston Biomedical, GlaxoSmithKline, Novartis, Array BioPharma, Taiho Pharmaceutical, Celgene, OncoMed, Daiichi Sankyo, Bayer, Apexigen, Kolltan Pharmaceuticals, SynDevRx, Merck, Macrogenics, Five Prime Therapeutics, EMD Serono, TG Therapeutics, Boehringer Ingelheim, Forty Seven, Stem CentRx, Onyx, Sanofi, Takeda, Abbott/AbbVie, Eisai, Celldex, Agios, ARMO BioSciences, CytomX Therapeutics, Nektar, Ipsen, Merrimack, Tarveda Therapeutics, Tyrogenex, Oncogenex, Marshall Edwards, Pieris Pharmaceuticals, Mersana, Calithera Biosciences, Blueprint Medicines, Gritstone Oncology, Evelo Therapeutics, FORMA Therapeutics, Forty Seven, EMD Serono, Merus, Jacobio, eFFECTOR Therapeutics, Novocure, Sorrento Therapeutics, Arrys Therapeutics, TRACON Pharma, Sierra Oncology, Innate Pharma, Prelude Therapeutics, Arch Oncology, Harpoon therapeutics, Phoenix Biotech, Unum Therapeutics, Vyriad, Harpoon therapeutics, Cyteir, Molecular Partners, Innate Pharma, ADC Therapeutics, Torque, Tizona Therapeutics Inc, Janssen, Amgen, BeiGene, Pfizer, Millenium Pharmaceuticals, ImClone Systems, Acerta Pharma, Rgenix, Bellicum Pharmaceuticals, Arcus Biosciences, Gossamer Bio, Seattle Genetics, Tempest Therapeutics, Shattuck Labs, Synthorx, Revolution Medicines, Bicycle Therapeutics, Zymeworks, Relay Therapeutics, Evelo Therapeutics, Scholar Rock, NGM Biopharmaceuticals, Numab, AtlasMedx, Treadwell Therapeutics, IGM, MabSpace Biosciences, Hutchison MediPharma, Repare Therapeutics, NeoImmuneTech, Regeneron, PureTech, G1 Therapeutics, Erasca Inc, Rubius Therapeutics, Pionyr, Loxo/Lilly, BioNTech AG, Elicio TherapeuticsTravel, Accommodations, Expenses: Merck, Roche/Genentech, Celgene, Daiichi Sankyo, Gilead Sciences, Bristol Myers Squibb, Lilly, MedImmune, Taiho Pharmaceutical, Novartis, OncoMed, Boehringer Ingelheim, ARMO BioSciences, Ipsen, FORMA Therapeutics Nathan StandiferEmployment: AstraZenecaStock and Other Ownership Interests: AstraZenecaPatents, Royalties, Other Intellectual Property: Patent with AstraZeneca Philip HeEmployment: AstraZeneca, SanofiStock and Other Ownership Interests: Celldex, AstraZeneca, Sanofi Mallory MakowskyEmployment: AstraZeneca Alejandra NegroEmployment: AstraZenecaStock and Other Ownership Interests: AstraZeneca Masatoshi KudoHonoraria: MSD, Eisai, Bayer, Lilly Japan, EA Pharma, Bristol Myers Squibb JapanConsulting or Advisory Role: MSD, Eisai, Ono Pharmaceutical, BMS, RocheResearch Funding: Otsuka, Taiho Pharmaceutical, AbbVie, Takeda, Eisai, Gilead Sciences, EA Pharma, Sumitomo Dainippon, Ono Pharmaceutical Ghassan K. Abou-AlfaConsulting or Advisory Role: Silenseed, Sillajen, Agios, Bayer, Eisai, Ipsen, Merck Serono, AstraZeneca, CytomX Therapeutics, BeiGene, Genoscience Pharma, Loxo, Minapharm, QED Therapeutics, RedHill Biopharma, SOBI, twoXAR, Yiviva, Flatiron Health, Roche/Genentech, Autem Medical, Berry Genomics, Incyte, TheraBionic, Vector Health, Helio, Alnylam, Adicet Bio, Exelixis, Legend Biotech, Nerviano Medical Sciences, Surface Oncology, YivivaResearch Funding: Bayer, Exelixis, CASI Pharmaceuticals, AstraZeneca, Bristol Myers Squibb, Incyte, Agios, Polaris, Puma Biotechnology, QED TherapeuticsTravel, Accommodations, Expenses: PolarisNo other potential conflicts of interest were reported.

Figures

FIG 1.
FIG 1.
CONSORT diagram of patient disposition in parts 2 and 3. AE, adverse event; D, durvalumab; HCC, hepatocellular carcinoma; T, tremelimumab; T300 + D, tremelimumab 300 mg plus durvalumab 1,500 mg for one dose each during the first cycle followed by durvalumab 1,500 mg once every 4 weeks; T75 + D, tremelimumab 75 mg once every 4 weeks (four doses) plus durvalumab 1,500 mg once every 4 weeks.
FIG 2.
FIG 2.
Kaplan-Meier analysis of OS. aTime from random assignment (parts 2A and 3) or first dose (part 2B). bOne event observed at 27 months in the T300 + D arm. D, durvalumab; OS, overall survival; T, tremelimumab; T300 + D, tremelimumab 300 mg plus durvalumab 1,500 mg for one dose each during the first cycle followed by durvalumab 1,500 mg once every 4 weeks; T75 + D, tremelimumab 75 mg once every 4 weeks (four doses) plus durvalumab 1,500 mg once every 4 weeks.
FIG 3.
FIG 3.
Biomarker analysis of day 15 patient whole-blood samples. (A) Canonical score plot derived from quadratic discriminant analysis of 26 lymphocyte population values that identified two combinations of populations (canons) that best classify each patient into the assigned treatment arm. Canon 1 is composed of CD4+ T-cell populations and canon 2 of CD8+ T-cell populations. Percent misclassified: 1.7% (2 of 117); entropy R2: 0.92. (B) Analysis of patient CD8+ Ki67+ T-cell counts stratified by treatment arm and response. CR, complete response; D, durvalumab; PD, progressive disease; PR, partial response; SD, stable disease; T, tremelimumab; T300 + D, tremelimumab 300 mg plus durvalumab 1,500 mg for one dose each during the first cycle followed by durvalumab 1,500 mg once every 4 weeks; T75 + D, tremelimumab 75 mg once every 4 weeks (four doses) plus durvalumab 1,500 mg once every 4 weeks.
FIG A1.
FIG A1.
Study design for parts 1-3 (part 4 evaluated durvalumab plus bevacizumab in patients with first-line unresectable hepatocellular carcinoma and will be published separately). D, durvalumab; FSI, first subject in; LSI, last subject in; n, No. of enrolled patients; R, randomly assigned; T, tremelimumab; T300 + D, tremelimumab 300 mg plus durvalumab 1,500 mg for one dose each during the first cycle followed by durvalumab 1,500 mg once every 4 weeks; T75 + D, tremelimumab 75 mg once every 4 weeks (four doses) plus durvalumab 1,500 mg once every 4 weeks.
FIG A2.
FIG A2.
Kaplan-Meier analysis of OS, part 3 only. aTime from random assignment. D, durvalumab; NR, no response; OS, overall survival; T, tremelimumab; T300 + D, tremelimumab 300 mg plus durvalumab 1,500 mg for one dose each during the first cycle followed by durvalumab 1,500 mg once every 4 weeks; T75 + D, tremelimumab 75 mg once every 4 weeks (four doses) plus durvalumab 1,500 mg once every 4 weeks.
FIG A3.
FIG A3.
Kaplan-Meier analysis of progression-free survival, part 3 only. aTime from random assignment. D, durvalumab; PFS, progression-free survival; T, tremelimumab; T300 + D, tremelimumab 300 mg plus durvalumab 1,500 mg for one dose each during the first cycle followed by durvalumab 1,500 mg once every 4 weeks; T75 + D, tremelimumab 75 mg once every 4 weeks [four doses] plus durvalumab 1,500 mg once every 4 weeks.
FIG A4.
FIG A4.
Target lesion response for (A) T300 + D (ORR = 24.0%), (B) durvalumab (ORR = 10.6%), (C) tremelimumab (ORR = 7.2%), and (D) T75 + D treatment cohorts (ORR = 9.5%) in parts 2 and 3. aPatients who achieved a response. D, durvalumab; HBV, hepatitis B virus; HCV, hepatitis C virus; M, PD-L1 status missing; ORR, overall response rate; PD-L1, programmed cell death ligand-1; T, tremelimumab; T300 + D, tremelimumab 300 mg plus durvalumab 1,500 mg for one dose each during the first cycle followed by durvalumab 1,500 mg once every 4 weeks; T75 + D, tremelimumab 75 mg once every 4 weeks (four doses) plus durvalumab 1,500 mg once every 4 weeks.
FIG A5.
FIG A5.
Best response for target lesion from baseline. (A) T300 + D. (B) Durvalumab. (C) Tremelimumab. (D) T75 + D. CR, complete response; D, durvalumab; PD, progressive disease; PR, partial response; SD, stable disease; T, tremelimumab; T300 + D, tremelimumab 300 mg plus durvalumab 1,500 mg for one dose each during the first cycle followed by durvalumab 1,500 mg once every 4 weeks; T75 + D, tremelimumab 75 mg once every 4 weeks (four doses) plus durvalumab 1,500 mg once every 4 weeks.
FIG A6.
FIG A6.
Kaplan-Meier analysis of PFS, parts 2 and 3. aTime from random assignment (part 2A, 3) or first dose (part 2B). D, durvalumab; PFS, progression-free survival; T, tremelimumab; T300 + D, tremelimumab 300 mg plus durvalumab 1,500 mg for one dose each during the first cycle followed by durvalumab 1,500 mg once every 4 weeks; T75 + D, tremelimumab 75 mg once every 4 weeks (four doses) plus durvalumab 1,500 mg once every 4 weeks.
FIG A7.
FIG A7.
Correlation (correlation coefficient > 0.1) of lymphocyte population counts for all treatment arms combined with canon-1 or canon-2 scores. ((A) CD4+Ki67+ T cells. (B) CD8+Ki67+ T cells. (C) CD4+ICOS+ T cells. (D) CD4+HLA-DR+ T cells. (E) CD8+ICOS+ T cells. (F) CD4+ Tem cells. (G) CD4+ Tcm cells. (H) CD4+CD38+ T cells. HLA-DR, Human Leukocyte Antigen of the DR type; ICOS, inducible T cell costimulator; Tcm, central memory T cells; Tem, effector memory T cells.
FIG A8.
FIG A8.
CD3+ CD8+ Ki67+ T-cell analysis of patient samples by response at day 1 and day 15. CR, complete response; D, durvalumab; PD, progressive disease; PR, partial response; SD, stable disease; T, tremelimumab; T300 + D, tremelimumab 300 mg plus durvalumab 1,500 mg for one dose each during the first cycle followed by durvalumab 1,500 mg once every 4 weeks; T75 + D, tremelimumab 75 mg once every 4 weeks (four doses) plus durvalumab 1,500 mg once every 4 weeks.
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