Four-year overall survival update from the phase III HIMALAYA study of tremelimumab plus durvalumab in unresectable hepatocellular carcinoma
B. SangroStephen L. ChanRobin Kate KelleyGeorge LauMasatoshi KudoWattana SukeepaisarnjaroenM. YarchoanEnrico N. De ToniJ. FuruseYoon‐Koo KangPeter R. GalleLorenza RimassaAlexandra HeurguéVincent C. TamTu Van DaoS.C. ThungappaВ. В. БредерY. OstapenkoMaría ReigM. MakowskyMichael PaskowCharu GuptaJohn F. KurlandAlejandra NegroGhassan K. Abou‐AlfaSérgio Santos de AzevêdoMaria Ignez BraghiroliGustavo GirottoArinilda BragagnoliRicardo BrancoAdilson FaccioAndrea MorettoNils Gunnar SkareJamille DutraLuciana Spillari ViolaKarina ViannaFernando MetonCláudia Vaz de Melo SetteAmanda FaulhaberVincent C. TamFélix CoutureJim BiagiHélène CastelKaren MulderYoo‐Joung KoKevin ZbukStephen WelchAnnie BeaudoinAlexandra HeurguéÉric AssenatIsabelle ArchambeaudDavid TougeronJean‐Marie PéronMarine GilabertJean‐Pierre BronowickiStéphane CattanJean‐Frédéric BlancMohamed BouattourJean-Marc PhélipValérie BoigePierre MichelAnne-Claire FrinEnrico N. De ToniMarie‐Luise BerresArndt VogelThomas BergThomas Jens EttrichDirk WaldschmidtH. WedemeyerMarcus‐Alexander WörnsMichael BitzerKarl-Heinz WeissGeorge LauStephen L. ChanThomas YauY. TaiAnn Shing LeeSatheesh Chiradoni ThungappaLokesh K. NVikas Sureshchand OstwalKattimani Kiran AshokSushant MittalHari Om GoyalSankar SrinivasanGhanashyam BiswasMallavarapu MohanSewanti LimayeNirav AsarawalaLorenza RimassaAlfredo FalconeLuca GianniAntonio GasbarriniBruno DanieleAntonio AvalloneGiovanni Luca FrassinetiFausto RoilaMasatoshi KudoTomokazu KawaokaManabu MorimotoYasuhiro TakikawaNaoya KatoTatsuya YamashitaYukio OsakiKenta MotomuraRyosuke TateishiKazuyoshi OhkawaYoshiyuki WadaHideki OnishiNaoki SasahiraYoshitaka InabaMasayuki KurosakiKunihiko TsujiYoshiyuki TakeiTakeshi AramakiAtsushi HagiharaJunji FuruseKiyohide KiokaHironori KogaYutaka SasakiKazushi NumataToshifumi TadaYasunori KawaguchiSeijin NadanoAlexander VasilyevВ. В. БредерO. N. LipatovMikhail DvorkinOleg ZarubenkovС. И. КутуковаRoman PonomarevK. ShostkaAnna AlyasovaЭ. Э. ТопузовAlexey SevertsevYuryi PetrovД. В. ЕрыгинБ. А. БердовYoon‐Koo KangWon Young TakJoong‐Won ParkHo Yeong LimJeong HeoJee Hyun KimTae‐You KimHye Jin ChoiMaría VarelaMaría ReigBruno SangroCarlos Gómez MartinCarmen Guillén‐PonceCarlos LópezAnn‐Lii ChengYee ChaoYin‐Hsun FengLong‐Bin JengChao‐Hung HungMing‐Mo HouJing‐Houng WangChia‐Jui YenWattana SukeepaisarnjaroenPatrapim SunpaweravongChaiyut CharoentumSuebpong TanasanvimonEkaphop SirachainanTeerapat UngtrakulNaiyarat PrasongsookKunlatida ManeenilWittawat JitpewngarmYurii OstapenkoDenys SkoryiIgor BondarenkoYaroslav ShparykDmytro TrukhinYevhen HotkoGrygorii UrsolAnna KryzhanivskaGhassan K. Abou‐AlfaKabir ModyFarshid DayyaniRaed Moh’d Taiseer Al-RajabiMark YarchoanSunil GandhiOxana CryslerAiwu Ruth HeJ. N. ReevesNathan BaharyAmit MahipalRobin Kate KelleyAnirudha DasguptaJulie RoweRamya ThotaMuhammad Shaalan BegMichael A. MorseSUNGHEE CHOITodd S. CrocenziBradley G. SomerThomas A. AbramsCrystal S. DenlingerYue ZhangNisha SharmaTu Van DaoNguyễn Tiến ThịnhLe Thi Tuyet Phuong
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BackgroundIn the phase III HIMALAYA study (NCT03298451) in unresectable hepatocellular carcinoma (uHCC), STRIDE (Single Tremelimumab Regular Interval Durvalumab) significantly improved overall survival (OS) versus sorafenib; durvalumab monotherapy was noninferior to sorafenib for OS. Results reported herein are from a four-year updated OS analysis of HIMALAYA.Patients and methodsParticipants with uHCC and no previous systemic treatment were randomized to STRIDE (n=393), durvalumab (n=389), or sorafenib (n=389). The updated data cut-off was January 23, 2023. OS and serious adverse events (AEs) were assessed. Additionally, baseline characteristics and subsequent therapies were analyzed in long-term survivors (≥36 months beyond randomization).ResultsFor STRIDE, durvalumab, and sorafenib, median (95% CI) follow-up was 49.12 (46.95-50.17), 48.46 (46.82-49.81), and 47.31 (45.08-49.15) months, respectively. OS HR (95% CI) for STRIDE versus sorafenib was 0.78 (0.67-0.92). The 36-month OS rate for STRIDE was 30.7% versus 19.8% for sorafenib. The 48-month OS rate remained higher for STRIDE at 25.2%, versus 15.1% for sorafenib. The long-term OS benefit of STRIDE was observed across clinically relevant subgroups and was further improved in participants who achieved disease control. Long-term survivors with STRIDE (n=103) included participants across clinically relevant subgroups, and 57.3% (59/103) had no reported subsequent anticancer therapy. No new serious treatment-related AEs occurred with STRIDE from the primary analysis (17.5%; 68/388). Durvalumab maintained OS noninferiority to sorafenib and no late onset safety signals were identified.ConclusionsThese data represent the longest follow-up to date in phase III studies in uHCC. The unprecedented three- and four-year OS rates reinforce the sustained long-term OS benefit of STRIDE versus sorafenib. STRIDE maintained a tolerable yet differentiated safety profile from other current uHCC therapies. Results continue to support the long-term benefits of STRIDE in a diverse population, reflective of uHCC globally.Keywords:
Durvalumab
Tremelimumab
Tumor immunotherapy is an important clinical strategy for the treatment of various solid and hematological malignancies, and its use is on the rise. Immune checkpoint inhibitors (ICIs) are immunotherapies that boost anticancer immune responses by targeting receptors on the surface of T-lymphocytes. Two important ICIs are anti-programmed death ligand-1 (anti-PD-L1) monoclonal antibodies and anti-cytotoxic T-lymphocyte-associated antigen-4 (anti-CTLA-4) monoclonal antibodies. Tremelimumab (anti-CTLA-4) and durvalumab (anti-PD-L1) have been shown to be effective monotherapies. However, their combination has demonstrated effective and encouraging antitumor activity with manageable safety in patients with unresectable hepatocellular carcinoma. We present the case of an 80-year-old male with hepatocellular carcinoma who had undergone drug-eluting bead transarterial chemoembolization (DEB-TACE) on three occasions and had been started on a combination of ICIs, durvalumab, and tremelimumab. He subsequently developed various immune-related adverse effects in different organ systems, including hepatic and cardiovascular complications. Appropriate treatment was administered, but ultimately, he passed away. We aim to discuss the initial evaluation for suspected immune-related adverse events, specifically those related to myocarditis and its various manifestations, prognosis, and treatment.
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Meeting abstracts As single agents, durvalumab (MEDI4736), a human IgG1 anti-PD-L1 antibody, and tremelimumab, a human IgG2 anti-CTLA-4 antibody, have shown acceptable safety profiles and antitumor activity. Similar to other anti-PD-L1/anti-PD-1 monotherapies, durvalumab has shown greater objective
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On October 21, 2022, the FDA approved tremelimumab (Imjudo) in combination with durvalumab for adult patients with unresectable hepatocellular carcinoma. The approval was based on the results from the HIMALAYA study, in which patients with unresectable hepatocellular carcinoma who were naïve to previous systemic treatment were randomly assigned to receive one of three study arms: tremelimumab in combination with durvalumab (n = 393), durvalumab (n = 389), or sorafenib (n = 389). The primary objective of improvement in overall survival (OS) for tremelimumab in combination with durvalumab compared with sorafenib met statistical significance with a stratified HR of 0.78 [95% confidence interval (CI), 0.66-0.92; P = 0.0035]. The median OS was 16.4 months (95% CI, 14.2-19.6) with tremelimumab in combination with durvalumab and 13.8 months (95% CI, 12.3-16.1) with sorafenib. Adverse reactions occurring in ≥20% of patients receiving tremelimumab in combination with durvalumab were rash, fatigue, diarrhea, pruritus, musculoskeletal pain, and abdominal pain. The recommended tremelimumab dose for patients weighing 30 kg or more is 300 mg, i.v., as a single dose in combination with durvalumab 1,500 mg at cycle 1/day 1, followed by durvalumab 1,500 mg, i.v., every 4 weeks. For those weighing less than 30 kg, the recommended tremelimumab dose is 4 mg/kg, i.v., as a single dose in combination with durvalumab 20 mg/kg, i.v., followed by durvalumab 20 mg/kg, i.v., every 4 weeks.
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Cancer immunotherapy represents one of the most important innovations in modern medicine. Durvalumab is an anti-programmed cell death ligand 1 (PDL-1) agent which is currently under investigation in several studies in combination with the anti-cytotoxic T lymphocyte-associated protein 4 (CTLA-4) drug tremelimumab. The aim of this review was to systematically identify and revise the current scientific literature investigating the combination of these two drugs in solid tumors. A digital search on the Medline (PubMed interface) and Scopus databases for articles published from inception to 26 February 2021 was performed. The terms used for the search were durvalumab AND tremelimumab. Trials reported in English involving adult patients with solid cancers treated with the combination durvalumab plus tremelimumab were retrieved; the references of the articles were cross-checked to identify missing papers. The electronic search produced 267 results; after exclusion of duplicates, irrelevant articles, reviews, and papers not in English or missing data, 19 articles were included for revision. The total number of patients treated with the combination of durvalumab and tremelimumab in the studies retrieved was 2052. The combination of durvalumab plus tremelimumab showed some oncological advantages in comparison with traditional chemotherapies in some subsets of tumors, but generally has not shown consistent advantages in comparison with the employment of durvalumab monotherapy. A number of the studies examined had intrinsic methodological limitations; therefore, future well-designed studies involving larger cohorts are warranted.
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Importance
Dual blockade of programmed death ligand 1 (PD-L1) and cytotoxic T-lymphocyte associated protein 4 (CTLA-4) may overcome immune checkpoint inhibition. It is unknown whether dual blockade can potentiate antitumor activity without compromising safety in patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) and low or no PD-L1 tumor cell expression.Objective
To assess safety and objective response rate of durvalumab combined with tremelimumab.Design, Setting, and Participants
The CONDOR study was a phase 2, randomized, open-label study of Durvalumab, Tremelimumab, and Durvalumab in Combination With Tremelimumab in Patients With R/M HNSCC. Eligibility criteria included PD-L1–low/negative disease that had progressed after 1 platinum-containing regimen in the R/M setting. Patients were randomized (N = 267) from April 15, 2015, to March 16, 2016, at 127 sites in North America, Europe, and Asia Pacific.Interventions
Durvalumab (20 mg/kg every 4 weeks) + tremelimumab (1 mg/kg every 4 weeks) for 4 cycles, followed by durvalumab (10 mg/kg every 2 weeks), or durvalumab (10 mg/kg every 2 weeks) monotherapy, or tremelimumab (10 mg/kg every 4 weeks for 7 doses then every 12 weeks for 2 doses) monotherapy.Main Outcomes and Measures
Safety and tolerability and efficacy measured by objective response rate.Results
Among the 267 patients (220 men [82.4%]), median age (range) of patients was 61.0 (23-82) years. Grade 3/4 treatment-related adverse events occurred in 21 patients (15.8%) treated with durvalumab + tremelimumab, 8 (12.3%) treated with durvalumab, and 11 (16.9%) treated with tremelimumab. Grade 3/4 immune-mediated adverse events occurred in 8 patients (6.0%) in the combination arm only. Objective response rate (95% CI) was 7.8% (3.78%-13.79%) in the combination arm (n = 129), 9.2% (3.46%-19.02%) for durvalumab monotherapy (n = 65), and 1.6% (0.04%-8.53%) for tremelimumab monotherapy (n = 63); median overall survival (95% CI) for all patients treated was 7.6 (4.9-10.6), 6.0 (4.0-11.3), and 5.5 (3.9-7.0) months, respectively.Conclusions and Relevance
In patients with R/M HNSCC and low or no PD-L1 tumor cell expression, all 3 regimens exhibited a manageable toxicity profile. Durvalumab and durvalumab + tremelimumab resulted in clinical benefit, with minimal observed difference between the two. A phase 3 study is under way.Trial Registration
clinicaltrials.gov Identifier:NCT02319044Tremelimumab
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