Durvalumab, with or without tremelimumab, plus platinum–etoposide versus platinum–etoposide alone in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): updated results from a randomised, controlled, open-label, phase 3 trial
Jonathan W. GoldmanMikhail DvorkinYuanbin ChenNiels ReinmuthKatsuyuki HottaDmytro TrukhinGalina StatsenkoMaximilian J. HochmairMustafa ÖzgüroğluJun Ho JiMarina Chiara GarassinoОлександр ВойткоArtem PoltoratskiySantiago PonceFrancesco VerderameLibor HavelIgor BondarenkoAndrzej KażarnowiczGyörgy LosonczyNikolay ConevJ. ArmstrongNatalie ByrnePiruntha ThiyagarajahHaiyi JiangLuís Paz-AresMikhail DvorkinDmytro TrukhinGalina StatsenkoОлександр ВойткоArtem PoltoratskiyIgor BondarenkoYuanbin ChenAndrzej KażarnowiczLuís Paz-AresMustafa ÖzgüroğluNikolay ConevMaximilian J. HochmairOtto C. BurghuberLibor Havelİrfan ÇiçinGyörgy LosonczyВ. МоисеенкоMustafa ErmanDariusz M. KowalskiMarek Z. WojtukiewiczHryhoriy AdamchukAlexander VasilyevSerhii ShevniaSpartak ValevNiels ReinmuthJun Ho JiAmelia InsaGrygorii UrsolAnne C. ChiangSylvia HartlZsolt HorváthGábor PajkosFrancesco VerderameKatsuyuki HottaSang‐We KimAlexey SmolinTuncay GökselShaker R. DakhilJaromı́r RoubecKrisztina BogosMarina Chiara GarassinoRobin CornelissenJong-Seok LeeM.R. García CampeloMarta López BreaAhmet AlacacıoğluIgnacio CasariniRumyana IlievaIvan TonevA SomfayJair BarAlona ZerMauro MinelliRoberta BartolucciFausto RoilaHaruhiro SaitoKoichi AzumaGyeong‐Won LeeAlexander LuftM. UrdaJuan Ignacio Delgado MingoranceM. Majem TarruellaDavid R. SpigelKrassimir KoynovMilada ZemanováJens PanseChristian SchulzZsolt Pápai SzékelyVeronika SárosiAngelo DelmonteAnna BettiniMakoto NishioIsamu OkamotoLizza E.L. HendriksSławomir MańdziukYun Gyoo LeeLyubov VladimirovaD. CasadoM. Dómine GómezAlejandro NavarroTeresa Morán BuenoShang‐Yin WuJeanna KnobleJana SkřičkováVioletka VenkovaWerner HilgersEckart LaackHelge BischoffAndrea FülöpIbolya LaczóJudit KósaAndrás TelekesTatsuya YoshidaShintaro KandaToyoaki HidaHidetoshi HayashiTadashi MaedaTetsuji KawamuraYasuharu NakaharaNiels ClaessensKi Hyeong LeeChao‐Hua ChiuSheng‐Hao LinChien-Te LiAhmet DemirkazıkEric SchaeferPetros NikolinakosJeffrey SchneiderSunil BabuBernd LamprechtMichael StudnickaCarlos Fausto Nino GoriniJuraj KultanVı́tězslav KolekPierre-Jean SouquetDenis Moro‐SibilotMaya GottfriedEgbert F. SmitKyung Hee LeePeter KasanJozef ChovanecO. GoloborodkoOleksii KolesnikYuriy OstapenkoShailendra LakhanpalBasir HaqueWinston ChuaJoseph StilwillS. SenaGustavo GirottoPedro Rafael Martins De MarchiFabrício Augusto Martinelli de OliveiraPedro Dos ReisRositsa KrastevaYanqiu ZhaoChengshui ChenLeona KoubkováG. RobinetC. ChouaïdChristian GrohéJürgen AltEszter CsánkyÉva Somogyiné EzerNorman HechingYoung Hak KimShinji AatagiShoichi KuyamaDaijiro HaradaNaoyuki NogamiHiroshi NokiharaHisatsugu GotoAgnes Staal van den BrekelEun Kyung ChoJoo-Hang KimDoina GaneaTudor‐Eliade CiuleanuEkaterine PopovaDina SakaevaMarian StreškoPavol DemoRobert GodalYufeng WeiYen‐Hsun ChenTe‐Chun HsiaKang‐Yun LeeHuang‐Chih ChangChin‐Chou WangAfshin DowlatiChristopher SumeySteven PowellJonathan W. GoldmanJuan José ZarbáEmilio BatageljAndrea Viviana PastorMauro ZukinClarissa BaldottoLuís Alberto SchlittlerAknar CalabrichCláudia Vaz de Melo SetteA. P. DudovCaicun ZhouH. LénaSusanne LangZsuzsanna PápaiKōichi GotoShigeki UmemuraKenya KanazawaYu HaraMasahiro ShinodaMasahiro MoriseJ.T.J.N. HiltermannRobert MrózAndrei UngureanuIgor AndrašinaGee‐Chen ChangIhor VynnychenkoYaroslav ShparykAnna KryzhanivskaHelen J. RossKailhong MiRodney JamilMichael WilliamsonJoseph E. SpahrZhigang HanMengzhao WangZhixiong YangJie HuWei LiJun ZhaoJifeng FengShenglin MaXiangdong ZhouZongan LiangYi HuYuan ChenMinghong BiYongqian ShuKejun NanJianying ZhouWei ZhangRui MaNong YangLin ZhongGang WuJian FangHelong ZhangKai WangZhendong Chen
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Tremelimumab
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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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Immune checkpoint inhibitors have significantly improved outcomes in first line cutaneous melanoma. However, there is a high unmet need for patients who progress on these therapies and combination therapies are being explored to improve outcomes. Tebentafusp is a first-in-class gp100×CD3 ImmTAC bispecific that demonstrated overall survival (OS) benefit (HR 0.51) in metastatic uveal melanoma despite a modest overall response rate of 9%. This phase 1b trial evaluated the safety and initial efficacy of tebentafusp in combination with durvalumab (anti-programmed death ligand 1 (PDL1)) and/or tremelimumab (anti-cytotoxic T lymphocyte-associated antigen 4) in patients with metastatic cutaneous melanoma (mCM), the majority of whom progressed on prior checkpoint inhibitors.
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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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