Durvalumab plus platinum–etoposide versus platinum–etoposide in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): a randomised, controlled, open-label, phase 3 trial
Luís Paz-AresMikhail DvorkinYuanbin ChenNiels ReinmuthKatsuyuki HottaDmytro TrukhinGalina StatsenkoMaximilian J. HochmairMustafa ÖzgüroğluJun Ho JiОлександр ВойткоArtem PoltoratskiySantiago PonceFrancesco VerderameLibor HavelIgor BondarenkoAndrzej KażarnowiczGyörgy LosonczyNikolay ConevJ. ArmstrongNatalie ByrneNorah J. ShireHaiyi JiangJonathan W. GoldmanEmilio BatageljIgnacio CasariniAnea Viviana PastorS. SenaJuan José ZarbáOtto C. BurghuberSylvia HartlMaximilian J. HochmairBernd LamprechtMichael StudnickaLuís Alberto SchlittlerFabrício Augusto Martinelli de OliveiraAknar CalabrichGustavo GirottoPeo Dos ReisCarlos Fausto Nino GoriniPeo Rafael Martins De MarchiClarissa BaldottoCláudia Vaz de Melo SetteMauro ZukinNikolay ConevAssen DudovRumyana IlievaKrassimir KoynovRositsa KrastevaIvan TonevSpartak ValevVioletka VenkovaMinghong BiChengshui ChenYuan ChenZhendong ChenJian FangJifeng FengZhigang HanJie HuYi HuXing LiZongan LiangLin ZhongRui MaShenglin MaKejun NanYongqian ShuKai WangMengzhao WangGang WuNong YangZhixiong YangHelong ZhangWei ZhangJun ZhaoYanqiu ZhaoCaicun ZhouJianying ZhouXiangdong ZhouLibor HavelVı́tězslav KolekLeona KoubkováJaromı́r RoubecJana SkřičkováMilada ZemanováC. ChouaïdWerner HilgersH. LénaDenis Moro‐SibilotG. RobinetPierre-Jean SouquetJürgen AltHelge BischoffChristian GrohéEckart LaackSusanne LangJens PanseNiels ReinmuthChristian SchulzKrisztina BogosEszter CsánkyAnea FülöpZsolt HorváthJudit KósaIbolya LaczóGyörgy LosonczyGábor PajkosZsuzsanna PápaiZsolt Pápai SzékelyVeronika SárosiA SomfayÉva Somogyiné EzerAnás TelekesJair BarMaya GottfriedNorman HechingAlona ZerRoberta BartolucciAnna BettiniAngelo DelmonteMarina Chiara GarassinoMauro MinelliFausto RoilaFrancesco VerderameShinji AtagiKoichi AzumaHisatsugu GotoKōichi GotoYu HaraHidetoshi HayashiToyoaki HidaKatsuyuki HottaKenya KanazawaShintaro KandaYoung Hak KimShoichi KuyamaTadashi MaedaMasahiro MoriseYasuharu NakaharaMakoto NishioNaoyuki NogamiIsamu OkamotoHaruhiro SaitoMasahiro ShinodaShigeki UmemuraTatsuya YoshidaNiels ClaessensRobin CornelissenLizza HeniksJ.T.J.N. HiltermannEgbert F. SmitAgnes Staal van den BrekelAndrzej KażarnowiczDariusz M. KowalskiSławomir MańdziukRobert MrózMarek Z. WojtukiewiczTudor‐Eliade CiuleanuDoina GaneaAnei UngureanuMikhail DvorkinAlexander LuftВ. МоисеенкоArtem PoltoratskiyDina SakaevaAlexey SmolinGalina StatsenkoAlexander VasilyevLyubov VladimirovaIgor AnasinaJozef ChovanecPavol DemoRobert GodalPeter KasanMarian StreškoM. UrdaEun Kyung ChoJun Ho JiJoo-Hang KimSang‐We KimGyeong‐Won LeeJong-Seok LeeKi Hyeong LeeKyung Hee LeeYun Gyoo LeeAmelia InsaM. Dómine GómezJuan Ignacio Delgado MingoranceD. CasadoMarta López BreaM. Majem TarruellaTeresa Morán BuenoAlejano Navarro MendivilLuis Paz-Ares RodríguezSantiago Ponce AixM.R. García CampeloGee‐Chen ChangYen‐Hsun ChenChao‐Hua ChiuTe‐Chun HsiaKang‐Yun LeeChien-Te LiChin‐Chou WangYufeng WeiShang‐Yin WuAhmet Alacacıoğluİrfan ÇiçinAhmet DemirkazıkMustafa ErmanTuncay GökselMustafa ÖzgüroğluHryhoriy AdamchukIgor BondarenkoOleksii KolesnikAnna KryzhanivskaYuriv OstapenkoSerhii ShevniaYaroslav ShparykDmytro TrukhinGrygorii UrsolОлександр ВойткоОлександр ВойткоIhor VynnychenkoSunil BabuYuanbin ChenAnne C. ChiangWinston ChuaShaker R. DakhilAfshin DowlatiJonathan W. GoldmanBasir HaqueRodney JamilJeanna KnobleShailena LakhanpalKailhong MiPetros NikolinakosSteven PowellHelen J. RossEric SchaeferJeffrey SchneiderJoseph E. SpahrDavid R. SpigelJoseph StilwillChristopher SumeyMichael Williamson
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Durvalumab
Introduction: The prominent immune checkpoint molecule, programmed cell death ligand-1 (PD-L1), is the object of increasing attention. Here, we report a meta-analysis investigating the safety and efficacy of durvalumab (MEDI4736), an inhibitor of PD-L1, in various solid tumors. Methods: A systematic search of PubMed, Embase, and related articles was performed. Safety data were analyzed using Comprehensive Meta-Analysis software program version 2. Ultimately, 17 studies with 1,529 patients were included in our analysis. Results: The major adverse events associated with durvalumab were pruritus and fatigue, while pruritus, increased alanine transaminase, and increased aspartate aminotransferase were common among patients treated with a combination of durvalumab and tremelimumab. Higher PD-L1 expression was associated with a superior objective response rate. Conclusion: Durvalumab is safe in patients with many solid cancers and, in combination with tremelimumab, it has a tolerable safety profile and is associated with improved prognosis. PD-L1 expression is a biomarker of the efficacy of durvalumab. Keywords: durvalumab, solid cancers, adverse effects, efficacy, meta-analysis
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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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When resection is not an option, platinum-based chemoradiotherapy (CRT) has been the historic standard of care in non-small cell lung cancer (NSCLC). Prognosis remains poor with CRT alone. Durvalumab has shown significant improvement (versus placebo) in progression-free and overall survival in patients with unresectable stage III NSCLC without progression following CRT.This article aims to provide an overview of the efficacy and safety outcomes with durvalumab in patients with stage III NSCLC and identify management strategies for potential adverse events (AEs).A review of published literature and guidelines was performed to evaluate durvalumab clinical outcomes and AE management strategies.Durvalumab has established efficacy in patients with unresectable stage III NSCLC and is now the standard of care following CRT. Nurses need to be trained to recognize potential immune-related AEs in patients treated with immune checkpoint inhibitors.
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Introduction: The prognosis of patients with advanced non-small cell lung cancer (NSCLC) remains poor, with a 5-year overall survival rate of around 15%. Immune checkpoint inhibitors, such as programmed cell death protein 1 and programmed death-ligand 1 (PD-L1) inhibitors, have opened a new era in the management of NSCLC. Three checkpoint inhibitors (nivolumab, pembrolizumab, and atezolizumab) are currently approved by the US Food and Drug Administration (FDA) for advanced NSCLC. Durvalumab, an anti-PD-L1 antibody, is under investigation in several trials.Areas covered: This article reviews the pharmacological properties, clinical efficacy, and safety of durvalumab as monotherapy and in combination with other drugs for the treatment of locally advanced and advanced NSCLC.Expert opinion: Durvalumab as monotherapy or in combination with tremelimumab was effective with well-tolerated safety profiles for advanced NSCLC in several phase I or II studies. The PACIFIC study assessed the effectiveness of durvalumab as maintenance therapy following definitive chemoradiotherapy for unresectable stage III NSCLC, and met its primary endpoints of progression-free survival and overall survival. These results led to FDA approval for this NSCLC population. It will be exciting to follow ongoing phase III studies assessing how durvalumab fits into the rapidly evolving therapeutic landscape for advanced NSCLC.
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Introduction: Immune checkpoint inhibitors, monoclonal antibodies directed against programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1), have broadened treatment options for patients with non-small cell lung cancer (NSCLC). Durvalumab is a selective, high-affinity, human IgG1 monoclonal anti-PD-L1 antibody that blocks interactions of PD-L1 with PD-1 and CD80.Areas covered: We reviewed clinical data supporting the use of durvalumab as a monotherapy and combination therapy for the treatment of locally advanced and advanced NSCLC.Expert commentary: Durvalumab as a monotherapy or combination therapy has shown well-tolerated safety profiles for NSCLC in several trials. Durvalumab monotherapy in advanced NSCLC patients with PD-L1 ≥ 25% as later line (ATLANTIC study) therapy led to clinically meaningful improvements compared to standard of care. Combination therapy comprising durvalumab plus tremelimumab for advanced NSCLC did not show clinical efficacy in three phase III trials. Durvalumab administered after chemoradiotherapy in stage III NSCLC (PACIFIC study) significantly improved progression-free survival and overall survival. This result has led to approval of durvalumab for patients with locally advanced NSCLC as the standard of care. Ongoing trials provide insight into how durvalumab fits into the rapidly evolving therapeutic landscape for locally advanced or advanced NSCLC.
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Stage III non-small-cell lung cancer (NSCLC) represents a heterogeneous group of disease entities with multimodality treatments. For most patients, platinum-based doublet with concurrent chemoradiotherapy (CRT) has become the first-choice treatment over the past decade. Immune checkpoint inhibition has revolutionized the management of metastatic NSCLC; however, no major advances in systemic therapy for Stage III NSCLC have been made. The following report is the case of a patient with unresectable Stage IIIA NSCLC successfully treated with durvalumab. The patient completed 1 year of treatment without interruptions, and disease control has been maintained for more than 20 months since the start of durvalumab.
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What is durvalumab? Durvalumab is a human immunoglobulin G1 kappa monoclonal antibody that blocks PD-L1. How does durvalumab work? PD-L1 is frequently expressed on tumor cells and tumor-infiltrating immune cells. The binding of PD-L1 to PD-1 and CD80 (B7.1) inhibits T-cell activation and proliferation, resulting in T-cell exhaustion. Durvalumab binds to PD-L1 and blocks the interaction of PD-L1 to PD-1 and CD80 (B7.1), allowing heightened T-cell antitumor activity. What is this approved for? Durvalumab is approved for the treatment of locally advanced or metastatic urothelial carcinoma patients who have disease progression following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with a platinum-containing regimen. What is the basis for this approval? Durvalumab received FDA approval in May 2017 based on the results of an ongoing phase I/II open-label study. One hundred eighty-two stage IV, platinum-experienced urothelial carcinoma patients received durvalumab 10 mg/kg intravenously every 2 weeks for 12 months or until unacceptable toxicity or progressive disease. The primary endpoints were safety and confirmed objective response rate (ORR). The median age was 67 years and 71 percent were male. The ORR was 17.6 percent (95% CI, 12.3-23.9). Complete responses occurred in six patients (3.3%). Patients with PD-L1 high expression (≥ 25% of tumor or immune cells stained for PD-L1) had higher ORR when compared to patients with PD-L1 low or negative expression (27.4% to 4.1%, respectively). Seventy-five percent of responses were ongoing at the time of data cutoff and occurred early in the course of therapy. Duration of response was not reached (range, ≥ 0.9 to ≥ 19.9 months) (JAMA Oncol 2017;3(9):e172411). How do you administer this drug? Durvalumab is administered as an IV infusion diluted in 0.9 percent sodium chloride for injection, USP or 5 percent dextrose injection, USP to a final concentration of 1 to 15 mg/mL. It is given over 60 minutes via 0.2 or 0.22 micron in-line filter. Are there any pre-medications needed? None required. What are the common side effects associated with durvalumab (> or =10%)? The most common toxicities include fatigue, musculoskeletal pain, constipation, decreased appetite, nausea, urinary tract infection, peripheral edema, abdominal pain, fever, diarrhea/colitis, dyspnea, rash, and cough. What are the uncommon side effects associated with durvalumab (less than 10%)? Immune-mediated toxicities including the following may occur with durvalumab: pneumonitis, hepatitis, hypothyroidism, hyperthyroidism, adrenal insufficiency, diabetes mellitus, and nephritis. Infections including sepsis may occur in ~30 percent of patients. Approximately 2 percent will develop an infusion reaction. Are there any important drug interactions I should be aware of? No known drug interactions. How do I adjust the dose in the setting of renal or hepatic insufficiency? No dosage adjustment is needed in patients with mild or moderate renal insufficiency or mild hepatic insufficiency. Patients with severe renal impairment or moderate-to-severe hepatic impairment were not included in durvalumab clinical trials. Practical tips Clinically significant immune-related adverse events including rash, diarrhea/colitis, hepatitis, pneumonitis, and hypophysitis have been observed in patients receiving durvalumab. Patients should be educated to recognize and report symptoms to their health care team to determine if corticosteroids should be initiated to mediate toxicity. What should my patients know about durvalumab? Patients should contact their health care provider if they experience any of the following: New or worsening cough, shortness of breath, or chest pain Yellowing of the skin or whites of your eyes Dark colored urine or black, tarry stools Headaches Extreme tiredness Decrease in the amount of urine, frequent urination, or pain when urinating Fever or flu-like symptoms Swelling of the face or ankles Skin blistering What else should I know about durvalumab? Patients with autoimmune disease, irritable bowel disease, untreated CNS metastases, those with previous exposure to anti-PD-1 or anti-PD-L1 therapies, or those who require greater than 10 mg/day prednisone equivalents were excluded from durvalumab clinical trials (J Clin Oncol 2016;34(26):3119-3125). What useful links are available regarding durvalumab? https://www.imfinzi.com/ https://www.fda.gov/drugs/informationondrugs/approveddrugs/ucm555930.htm Any ongoing clinical trials related to durvalumab? Clinical trials with durvalumab as monotherapy and in combination with chemotherapy and biotherapy (particularly with tremelimumab, a cytotoxic T-lymphocyte antigen-4 monoclonal antibody) are being conducted in lung cancer, head and neck cancers, pancreatic adenocarcinoma, and other advanced hematologic and oncologic malignancies. More information is available about these clinical trials at https://clinicaltrials.gov. HEIDI D. FINNES, PHARMD, BCOP, is Senior Manager, Pharmacy Cancer Research, and Assistant Professor of Pharmacy, College of Medicine at the Mayo Clinic, Rochester, Minn. RAMASWAMY GOVINDAN, MD, Co-Director, Section of Medical Oncology, Professor of Medicine, Washington University School of Medicine, Alvin J. Siteman Cancer Center, serves as the Pharmacy Forum column physician advisor. SARA K. BUTLER, PHARMD, BCPS, BCOP, is Clinical Oncology Pharmacy Supervisor, Barnes-Jewish Hospital, St. Louis, Mo., and also serves as a Pharmacy Forum column co-editor. JANELLE E. MANN, PHARMD, BCOP, is an Investigational Drug Pharmacist, Washington University School of Medicine, Alvin J. Siteman Cancer Center, St. Louis, Mo., and serves as the Pharmacy Forum column co-editor.Heidi D. Finnes, PharmD, BCOP: Heidi D. Finnes, PharmD, BCOPRamaswamy Govindan, MD: Ramaswamy Govindan, MD
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