Zie ook in gerelateerde artikelen

25 februari 2022: Bron: Annals of Oncology Published:February 02, 2022

Uit de fase III CheckMate 743-studie blijkt dat immuuntherapie als eerstelijns met de combinatie van ipilimumab plus nivolumab betere overall overleving geeft in vergelijking met chemotherapie met platina plus pemetrexed bij patiënten met inoperabele kwaadaardige asbestkanker - longmesothelioom . De combinatie van ipilimumab (1 mg/kg elke 6 weken) plus nivolumab (3 mg/kg elke 2 weken) ging bij deze patiënten gepaard met een betere algehele overleving dan chemotherapie met cisplatin plus pemetrexed. Bij een mediane follow-up van 43,1 maanden was de overall overleving (OS) 4 maanden langer met ipilimumab plus nivolumab, met een 3-jaars OS van 23% versus 15% voor chemotherapie. Dat klinkt niet erg goed maar longmesothelioma is een agressieve ziekte en de kans dit te overleven is heel klein. 

Figure thumbnail gr1

Figure 1OS in (A) all randomized patients, (B) patients with epithelioid histology, and (C) patients with non-epithelioid histology. CI, confidence interval; HR, hazard ratio; OS, overall survival.

Kernpunten uit deze studie:

  • Met een follow-up van ≥3 jaar in de CheckMate 743 studie, bleef nivolumab + ipilimumab langdurig OS-voordeel opleveren in eerstelijns longmesothelioma.
  • Klinische voordelen bleven consistent in alle subgroepen van patiënten, inclusief epithelioïde versus niet-epithelioïde histologie.
  • Stoppen met nivolumab + ipilimumab vanwege aan de behandeling gerelateerde bijwerkingen had geen negatief effect op het langetermijnvoordeel.
  • Nivolumab + ipilimumab blijft een effectieve eerstelijns behandelingsoptie voor patiënten met inoperabele longmesothelioma.
  • Er zijn drie grotere lopende gerandomiseerde fase III-onderzoeken die chemotherapie en remming van het immuuncheckpoint combineren (NCT03762018, NCT02784171, NCT04334759).

Het studierapport is gratis in te zien. Klik op de titel van het abstract:

First-line nivolumab plus ipilimumab versus chemotherapy in patients with unresectable malignant pleural mesothelioma: 3-year outcomes from CheckMate 743

Open AccessPublished:February 02, 2022DOI:https://doi.org/10.1016/j.annonc.2022.01.074


  • With a ≥3-year follow-up in CheckMate 743, nivolumab + ipilimumab continued to provide long-term OS benefit in 1L MPM.
  • Clinical benefits remained consistent across patient subgroups, including epithelioid vs non-epithelioid histology.
  • Discontinuing nivolumab + ipilimumab due to treatment-related adverse events did not negatively impact long-term benefit.
  • Nivolumab + ipilimumab continues to be an efficacious 1L treatment option for patients with unresectable MPM.
  • There are three larger ongoing randomized phase III trials combining chemotherapy and immune checkpoint inhibition (NCT03762018, NCT02784171, NCT04334759).



In the phase 3 CheckMate 743 study (NCT02899299), first-line nivolumab plus ipilimumab significantly improved overall survival (OS) versus chemotherapy in patients with unresectable malignant pleural mesothelioma (MPM). We report updated data with 3-year minimum follow-up.

Patients and methods

Adults with previously untreated, histologically confirmed, unresectable MPM and Eastern Cooperative Oncology Group performance status of ≤1 were randomized 1:1 to nivolumab (3 mg/kg every 2 weeks) plus ipilimumab (1 mg/kg every 6 weeks) for up to 2 years, or 6 cycles of platinum plus pemetrexed chemotherapy. This report includes updated efficacy and safety outcomes, exploratory biomarker analyses including 4-gene inflammatory expression signature score, and a post hoc efficacy analysis in patients who discontinued treatment due to treatment-related adverse events (TRAEs).


With median follow-up of 43.1 months, nivolumab plus ipilimumab continued to prolong OS versus chemotherapy. Median OS was 18.1 versus 14.1 months (HR [95% CI], 0.73 [0.61–0.87]), and 3-year OS rates were 23% versus 15%, respectively. Three-year progression-free survival rates were 14% versus 1%, and objective response rates were 40% versus 44%. At 3 years, 28% versus 0% of responders had an ongoing response. Improved survival benefit with nivolumab plus ipilimumab versus chemotherapy was observed across subgroups, including histology. A high score of the 4-gene inflammatory signature appeared to correlate with improved survival benefit with nivolumab plus ipilimumab. No new safety signals were observed with nivolumab plus ipilimumab, despite patients being off therapy for one year. In patients who discontinued nivolumab plus ipilimumab due to TRAEs, median OS was 25.4 months, and 34% of responders maintained their responses for ≥3 years after discontinuation.


With 3 years’ minimum follow-up, nivolumab plus ipilimumab continued to provide long-term survival benefit over chemotherapy and a manageable safety profile, supporting the regimen as standard-of-care treatment for unresectable MPM, regardless of histology.


    • Larkin J.
    • Chiarion-Sileni V.
    • Gonzalez R.
    • et al.
    Five-year survival with combined nivolumab and ipilimumab in advanced melanoma.
    N Engl J Med. 2019; 3811535-1546
    • Motzer R.J.
    • Escudier B.
    • McDermott D.F.
    • et al.
    Survival outcomes and independent response assessment with nivolumab plus ipilimumab versus sunitinib in patients with advanced renal cell carcinoma: 42-month follow-up of a randomized phase 3 clinical trial.
    J Immunother Cancer. 2020; 8 (e000891)
    • Motzer R.J.
    • Rini B.I.
    • McDermott D.F.
    • et al.
    Nivolumab plus ipilimumab versus sunitinib in first-line treatment for advanced renal cell carcinoma: extended follow-up of efficacy and safety results from a randomised, controlled, phase 3 trial.
    Lancet Oncol. 2019; 201370-1385
    • Hellmann M.D.
    • Ciuleanu T.E.
    • Pluzanski A.
    • et al.
    Nivolumab plus ipilimumab in lung cancer with a high tumor mutational burden.
    N Engl J Med. 2018; 3782093-2104
    • Hellmann M.D.
    • Paz-Ares L.
    • Bernabe Caro R.
    • et al.
    Nivolumab plus ipilimumab in advanced non-small-cell lung cancer.
    N Engl J Med. 2019; 3812020-2031
    • Das R.
    • Verma R.
    • Sznol M.
    • et al.
    Combination therapy with anti-CTLA-4 and anti-PD-1 leads to distinct immunologic changes in vivo.
    J Immunol. 2015; 194950-959
    • Wei S.C.
    • Levine J.H.
    • Cogdill A.P.
    • et al.
    Distinct cellular mechanisms underlie anti-CTLA-4 and anti-PD-1 checkpoint blockade.
    Cell. 2017; 170 (1120-1133 e17)
    • Sharma P.
    • Allison J.P.
    Dissecting the mechanisms of immune checkpoint therapy.
    Nat Rev Immunol. 2020; 2075-76
    • Wei S.C.
    • Duffy C.R.
    • Allison J.P.
    Fundamental mechanisms of immune checkpoint blockade therapy.
    Cancer Discov. 2018; 81069-1086
    • Baas P.
    • Scherpereel A.
    • Nowak A.K.
    • et al.
    First-line nivolumab plus ipilimumab in unresectable malignant pleural mesothelioma (CheckMate 743): a multicentre, randomised, open-label, phase 3 trial.
    Lancet. 2021; 397375-386
  1. OpdivoTM (nivolumab) summary of product characteristics. 2021. (Accessed September 29, 2021, at https://www.ema.europa.eu/en/documents/product-information/opdivo-epar-product-information_en.pdf.)

  2. Opdivo® (nivolumab) prescribing information. 2021. (Accessed November 19, 2021, at https://packageinserts.bms.com/pi/pi_opdivo.pdf.)

  3. Opdivo® (nivolumab) Australian product information, May 2021. 2021. (Accessed September 29, 2020, at https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2016-PI-01052-1&d=202007161016933.)

  4. OPDIVO (nivolumab)® Prescribing Information. 2021. (Accessed September 29, 2021, at https://packageinserts.bms.com/gb/prescribing-information/opdivo-uk-ie.pdf.)

  5. FDA Approves Drug Combination for Treating Mesothelioma. 2020. (Accessed September 29, 2021, at https://www.fda.gov/news-events/press-announcements/fda-approves-drug-combination-treating-mesothelioma.)

  6. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Malignant Pleural Mesothelioma v2.2021. © National Comprehensive Cancer Network, Inc. 2021. All rights reserved. Accessed Nov 11, 2021. To view the most recent and complete version of the guideline, go online to NCCN.org. NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way.

    • Hodi F.S.
    • Wolchok J.D.
    • Schadendorf D.
    • et al.
    TMB and inflammatory gene expression associated with clinical outcomes following immunotherapy in advanced melanoma.
    Cancer Immunol Res. 2021; 91202-1213
    • Lei M.
    • Siemers N.O.
    • Pandya D.
    • et al.
    Analyses of PD-L1 and inflammatory gene expression association with efficacy of nivolumab +/- ipilimumab in gastric cancer/gastroesophageal junction cancer.
    Clin Cancer Res. 2021; 273926-3935
    • Sangro B.
    • Melero I.
    • Wadhawan S.
    • et al.
    Association of inflammatory biomarkers with clinical outcomes in nivolumab-treated patients with advanced hepatocellular carcinoma.
    J Hepatol. 2020; 731460-1469
    • Paz-Ares L.G.
    • Ramalingam S.S.
    • Ciuleanu T.E.
    • et al.
    First-line nivolumab plus ipilimumab in advanced non-small cell lung cancer: 4-year outcomes from the randomized, open-label, phase 3 CheckMate 227 Part 1 trial.
    J Thorac Oncol. 2021; (S1556-0864(21)03207-X)
    • Reck M.
    • Ciuleanu T.E.
    • Cobo M.
    • et al.
    First-line nivolumab plus ipilimumab with two cycles of chemotherapy versus chemotherapy alone (four cycles) in advanced non-small-cell lung cancer: CheckMate 9LA 2-year update.
    ESMO Open. 2021; 6100273
    • Borghaei H.
    • Gettinger S.
    • Vokes E.E.
    • et al.
    Five-year outcomes from the randomized, phase III trials CheckMate 017 and 057: nivolumab versus docetaxel in previously treated non-small-cell lung cancer.
    J Clin Oncol. 2021; 39723-733
    • de Gooijer C.J.
    • Borm F.J.
    • Scherpereel A.
    • Baas P.
    Immunotherapy in malignant pleural mesothelioma.
    Front Oncol. 2020; 10187
    • Fehrenbacher L.
    • Spira A.
    • Ballinger M.
    • et al.
    Atezolizumab versus docetaxel for patients with previously treated non-small-cell lung cancer (POPLAR): a multicentre, open-label, phase 2 randomised controlled trial.
    Lancet. 2016; 3871837-1846
    • Garon E.B.
    • Rizvi N.A.
    • Hui R.
    • et al.
    Pembrolizumab for the treatment of non-small-cell lung cancer.
    N Engl J Med. 2015; 3722018-2028
    • Gandhi L.
    • Rodriguez-Abreu D.
    • Gadgeel S.
    • et al.
    Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer.
    N Engl J Med. 2018; 3782078-2092
    • Hellmann M.D.
    • Nathanson T.
    • Rizvi H.
    • et al.
    Genomic Features of Response to Combination Immunotherapy in Patients with Advanced Non-Small-Cell Lung Cancer.
    Cancer cell. 2018; 33843-852 e4
    • Rouquette I.
    • Taranchon-Clermont E.
    • Gilhodes J.
    • et al.
    Immune biomarkers in thymic epithelial tumors: expression patterns, prognostic value and comparison of diagnostic tests for PD-L1.
    Biomark Res. 2019; 728
    • Disselhorst M.J.
    • Quispel-Janssen J.
    • Lalezari F.
    • et al.
    Ipilimumab and nivolumab in the treatment of recurrent malignant pleural mesothelioma (INITIATE): results of a prospective, single-arm, phase 2 trial.
    Lancet Respir Med. 2019; 7260-270
    • Quispel-Janssen J.
    • van der Noort V.
    • de Vries J.F.
    • et al.
    Programmed death 1 blockade with nivolumab in patients with recurrent malignant pleural mesothelioma.
    J Thorac Oncol. 2018; 131569-1576
    • Nowak A.K.
    • Lesterhuis W.J.
    • Kok P.S.
    • et al.
    Durvalumab with first-line chemotherapy in previously untreated malignant pleural mesothelioma (DREAM): a multicentre, single-arm, phase 2 trial with a safety run-in.
    Lancet Oncol. 2020; 211213-1223
    • Scherpereel A.
    • Mazieres J.
    • Greillier L.
    • et al.
    Nivolumab or nivolumab plus ipilimumab in patients with relapsed malignant pleural mesothelioma (IFCT-1501 MAPS2): a multicentre, open-label, randomised, non-comparative, phase 2 trial.
    Lancet Oncol. 2019; 20239-253
    • Fennell D.A.
    • Ewings S.
    • Ottensmeier C.
    • et al.
    Nivolumab versus placebo in patients with relapsed malignant mesothelioma (CONFIRM): a multicentre, double-blind, randomised, phase 3 trial.
    Lancet Oncol. 2021; 221530-1540
    • Mansfield A.S.
    • Roden A.C.
    • Peikert T.
    • et al.
    B7-H1 expression in malignant pleural mesothelioma is associated with sarcomatoid histology and poor prognosis.
    J Thorac Oncol. 2014; 91036-1040
    • Lei M.
    • Siemers N.
    • Pandya D.
    • et al.
    Abstract 2673: Association of PD-L1 combined positive score and immune gene signatures with efficacy of nivolumab (NIVO) ± ipilimumab (IPI) in patients with metastatic gastroesophageal cancer (mGEC).
    Cancer Research. 2019; 792673
    • Hellmann M.D.
    • Callahan M.K.
    • Awad M.M.
    • et al.
    Tumor mutational burden and efficacy of nivolumab monotherapy and in combination with ipilimumab in small-cell lung cancer.
    Cancer cell. 2018; 33853-861
    • Ma Y.
    • Li Q.
    • Du Y.
    • et al.
    Blood tumor mutational burden as a predictive biomarker in patients with advanced non-small cell lung cancer (NSCLC).
    Front Oncol. 2021; 11640761
    • Samstein R.M.
    • Lee C.H.
    • Shoushtari A.N.
    • et al.
    Tumor mutational load predicts survival after immunotherapy across multiple cancer types.
    Nat Genet. 2019; 51202-206
    • Bueno R.
    • Stawiski E.W.
    • Goldstein L.D.
    • et al.
    Comprehensive genomic analysis of malignant pleural mesothelioma identifies recurrent mutations, gene fusions and splicing alterations.
    Nat Genet. 2016; 48407-416
    • Shao C.
    • Li G.
    • Huang L.
    • et al.
    Prevalence of high tumor mutational burden and association with survival in patients with less common solid tumors.
    JAMA Netw Open. 2020; 3e2025109
    • Strickler J.H.
    • Hanks B.A.
    • Khasraw M.
    Tumor mutational burden as a predictor of immunotherapy response: is more always better?.
    Clin Cancer Res. 2021; 271236-1241
    • Yarchoan M.
    • Hopkins A.
    • Jaffee E.M.
    Tumor mutational burden and response rate to PD-1 inhibition.
    N Engl J Med. 2017; 3772500-2501
    • Kazandjian D.
    • Gong Y.
    • Keegan P.
    • Pazdur R.
    • Blumenthal G.M.
    Prognostic value of the lung immune prognostic index for patients treated for metastatic non-small cell lung cancer.
    JAMA Oncol. 2019; 51481-1485
    • Mezquita L.
    • Auclin E.
    • Ferrara R.
    • et al.
    Association of the lung immune prognostic index with immune checkpoint inhibitor outcomes in patients with advanced non-small cell lung cancer.
    JAMA Oncol. 2018; 4351-357
    • Cao M.
    • Zhang J.
    • Xu H.
    • et al.
    Identification and development of a novel 4-gene immune-related signature to predict osteosarcoma prognosis.
    Front Mol Biosci. 2020; 7608368
    • Mansfield A.S.
    • Peikert T.
    • Smadbeck J.B.
    • et al.
    Neoantigenic potential of complex chromosomal rearrangements in mesothelioma.
    J Thorac Oncol. 2019; 14276-287
    • Lettieri S.
    • Bortolotto C.
    • Agustoni F.
    • et al.
    The evolving landscape of the molecular epidemiology of malignant pleural mesothelioma.
    J Clin Med. 2021; 10
  7. Forde PM, Sun Z, Anagnostou V, et al. PrE0505: phase II multicenter study of anti-PD-L1, durvalumab, in combination with cisplatin and pemetrexed for the first-line treatment of unresectable malignant pleural mesothelioma (MPM)—aPrECOG LLC study. American Society of Clinical Oncology; 2020.

  8. Forde PM, Nowak AK, Kok P-S, et al. DREAM3R: Durvalumab with chemotherapy as first-line treatment in advanced pleural mesothelioma—A phase 3 randomized trial. Wolters Kluwer Health; 2021.

    • Maio M.
    • Scherpereel A.
    • Calabrò L.
    • et al.
    Tremelimumab as second-line or third-line treatment in relapsed malignant mesothelioma (DETERMINE): a multicentre, international, randomised, double-blind, placebo-controlled phase 2b trial.
    Lancet Oncol. 2017; 181261-1273
    • Miyamoto Y.
    • Kozuki T.
    • Aoe K.
    • et al.
    JME-001 phase II trial of first-line combination chemotherapy with cisplatin, pemetrexed, and nivolumab for unresectable malignant pleural mesothelioma.
    J Immunother Cancer. 2021; 9

Plaats een reactie ...

Reageer op "Immuuntherapie met nivolumab plus ipilimumab verbetert significant de algehele overleving versus chemotherapie (23 vs 15 procent op 3-jaars meting) bij patiënten met niet operabele mesothelioom van de longen"

Gerelateerde artikelen

Gerelateerde artikelen

Immuuntherapie met nivolumab >> Dendritische celtherapie heeft >> Pembrolizumab, een anti-PD >> Mesothelioma - asbestkanker: >> Mesothelioma: Nieuwe chemotherapie >> Mesothelioma - asbestkanker >> mesothelioma - asbestkanker: >> Mesothelioma informatie: longvlieskanker >>