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Incidence of hepatotoxicity associated with addition of immune checkpoint blockade to systemic solid tumor therapy: a meta-analysis of phase 3 randomized controlled trials

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Abstract

Hepatotoxicity is a major immune-related adverse event that may become life-threatening. The impact of adding immune checkpoint blockade (ICB) to systemic therapy on the incidence of hepatotoxicity remains unknown. We performed a systematic review and meta-analysis to compare the incidence of hepatotoxicity among patients with cancer who received therapy with and without addition of ICB. PubMed, Embase, Web of Science, and Cochrane Library were searched to select phase 3 randomized controlled trials (RCTs) evaluating the effect of adding ICB to systemic therapy, placebo, or supportive care. The odds ratio (OR) of any grade and grade 3–5 hepatitis, elevations in aspartate aminotransferase (AST), and alanine aminotransferase (ALT) was pooled for meta-analysis. 43 RCTs with 28,905 participants were analyzed. Addition of ICB increased the incidence of hepatitis (any grade: OR, 2.13, 95% confidence interval [CI] 1.52–2.97, grade 3–5: OR, 2.66, 95% CI 1.72–4.11), elevated AST (any grade: OR, 2.16, 95% CI 1.73–2.70, grade 3–5: OR, 2.72, 95% CI 1.86–3.99), and elevated ALT (any grade: OR, 2.01, 95% CI 1.59–2.54, grade 3–5: OR, 2.40, 95% CI 1.62–3.55). Subgroup analysis based on the ICB mechanism revealed no significant heterogeneity among each mechanism for hepatitis (any Grade: I2 = 11.1%, p for heterogeneity = 0.32, grade 3–5: I2 = 0%, p = 0.48). Adding ICB to systemic therapy increases the incidence of hepatotoxicity regardless of the mechanism of ICB. Hepatotoxicity is common and vigilant monitoring of liver function is required during ICB therapy for patients with cancer.

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Data availability

Data are available in a public, open access repository. All data relevant to the study are included in the article or uploaded as supplementary information.

Abbreviations

AST:

Aspartate aminotransferase

ALT:

Alanine aminotransferase

CI:

Confidence interval

CTLA-4:

Cytotoxic T-lymphocyte antigen

ICB:

Immune checkpoint blockade

irAE:

Immune-related adverse event

OR:

Odds ratio

PD-1:

Programmed cell death 1

PD-L1:

Programmed death-ligand 1

PRISMA:

Preferred reporting items for systematic reviews and mata-analysis

RCT:

Randomized clinical trial

trAE:

Treatment-related adverse event

References

  1. Postow MA, Sidlow R, Hellmann MD (2018) Immune-Related adverse events associated with immune checkpoint blockade. N Engl J Med 378:158–168. https://doi.org/10.1056/NEJMra1703481

    Article  PubMed  CAS  Google Scholar 

  2. Weber JS, Hodi FS, Wolchok JD et al (2017) Safety profile of nivolumab monotherapy: a pooled analysis of patients with advanced melanoma. J Clin Oncol 35:785–792. https://doi.org/10.1200/jco.2015.66.1389

    Article  PubMed  CAS  Google Scholar 

  3. Ibrahim RA, Berman DM, Depril V et al (2011) Ipilimumab safety profile: summary of findings from completed trials in advanced melanoma. J Clin Oncol 29:8583. https://doi.org/10.1200/jco.2011.29.15_suppl.8583

    Article  Google Scholar 

  4. Rosenberg JE, Hoffman-Censits J, Powles T et al (2016) Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial. Lancet 387:1909–1920. https://doi.org/10.1016/s0140-6736(16)00561-4

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  5. Ziemer M, Koukoulioti E, Beyer S, Simon JC, Berg T (2017) Managing immune checkpoint-inhibitor-induced severe autoimmune-like hepatitis by liver-directed topical steroids. J Hepatol 66:657–659. https://doi.org/10.1016/j.jhep.2016.11.015

    Article  PubMed  Google Scholar 

  6. Brahmer JR, Lacchetti C, Schneider BJ et al (2018) Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American society of clinical oncology clinical practice guideline. J Clin Oncol 36:1714–1768. https://doi.org/10.1200/jco.2017.77.6385

    Article  PubMed  CAS  Google Scholar 

  7. Lin LL, Lin GF, Yang F, Chen XQ (2020) A systematic review and meta-analysis of immune-mediated liver dysfunction in non-small cell lung cancer. Int Immunopharmacol 83:106537. https://doi.org/10.1016/j.intimp.2020.106537

    Article  PubMed  CAS  Google Scholar 

  8. Guo X, Li W, Hu J, Zhu EC, Su Q (2020) Hepatotoxicity in patients with solid tumors treated with PD-1/PD-L1 inhibitors alone, PD-1/PD-L1 inhibitors plus chemotherapy, or chemotherapy alone: systematic review and meta-analysis. Eur J Clin Pharmacol 76:1345–1354. https://doi.org/10.1007/s00228-020-02903-2

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. Zhang X, Ran Y, Wang K, Zhu Y, Li J (2016) Incidence and risk of hepatic toxicities with PD-1 inhibitors in cancer patients: a meta-analysis. Drug Des Devel Ther 10:3153–3161. https://doi.org/10.2147/dddt.S115493

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  10. Wang W, Lie P, Guo M, He J (2017) Risk of hepatotoxicity in cancer patients treated with immune checkpoint inhibitors: a systematic review and meta-analysis of published data. Int J Cancer 141:1018–1028. https://doi.org/10.1002/ijc.30678

    Article  PubMed  CAS  Google Scholar 

  11. Motzer R, Alekseev B, Rha SY et al (2021) Lenvatinib plus pembrolizumab or everolimus for advanced renal cell carcinoma. N Engl J Med 384:1289–1300. https://doi.org/10.1056/NEJMoa2035716

    Article  PubMed  CAS  Google Scholar 

  12. Finn RS, Qin S, Ikeda M et al (2020) Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N Engl J Med 382:1894–1905. https://doi.org/10.1056/NEJMoa1915745

    Article  PubMed  CAS  Google Scholar 

  13. Paz-Ares L, Luft A, Vicente D et al (2018) Pembrolizumab plus chemotherapy for squamous non-small-cell lung cancer. N Engl J Med 379:2040–2051. https://doi.org/10.1056/NEJMoa1810865

    Article  PubMed  CAS  Google Scholar 

  14. Fujiwara Y, Horita N, Namkoong H, Galsky MD (2021) The effect of adding immune checkpoint inhibitors on the risk of pneumonitis for solid tumours: a meta-analysis of phase III randomised controlled trials. Eur J Cancer 150:168–178. https://doi.org/10.1016/j.ejca.2021.03.012

    Article  PubMed  CAS  Google Scholar 

  15. Fujiwara Y, Horita N, Namkoong H, Miyashita H, Harrington M, Galsky MD (2021) Incidence of hepatitis associated with addition of immune checkpoint blockade to conventional solid tumor therapy: a meta-analysis of phase 3 randomized clinical trials. J Clin Oncol 39:2645. https://doi.org/10.1200/JCO.2021.39.15_suppl.2645

    Article  Google Scholar 

  16. Higgins JPT, Altman DG, Gøtzsche PC et al (2011) The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. BMJ 343:d5928. https://doi.org/10.1136/bmj.d5928

    Article  PubMed  PubMed Central  Google Scholar 

  17. Review Manager (RevMan) [Computer program]. Version 5.4 TCC (2020)

  18. Peeraphatdit TB, Wang J, Odenwald MA, Hu S, Hart J, Charlton MR (2020) Hepatotoxicity from immune checkpoint inhibitors: a systematic review and management recommendation. Hepatology 72:315–329. https://doi.org/10.1002/hep.31227

    Article  PubMed  Google Scholar 

  19. De Martin E, Michot JM, Papouin B et al (2018) Characterization of liver injury induced by cancer immunotherapy using immune checkpoint inhibitors. J Hepatol 68:1181–1190. https://doi.org/10.1016/j.jhep.2018.01.033

    Article  PubMed  CAS  Google Scholar 

  20. Johncilla M, Misdraji J, Pratt DS, Agoston AT, Lauwers GY, Srivastava A, Doyle LA (2015) Ipilimumab-associated Hepatitis: clinicopathologic characterization in a series of 11 cases. Am J Surg Pathol 39:1075–1084. https://doi.org/10.1097/pas.0000000000000453

    Article  PubMed  Google Scholar 

  21. Zen Y, Yeh MM (2018) Hepatotoxicity of immune checkpoint inhibitors: a histology study of seven cases in comparison with autoimmune hepatitis and idiosyncratic drug-induced liver injury. Mod Pathol 31:965–973. https://doi.org/10.1038/s41379-018-0013-y

    Article  PubMed  Google Scholar 

  22. Simonelli M, Di Tommaso L, Baretti M, Santoro A (2016) Pathological characterization of nivolumab-related liver injury in a patient with glioblastoma. Immunotherapy 8:1363–1369. https://doi.org/10.2217/imt-2016-0057

    Article  PubMed  CAS  Google Scholar 

  23. Johnson DB, Sullivan RJ, Ott PA et al (2016) Ipilimumab therapy in patients with advanced melanoma and preexisting autoimmune disorders. JAMA Oncol 2:234–240. https://doi.org/10.1001/jamaoncol.2015.4368

    Article  PubMed  Google Scholar 

  24. Menzies AM, Johnson DB, Ramanujam S et al (2017) Anti-PD-1 therapy in patients with advanced melanoma and preexisting autoimmune disorders or major toxicity with ipilimumab. Ann Oncol 28:368–376. https://doi.org/10.1093/annonc/mdw443

    Article  PubMed  CAS  Google Scholar 

  25. Kitagataya T, Suda G, Nagashima K et al (2020) Prevalence, clinical course, and predictive factors of immune checkpoint inhibitor monotherapy-associated hepatitis in Japan. J Gastroenterol Hepatol 35:1782–1788. https://doi.org/10.1111/jgh.15041

    Article  PubMed  CAS  Google Scholar 

  26. Wang DY, Salem JE, Cohen JV et al (2018) Fatal toxic effects associated with immune checkpoint inhibitors: a systematic review and meta-analysis. JAMA Oncol 4:1721–1728. https://doi.org/10.1001/jamaoncol.2018.3923

    Article  PubMed  PubMed Central  Google Scholar 

  27. Bajorin DF, Witjes JA, Gschwend JE et al (2021) adjuvant nivolumab versus placebo in muscle-invasive urothelial carcinoma. N Engl J Med 384:2102–2114. https://doi.org/10.1056/NEJMoa2034442

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  28. Bellmunt J, Hussain M, Gschwend JE et al (2021) Adjuvant atezolizumab versus observation in muscle-invasive urothelial carcinoma (IMvigor010): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol 22:525–537. https://doi.org/10.1016/s1470-2045(21)00004-8

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Boyer M, Şendur MAN, Rodríguez-Abreu D et al (2021) Pembrolizumab plus ipilimumab or placebo for metastatic non-small-cell lung cancer with PD-L1 tumor proportion score ≥ 50%: randomized, double-blind phase III KEYNOTE-598 study. J Clin Oncol 39:2327–2338. https://doi.org/10.1200/jco.20.03579

    Article  PubMed  CAS  Google Scholar 

  30. Cortes J, Cescon DW, Rugo HS et al (2020) Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer (KEYNOTE-355): a randomised, placebo-controlled, double-blind, phase 3 clinical trial. Lancet 396:1817–1828. https://doi.org/10.1016/s0140-6736(20)32531-9

    Article  PubMed  CAS  Google Scholar 

  31. Di Giacomo AM, Chiarion-Sileni V, Del Vecchio M et al (2021) Primary analysis and 4-year follow-up of the phase III NIBIT-M2 trial in melanoma patients with brain metastases. Clin Cancer Res 27:4737–4745. https://doi.org/10.1158/1078-0432.Ccr-21-1046

    Article  PubMed  Google Scholar 

  32. Eggermont AM, Chiarion-Sileni V, Grob JJ et al (2016) Prolonged survival in stage III melanoma with ipilimumab adjuvant therapy. N Engl J Med 375:1845–1855. https://doi.org/10.1056/NEJMoa1611299

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. Eggermont AMM, Blank CU, Mandala M et al (2018) Adjuvant pembrolizumab versus placebo in resected stage III melanoma. N Engl J Med 378:1789–1801. https://doi.org/10.1056/NEJMoa1802357

    Article  PubMed  CAS  Google Scholar 

  34. Ferris RL, Haddad R, Even C et al (2020) Durvalumab with or without tremelimumab in patients with recurrent or metastatic head and neck squamous cell carcinoma: EAGLE, a randomized, open-label phase III study. Ann Oncol 31:942–950. https://doi.org/10.1016/j.annonc.2020.04.001

    Article  PubMed  CAS  Google Scholar 

  35. Finn RS, Ryoo BY, Merle P et al (2020) Pembrolizumab as second-line therapy in patients with advanced hepatocellular carcinoma in KEYNOTE-240: a randomized, double-blind Phase III Trial. J Clin Oncol 38:193–202. https://doi.org/10.1200/jco.19.01307

    Article  PubMed  CAS  Google Scholar 

  36. Galsky MD, Arija JÁA, Bamias A et al (2020) Atezolizumab with or without chemotherapy in metastatic urothelial cancer (IMvigor130): a multicentre, randomised, placebo-controlled phase 3 trial. Lancet 395:1547–1557. https://doi.org/10.1016/s0140-6736(20)30230-0

    Article  PubMed  CAS  Google Scholar 

  37. Govindan R, Szczesna A, Ahn MJ et al (2017) Phase III trial of ipilimumab combined with paclitaxel and carboplatin in advanced squamous non-small-cell lung cancer. J Clin Oncol 35:3449–3457. https://doi.org/10.1200/jco.2016.71.7629

    Article  PubMed  CAS  Google Scholar 

  38. Gutzmer R, Stroyakovskiy D, Gogas H et al (2020) Atezolizumab, vemurafenib, and cobimetinib as first-line treatment for unresectable advanced BRAF(V600) mutation-positive melanoma (IMspire150): primary analysis of the randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 395:1835–1844. https://doi.org/10.1016/s0140-6736(20)30934-x

    Article  PubMed  CAS  Google Scholar 

  39. Hodi FS, O’Day SJ, McDermott DF et al (2010) Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 363:711–723. https://doi.org/10.1056/NEJMoa1003466

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  40. Hodi FS, Chiarion-Sileni V, Gonzalez R et al (2018) Nivolumab plus ipilimumab or nivolumab alone versus ipilimumab alone in advanced melanoma (CheckMate 067): 4-year outcomes of a multicentre, randomised, phase 3 trial. Lancet Oncol 19:1480–1492. https://doi.org/10.1016/s1470-2045(18)30700-9

    Article  PubMed  CAS  Google Scholar 

  41. Horn L, Mansfield AS, Szczęsna A et al (2018) First-line atezolizumab plus chemotherapy in extensive-stage small-cell lung cancer. N Engl J Med 379:2220–2229. https://doi.org/10.1056/NEJMoa1809064

    Article  PubMed  CAS  Google Scholar 

  42. Janjigian YY, Shitara K, Moehler M et al (2021) First-line nivolumab plus chemotherapy versus chemotherapy alone for advanced gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma (CheckMate 649): a randomised, open-label, phase 3 trial. Lancet 398:27–40. https://doi.org/10.1016/s0140-6736(21)00797-2

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  43. Jotte R, Cappuzzo F, Vynnychenko I et al (2020) Atezolizumab in combination with carboplatin and nab-paclitaxel in advanced squamous NSCLC (IMpower131): results from a randomized phase III trial. J Thorac Oncol 15:1351–1360. https://doi.org/10.1016/j.jtho.2020.03.028

    Article  PubMed  CAS  Google Scholar 

  44. Kang YK, Boku N, Satoh T et al (2017) Nivolumab in patients with advanced gastric or gastro-oesophageal junction cancer refractory to, or intolerant of, at least two previous chemotherapy regimens (ONO-4538-12, ATTRACTION-2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 390:2461–2471. https://doi.org/10.1016/s0140-6736(17)31827-5

    Article  PubMed  CAS  Google Scholar 

  45. Kelly RJ, Ajani JA, Kuzdzal J et al (2021) Adjuvant nivolumab in resected esophageal or gastroesophageal junction cancer. N Engl J Med 384:1191–1203. https://doi.org/10.1056/NEJMoa2032125

    Article  PubMed  CAS  Google Scholar 

  46. Kwon ED, Drake CG, Scher HI et al (2014) Ipilimumab versus placebo after radiotherapy in patients with metastatic castration-resistant prostate cancer that had progressed after docetaxel chemotherapy (CA184-043): a multicentre, randomised, double-blind, phase 3 trial. Lancet Oncol 15:700–712. https://doi.org/10.1016/s1470-2045(14)70189-5

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  47. Lee NY, Ferris RL, Psyrri A et al (2021) Avelumab plus standard-of-care chemoradiotherapy versus chemoradiotherapy alone in patients with locally advanced squamous cell carcinoma of the head and neck: a randomised, double-blind, placebo-controlled, multicentre, phase 3 trial. Lancet Oncol 22:450–462. https://doi.org/10.1016/s1470-2045(20)30737-3

    Article  PubMed  CAS  Google Scholar 

  48. Miles D, Gligorov J, André F et al (2021) Primary results from IMpassion131, a double-blind, placebo-controlled, randomised phase III trial of first-line paclitaxel with or without atezolizumab for unresectable locally advanced/metastatic triple-negative breast cancer. Ann Oncol 32:994–1004. https://doi.org/10.1016/j.annonc.2021.05.801

    Article  PubMed  CAS  Google Scholar 

  49. Mittendorf EA, Zhang H, Barrios CH et al (2020) Neoadjuvant atezolizumab in combination with sequential nab-paclitaxel and anthracycline-based chemotherapy versus placebo and chemotherapy in patients with early-stage triple-negative breast cancer (IMpassion031): a randomised, double-blind, phase 3 trial. Lancet 396:1090–1100. https://doi.org/10.1016/s0140-6736(20)31953-x

    Article  PubMed  CAS  Google Scholar 

  50. Moore KN, Bookman M, Sehouli J et al (2021) Atezolizumab, bevacizumab, and chemotherapy for newly diagnosed stage III or IV ovarian cancer: placebo-controlled randomized phase III trial (IMagyn050/GOG 3015/ENGOT-OV39). J Clin Oncol 39:1842–1855. https://doi.org/10.1200/jco.21.00306

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  51. Nishio M, Barlesi F, West H et al (2021) Atezolizumab plus chemotherapy for first-line treatment of nonsquamous NSCLC: results from the randomized phase 3 IMpower132 trial. J Thorac Oncol 16:653–664. https://doi.org/10.1016/j.jtho.2020.11.025

    Article  PubMed  CAS  Google Scholar 

  52. Paz-Ares L, Dvorkin M, Chen Y et al (2019) 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. Lancet 394:1929–1939. https://doi.org/10.1016/s0140-6736(19)32222-6

    Article  PubMed  CAS  Google Scholar 

  53. Goldman JW, Dvorkin M, Chen Y et al (2021) 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. Lancet Oncol 22:51–65. https://doi.org/10.1016/s1470-2045(20)30539-8

    Article  PubMed  CAS  Google Scholar 

  54. Planchard D, Reinmuth N, Orlov S et al (2020) ARCTIC: durvalumab with or without tremelimumab as third-line or later treatment of metastatic non-small-cell lung cancer. Ann Oncol 31:609–618. https://doi.org/10.1016/j.annonc.2020.02.006

    Article  PubMed  CAS  Google Scholar 

  55. Powles T, van der Heijden MS, Castellano D et al (2020) Durvalumab alone and durvalumab plus tremelimumab versus chemotherapy in previously untreated patients with unresectable, locally advanced or metastatic urothelial carcinoma (DANUBE): a randomised, open-label, multicentre, phase 3 trial. Lancet Oncol 21:1574–1588. https://doi.org/10.1016/s1470-2045(20)30541-6

    Article  PubMed  CAS  Google Scholar 

  56. Powles T, Park SH, Voog E et al (2020) Avelumab maintenance therapy for advanced or metastatic urothelial carcinoma. N Engl J Med 383:1218–1230. https://doi.org/10.1056/NEJMoa2002788

    Article  PubMed  CAS  Google Scholar 

  57. Powles T, Csőszi T, Özgüroğlu M et al (2021) Pembrolizumab alone or combined with chemotherapy versus chemotherapy as first-line therapy for advanced urothelial carcinoma (KEYNOTE-361): a randomised, open-label, phase 3 trial. Lancet Oncol 22:931–945. https://doi.org/10.1016/s1470-2045(21)00152-2

    Article  PubMed  CAS  Google Scholar 

  58. Pujade-Lauraine E, Fujiwara K, Ledermann JA et al (2021) Avelumab alone or in combination with chemotherapy versus chemotherapy alone in platinum-resistant or platinum-refractory ovarian cancer (JAVELIN Ovarian 200): an open-label, three-arm, randomised, phase 3 study. Lancet Oncol 22:1034–1046. https://doi.org/10.1016/s1470-2045(21)00216-3

    Article  PubMed  CAS  Google Scholar 

  59. Reck M, Luft A, Szczesna A et al (2016) Phase III randomized trial of ipilimumab plus etoposide and platinum versus placebo plus etoposide and platinum in extensive-stage small-cell lung cancer. J Clin Oncol 34:3740–3748. https://doi.org/10.1200/jco.2016.67.6601

    Article  PubMed  CAS  Google Scholar 

  60. Rizvi NA, Cho BC, Reinmuth N et al (2020) Durvalumab with or without tremelimumab vs standard chemotherapy in first-line treatment of metastatic non-small cell lung cancer: the MYSTIC phase 3 randomized clinical trial. JAMA Oncol 6:661–674. https://doi.org/10.1001/jamaoncol.2020.0237

    Article  PubMed  PubMed Central  Google Scholar 

  61. Robert C, Thomas L, Bondarenko I et al (2011) Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med 364:2517–2526. https://doi.org/10.1056/NEJMoa1104621

    Article  PubMed  CAS  Google Scholar 

  62. Rodríguez-Abreu D, Powell SF, Hochmair MJ et al (2021) Pemetrexed plus platinum with or without pembrolizumab in patients with previously untreated metastatic nonsquamous NSCLC: protocol-specified final analysis from KEYNOTE-189. Ann Oncol 32:881–895. https://doi.org/10.1016/j.annonc.2021.04.008

    Article  PubMed  CAS  Google Scholar 

  63. Gandhi L, Rodríguez-Abreu D, Gadgeel S et al (2018) Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N Engl J Med 378:2078–2092. https://doi.org/10.1056/NEJMoa1801005

    Article  PubMed  CAS  Google Scholar 

  64. Rudin CM, Awad MM, Navarro A et al (2020) Pembrolizumab or placebo plus etoposide and platinum as first-line therapy for extensive-stage small-cell lung cancer: randomized, double-blind, phase III KEYNOTE-604 study. J Clin Oncol 38:2369–2379. https://doi.org/10.1200/jco.20.00793

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  65. Schmid P, Rugo HS, Adams S et al (2020) Atezolizumab plus nab-paclitaxel as first-line treatment for unresectable, locally advanced or metastatic triple-negative breast cancer (IMpassion130): updated efficacy results from a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 21:44–59. https://doi.org/10.1016/s1470-2045(19)30689-8

    Article  PubMed  CAS  Google Scholar 

  66. Schmid P, Cortes J, Pusztai L et al (2020) Pembrolizumab for early triple-negative breast cancer. N Engl J Med 382:810–821. https://doi.org/10.1056/NEJMoa1910549

    Article  PubMed  CAS  Google Scholar 

  67. Shitara K, Van Cutsem E, Bang YJ et al (2020) Efficacy and safety of pembrolizumab or pembrolizumab plus chemotherapy vs chemotherapy alone for patients with first-line, advanced gastric cancer: The KEYNOTE-062 phase 3 randomized clinical trial. JAMA Oncol 6:1571–1580. https://doi.org/10.1001/jamaoncol.2020.3370

    Article  PubMed  Google Scholar 

  68. Socinski MA, Jotte RM, Cappuzzo F et al (2018) Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC. N Engl J Med 378:2288–2301. https://doi.org/10.1056/NEJMoa1716948

    Article  PubMed  CAS  Google Scholar 

  69. Sugawara S, Lee JS, Kang JH et al (2021) Nivolumab with carboplatin, paclitaxel, and bevacizumab for first-line treatment of advanced nonsquamous non-small-cell lung cancer. Ann Oncol 32:1137–1147. https://doi.org/10.1016/j.annonc.2021.06.004

    Article  PubMed  CAS  Google Scholar 

  70. West H, McCleod M, Hussein M et al (2019) Atezolizumab in combination with carboplatin plus nab-paclitaxel chemotherapy compared with chemotherapy alone as first-line treatment for metastatic non-squamous non-small-cell lung cancer (IMpower130): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol 20:924–937. https://doi.org/10.1016/s1470-2045(19)30167-6

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

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Funding

This research was not supported by a specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

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Authors and Affiliations

  1. Department of Medicine, Icahn School of Medicine at Mount Sinai, Mount Sinai Beth Israel, 281 First Avenue, New York, NY, 10003, USA

    Yu Fujiwara, Matthew Harrington & Hirotaka Miyashita

  2. Chemotherapy Center, Yokohama City University Hospital, 3-9 Fukuura, Kanazawa-ku, Yokohama, 236-0004, Japan

    Nobuyuki Horita

  3. Department of Infectious Diseases, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan

    Ho Namkoong

  4. The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, 1470 Madison Avenue, New York, NY, 10029-6542, USA

    Matthew D. Galsky

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  1. Yu Fujiwara
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Contributions

YF had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: YF, NH, HN. Acquisition, analysis, or interpretation of data: All authors. Drafting of the manuscript: YF, NH, MH. Critical revision and final approval of the manuscript: All authors. Supervision: NH, MH, MDG.

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Correspondence to Yu Fujiwara.

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None of the authors have a conflict of interest to report for the submitted work. M.D.G. reports stock from Rappta Therapeutics; a consulting/advisory role for BioMotiv, Janssen, Dendreon, Merck, GlaxoSmithKline, Lilly, Astellas Pharma, Genentech, Bristol-Myers Squibb, Novartis, Pfizer, EMD Serono, AstraZeneca, Seattle Genetics, Incyte, Aileron Therapeutics, Dracen, Inovio Pharmaceuticals, NuMab, Dragonfly Therapeutics, Basilea, Urogen, Infinity Pharmaceuticals, and Gilead; and institutional research funding from Janssen Oncology, Dendreon, Novartis, Bristol-Myers Squibb, Merck, AstraZeneca, and Genentech/Roche.

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Fujiwara, Y., Horita, N., Harrington, M. et al. Incidence of hepatotoxicity associated with addition of immune checkpoint blockade to systemic solid tumor therapy: a meta-analysis of phase 3 randomized controlled trials. Cancer Immunol Immunother 71, 2837–2848 (2022). https://doi.org/10.1007/s00262-022-03203-7

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