Table 1.
Summary of Myocarditis occurrence in clinical trials for immune checkpoint inhibitors.
| Drug | Initial US approval | Labeled indications | Efficacy trial | Drug | Control | Myocarditis incidence |
|---|---|---|---|---|---|---|
| Ipilimumab/YERVOY, CTLA-4 | 2011 |
Unresectable or Metastatic Melanoma, Adjuvant Treatment of Melanoma5 In combination with Nivolumab: Advanced Renal Cell Carcinoma (RCC), Microsatellite Instability-High (MSI-H) or Mismatch Repair Deficient (dMMR) Metastatic Colorectal Cancer, Hepatocellular Carcinoma Metastatic Non-Small Cell Lung Cancer (NSCLC)5 |
Melanoma: MDX010-2012 Metastatic NSCLC: CHECKMATE-22713 |
Ipilimumab monotherapy, Ipilimumab in combination with a melanoma peptide vaccine Nivolumab, or Nivolumab + Ipilimumab, or Nivolumab + Platinum-doublet Chemotherapy |
Melanoma Vaccine Monotherapy Platinum Doublet Chemotherapy |
From prescribing Information in Adjuvant treatment of Melanoma: severe to fatal, 0.2% (CA184-029)a In first-line Treatment of Metastatic NSCLC: In Combination with Nivolumab (CHECKMATE-227)b |
| Pembrolizumab/KEYTRUDA, PD-1 | 2014 | Melanoma, Non-Small Cell Lung Cancer (NSCLC), Head and Neck Squamous Cell Cancer, Classical Hodgkin Lymphoma (cHL), Primary Mediastinal Large B-Cell Lymphoma, Urothelial Carcinoma, Microsatellite Instability-High Cancer, Gastric Cancer, Cervical Cancer, Hepatocellular Carcinoma, Merkel Cell Carcinoma6. In combination with Axitinib: first-line treatment against advanced/metastatic Renal Cell Carcinoma (mRCC) (https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-pembrolizumab-plus-axitinib-advanced-renal-cell-carcinoma) |
Melanoma: KEYNOTE-00614 Classical Hodgkin Lymphoma: Phase II KEYNOTE-08715 mRCC: KEYNOTE-42616 NSCLC: KEYNOTE 18917 NSCLC: KEYNOTE—40718 |
Pembrolizumab Pembrolizumab Pembrolizumab + axitinib Pembrolizumab + pemetrexed + platinum-based chemotherapy Pembrolizumab + carboplatin + paclitaxel or nab-paclitaxel |
Ipilimumab Single arm, Non-randomized Sunitinib Placebo + pemetrexed + platinum-based chemotherapy Placebo + carboplatin + paclitaxel or nab-paclitaxel |
In Classical Hodgkin Lymphoma: 0.5% (KEYNOTE-087)c In mRCC: Of the 11 patients who died from adverse events in the combination group, 1 died from myocarditis |
| Nivolumab/OPDIVO, PD-1 | 2014 | Unresectable or Metastatic Melanoma, Adjuvant Treatment of Melanoma, Metastatic NSCLC, Small Cell Lung Cancer, Advanced RCC, cHL, Squamous Cell Carcinoma of the Head and Neck, Urothelial Carcinoma, Microsatellite Instability-High or Mismatch Repair Deficient Metastatic Colorectal Cancer, Hepatocellular Carcinoma, Esophageal Squamous Cell Carcinoma (ESCC)19 |
Advanced Melanoma: CHECKMATE-03720 Metastatic NSCLC in combination with Ipilimumab: CHECKMATE-22713 |
Nivolumab Nivolumab, or Nivolumab + Ipilimumab, or Nivolumab + Platinum-doublet Chemotherapy |
Either Dacarbazine or Carboplatin and Paclitaxel Platinum Doublet Chemotherapy |
In metastatic NSCLC: (CHECKMATE-227)e |
| Cemiplimab/LIBTAYO, PD-1 | 2018 | Metastatic Cutaneous Squamous Cell Carcinoma (CSCC) or locally advanced CSCC7 | Study 1423 and 154021 | Cemiplimab, Cemiplimab + anti-cancer therapy (radiotherapy, cyclophosphamide, docetaxel, carboplatin, GM-CSF, paclitaxel, pemetrexed) | From prescribing informationf | |
| Atezolizumab/TECENTRIQ, PD-L1 | 2016 | Urothelial Carcinoma, NSCLC, Locally Advanced or Metastatic Triple-Negative Breast Cancer, Small Cell Lung Cancer (SCLC), Hepatocellular Carcinoma8 |
Urothelial Carcinoma: IMvigor21022 Non-squamous NSCLC: Impower15023 |
Atezolizumab Atezolizumab in Combination with Carboplatin + Paclitaxel with or without Bevacizumab |
Carboplatin + paclitaxel + bevacizumab | From prescribing informationg |
| Durvalumab/IMFINZI, PD-L1 | 2017 | Urothelial Carcinoma, NSCLC, SCLC9 |
Urothelial Carcinoma: Study 110824 NSCLC: PACIFIC25 SCLC: CASPIAN26 |
Durvalumab Durvalumab Durvalumab ± tremelimumab with platinum-based chemotherapy (carboplatin or cisplatin + etoposide) |
Placebo Platinum-based chemotherapy |
From prescribing informationh |
| Avelumab/BAVENCIO, PD-L1 | 2017 | Metastatic Merkel Cell Carcinoma, Locally Advanced or Metastatic Urothelial Carcinoma10In combination with Axitinib: first-line for advanced RCC10 |
Metastatic Merkel Cell Carcinoma: JAVELIN Merkel 20027 Urothelial Carcinoma: JAVELIN Solid Tumor28 Advanced RCC in combination with Axitinib: JAVELIN Renal 10111 |
Avelumab Avelumab Avelumab + axitinib |
Sunitinib |
In Advanced RCC in combination with axitinib (JAVELIN Renal 101): 0.2%i From prescribing informationj |
RCC renal cell carcinoma, mRCC metastatic renal cell carcinoma, NSCLC non-small cell lung cancer, SCLC small cell lung cancer, CSCC cutaneous squamous cell carcinoma.
aIn CA184-029, the following clinically significant irAEs were seen in less than 1% of YERVOY-treated patients unless specified: cytopenias, eosinophilia (2.1%), pancreatitis (1.3%), meningitis, pneumonitis, sarcoidosis, pericarditis, uveitis, and fatal myocarditis [see Adverse Reactions (6.1)]5.
bFatal adverse reactions occurred in 1.7% of patients; these included events of pneumonitis (4 patients), myocarditis, acute kidney injury, shock, hyperglycemia, multi- system organ failure, and renal failure5.
cOther clinically important adverse reactions that occurred in less than 10% of patients on KEYNOTE-087 included infusion reactions (9%), hyperthyroidism (3%), pneumonitis (3%), uveitis and myositis (1% each), and myelitis and myocarditis (0.5% each)6.
dOf the 11 patients (2.6%) in the pembrolizumab–axitinib group who died from adverse events, 4 (0.9%) died from treatment-related adverse events (from myasthenia gravis, myocarditis, necrotizing fasciitis, and pneumonitis, in 1 patient each)16.
eFatal adverse reactions occurred in 1.7% of patients; these included events of pneumonitis (4 patients), myocarditis, acute kidney injury, shock, hyperglycemia, multi-system organ failure, and renal failure5.
fLIBTAYO was permanently discontinued due to adverse reactions in 5% of patients; adverse reactions resulting in permanent discontinuation were pneumonitis, autoimmune myocarditis, hepatitis, aseptic meningitis, complex regional pain syndrome, cough, and muscular weakness7.
gThe following clinically significant irAEs occurred at an incidence of < 1% in 2616 patients who received TECENTRIQ as a single-agent and in 2421 patients who received TECENTRIQ in combination with platinum-based chemotherapy or were reported in other products in this class8.
hThe following clinically significant irAEs occurred at an incidence of less than 1% each in 1889 patients who received IMFINZI: aseptic meningitis, hemolytic anemia, immune thrombocytopenic purpura, myocarditis, myositis, and ocular inflammatory toxicity, including uveitis and keratitis9.
iDeath due to toxicity of trial treatment that occurred in 3 patients in the avelumab-plus-axitinib group (0.7%) was attributed to sudden death, myocarditis, and necrotizing pancreatitis11.
jThe following irAEs occurred at an incidence of less than 1% of patients who received BAVENCIO as a single agent or in 489 patients who received BAVENCIO in combination with axitinib: immune-mediated myocarditis including fatal cases, pancreatitis including fatal cases, immune-mediated myositis, psoriasis, arthritis, exfoliative dermatitis, erythema multiforme, pemphigoid, hypopituitarism, uveitis, Guillain-Barré syndrome, and systemic inflammatory response10.