Association of immune-related adverse events with the outcomes of immune checkpoint inhibitors in patients with dMMR/MSI-H metastatic colorectal cancer
Background Immune checkpoint inhibitors (ICIs) show a tremendous activity in microsatellite instability-high (MSI-H) metastatic colorectal cancer (mCRC), but a consistent fraction of patients does not respond. Prognostic/predictive markers are needed. Despite previous investigations in other tumor t...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMJ Publishing Group
2023-01-01
|
| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/11/1/e005493.full |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1832582690732244992 |
|---|---|
| author | Chiara Cremolini Sara Lonardi Filippo Pietrantonio Francesca Corti Elisabetta Fenocchio Massimiliano Salati Margherita Ambrosini Michael J Overman Lisa Salvatore Rossana Intini Priya Jayachandran Javier Ros Maria Elena Elez Marwan Fakih Aakash Tushar Shah Rosalba Miceli Monica Niger Vincenzo Nasca Giacomo Mazzoli Francesco Barretta |
| author_facet | Chiara Cremolini Sara Lonardi Filippo Pietrantonio Francesca Corti Elisabetta Fenocchio Massimiliano Salati Margherita Ambrosini Michael J Overman Lisa Salvatore Rossana Intini Priya Jayachandran Javier Ros Maria Elena Elez Marwan Fakih Aakash Tushar Shah Rosalba Miceli Monica Niger Vincenzo Nasca Giacomo Mazzoli Francesco Barretta |
| author_sort | Chiara Cremolini |
| collection | DOAJ |
| description | Background Immune checkpoint inhibitors (ICIs) show a tremendous activity in microsatellite instability-high (MSI-H) metastatic colorectal cancer (mCRC), but a consistent fraction of patients does not respond. Prognostic/predictive markers are needed. Despite previous investigations in other tumor types, immune-related adverse events (irAEs) have not been well evaluated in patients with MSI-H cancers treated with ICIs.Methods We conducted an international cohort study at tertiary cancer centers collecting clinic-pathological features from 331 patients with MSI-H mCRC treated with ICIs. Of note, the irAEs were summarized using a ‘burden score’ constructed in a way that the same score value could be obtained by cumulating many low-grade irAEs or few high-grade irAEs; as a result, the lower the burden the better. Clearly, the irAE burden is not a baseline information, thus it was modeled as a time-dependent variable in univariable and multivariable Cox models.Results Among 331 patients, irAEs were reported in 144 (43.5%) patients. After a median follow-up time of 29.7 months, patients with higher burden of skin, endocrine and musculoskeletal irAEs (the latter two’s effect was confirmed at multivariable analysis) had longer overall survival (OS), as opposed to gastrointestinal, pneumonitis, neurological, liver, renal and other irAEs, which showed an harmful effect. Similar results were observed for progression-free survival (PFS). Based on the results retrieved from organ-specific irAEs, ‘aggregated’ burden scores were developed to distinguish ‘protective’ (endocrine and musculoskeletal) and ‘harmful’ (gastrointestinal, pneumonitis, neurological, hepatic) irAEs showing prognostic effects on OS and PFS.Conclusions Our results demonstrate that not all irAEs could exert a protective effect on oncologic outcome. An easy-to-use model for ICIs toxicity (burden score of protective and harmful irAEs) may be used as surrogate marker of response. |
| format | Article |
| id | doaj-art-7d567d1042404b5e91439f87cbff2736 |
| institution | Kabale University |
| issn | 2051-1426 |
| language | English |
| publishDate | 2023-01-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-7d567d1042404b5e91439f87cbff27362025-01-29T12:35:12ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262023-01-0111110.1136/jitc-2022-005493Association of immune-related adverse events with the outcomes of immune checkpoint inhibitors in patients with dMMR/MSI-H metastatic colorectal cancerChiara Cremolini0Sara Lonardi1Filippo Pietrantonio2Francesca Corti3Elisabetta Fenocchio4Massimiliano Salati5Margherita Ambrosini6Michael J Overman7Lisa Salvatore8Rossana Intini9Priya Jayachandran10Javier Ros11Maria Elena Elez12Marwan Fakih13Aakash Tushar Shah14Rosalba Miceli15Monica Niger16Vincenzo Nasca17Giacomo Mazzoli18Francesco Barretta19Unit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, Pisa, ItalyDepartment of Oncology, Veneto Institute of Oncology IOV-IRCSS, Padova, ItalyDepartment of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, ItalyDepartment of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, ItalyMultidisciplinary Outpatient Oncology Clinic, Candiolo Cancer Institute FPO-IRCCS, Candiolo, ItalyDivision of Oncology, Department of Oncology and Hematology, University Hospital of Modena, PhD Clinical and Experimental Medicine (CEM), University of Modena and Reggio Emilia, Modena, ItalyDepartment of Medical Oncology, IRCCS Fondazione Istituto Nazionale dei Tumori, Milano, Italy6The University of Texas MD Anderson Cancer Center, Houston, TX, USAOncologia Medica, Università Cattolica del Sacro Cuore, Roma, ItalyMedical Oncology 1, Istituto Oncologico Veneto IOV-IRCCS, Padua, Italy1 Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California, USAHospital Vall Hebron, Vall d`Hebron University Hospital, Barcelona, SpainDepartment of Medical Oncology, Vall d`Hebron Barcelona Hospital Campus, Vall d`Hebron Institute of Oncology (VHIO), Universitat Autonoma de Barcelona, Barcelona, SpainDepartment of Medical Oncology, City of Hope Comprehensive Cancer Center, Duarte, California, USABaylor College of Medicine, Houston, Texas, USAUnit of Clinical Epidemiology and Trial Organization, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, ItalyDepartment of Medical Oncology, IRCCS Fondazione Istituto Nazionale dei Tumori, Milano, ItalyDepartment of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, ItalyDepartment of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, ItalyUnit of Clinical Epidemiology and Trial Organization, IRCCS Fondazione Istituto Nazionale dei Tumori, Milano, ItalyBackground Immune checkpoint inhibitors (ICIs) show a tremendous activity in microsatellite instability-high (MSI-H) metastatic colorectal cancer (mCRC), but a consistent fraction of patients does not respond. Prognostic/predictive markers are needed. Despite previous investigations in other tumor types, immune-related adverse events (irAEs) have not been well evaluated in patients with MSI-H cancers treated with ICIs.Methods We conducted an international cohort study at tertiary cancer centers collecting clinic-pathological features from 331 patients with MSI-H mCRC treated with ICIs. Of note, the irAEs were summarized using a ‘burden score’ constructed in a way that the same score value could be obtained by cumulating many low-grade irAEs or few high-grade irAEs; as a result, the lower the burden the better. Clearly, the irAE burden is not a baseline information, thus it was modeled as a time-dependent variable in univariable and multivariable Cox models.Results Among 331 patients, irAEs were reported in 144 (43.5%) patients. After a median follow-up time of 29.7 months, patients with higher burden of skin, endocrine and musculoskeletal irAEs (the latter two’s effect was confirmed at multivariable analysis) had longer overall survival (OS), as opposed to gastrointestinal, pneumonitis, neurological, liver, renal and other irAEs, which showed an harmful effect. Similar results were observed for progression-free survival (PFS). Based on the results retrieved from organ-specific irAEs, ‘aggregated’ burden scores were developed to distinguish ‘protective’ (endocrine and musculoskeletal) and ‘harmful’ (gastrointestinal, pneumonitis, neurological, hepatic) irAEs showing prognostic effects on OS and PFS.Conclusions Our results demonstrate that not all irAEs could exert a protective effect on oncologic outcome. An easy-to-use model for ICIs toxicity (burden score of protective and harmful irAEs) may be used as surrogate marker of response.https://jitc.bmj.com/content/11/1/e005493.full |
| spellingShingle | Chiara Cremolini Sara Lonardi Filippo Pietrantonio Francesca Corti Elisabetta Fenocchio Massimiliano Salati Margherita Ambrosini Michael J Overman Lisa Salvatore Rossana Intini Priya Jayachandran Javier Ros Maria Elena Elez Marwan Fakih Aakash Tushar Shah Rosalba Miceli Monica Niger Vincenzo Nasca Giacomo Mazzoli Francesco Barretta Association of immune-related adverse events with the outcomes of immune checkpoint inhibitors in patients with dMMR/MSI-H metastatic colorectal cancer Journal for ImmunoTherapy of Cancer |
| title | Association of immune-related adverse events with the outcomes of immune checkpoint inhibitors in patients with dMMR/MSI-H metastatic colorectal cancer |
| title_full | Association of immune-related adverse events with the outcomes of immune checkpoint inhibitors in patients with dMMR/MSI-H metastatic colorectal cancer |
| title_fullStr | Association of immune-related adverse events with the outcomes of immune checkpoint inhibitors in patients with dMMR/MSI-H metastatic colorectal cancer |
| title_full_unstemmed | Association of immune-related adverse events with the outcomes of immune checkpoint inhibitors in patients with dMMR/MSI-H metastatic colorectal cancer |
| title_short | Association of immune-related adverse events with the outcomes of immune checkpoint inhibitors in patients with dMMR/MSI-H metastatic colorectal cancer |
| title_sort | association of immune related adverse events with the outcomes of immune checkpoint inhibitors in patients with dmmr msi h metastatic colorectal cancer |
| url | https://jitc.bmj.com/content/11/1/e005493.full |
| work_keys_str_mv | AT chiaracremolini associationofimmunerelatedadverseeventswiththeoutcomesofimmunecheckpointinhibitorsinpatientswithdmmrmsihmetastaticcolorectalcancer AT saralonardi associationofimmunerelatedadverseeventswiththeoutcomesofimmunecheckpointinhibitorsinpatientswithdmmrmsihmetastaticcolorectalcancer AT filippopietrantonio associationofimmunerelatedadverseeventswiththeoutcomesofimmunecheckpointinhibitorsinpatientswithdmmrmsihmetastaticcolorectalcancer AT francescacorti associationofimmunerelatedadverseeventswiththeoutcomesofimmunecheckpointinhibitorsinpatientswithdmmrmsihmetastaticcolorectalcancer AT elisabettafenocchio associationofimmunerelatedadverseeventswiththeoutcomesofimmunecheckpointinhibitorsinpatientswithdmmrmsihmetastaticcolorectalcancer AT massimilianosalati associationofimmunerelatedadverseeventswiththeoutcomesofimmunecheckpointinhibitorsinpatientswithdmmrmsihmetastaticcolorectalcancer AT margheritaambrosini associationofimmunerelatedadverseeventswiththeoutcomesofimmunecheckpointinhibitorsinpatientswithdmmrmsihmetastaticcolorectalcancer AT michaeljoverman associationofimmunerelatedadverseeventswiththeoutcomesofimmunecheckpointinhibitorsinpatientswithdmmrmsihmetastaticcolorectalcancer AT lisasalvatore associationofimmunerelatedadverseeventswiththeoutcomesofimmunecheckpointinhibitorsinpatientswithdmmrmsihmetastaticcolorectalcancer AT rossanaintini associationofimmunerelatedadverseeventswiththeoutcomesofimmunecheckpointinhibitorsinpatientswithdmmrmsihmetastaticcolorectalcancer AT priyajayachandran associationofimmunerelatedadverseeventswiththeoutcomesofimmunecheckpointinhibitorsinpatientswithdmmrmsihmetastaticcolorectalcancer AT javierros associationofimmunerelatedadverseeventswiththeoutcomesofimmunecheckpointinhibitorsinpatientswithdmmrmsihmetastaticcolorectalcancer AT mariaelenaelez associationofimmunerelatedadverseeventswiththeoutcomesofimmunecheckpointinhibitorsinpatientswithdmmrmsihmetastaticcolorectalcancer AT marwanfakih associationofimmunerelatedadverseeventswiththeoutcomesofimmunecheckpointinhibitorsinpatientswithdmmrmsihmetastaticcolorectalcancer AT aakashtusharshah associationofimmunerelatedadverseeventswiththeoutcomesofimmunecheckpointinhibitorsinpatientswithdmmrmsihmetastaticcolorectalcancer AT rosalbamiceli associationofimmunerelatedadverseeventswiththeoutcomesofimmunecheckpointinhibitorsinpatientswithdmmrmsihmetastaticcolorectalcancer AT monicaniger associationofimmunerelatedadverseeventswiththeoutcomesofimmunecheckpointinhibitorsinpatientswithdmmrmsihmetastaticcolorectalcancer AT vincenzonasca associationofimmunerelatedadverseeventswiththeoutcomesofimmunecheckpointinhibitorsinpatientswithdmmrmsihmetastaticcolorectalcancer AT giacomomazzoli associationofimmunerelatedadverseeventswiththeoutcomesofimmunecheckpointinhibitorsinpatientswithdmmrmsihmetastaticcolorectalcancer AT francescobarretta associationofimmunerelatedadverseeventswiththeoutcomesofimmunecheckpointinhibitorsinpatientswithdmmrmsihmetastaticcolorectalcancer |