Responsiveness to immune checkpoint inhibitors versus other systemic therapies in RET-aberrant malignancies
Purpose The receptor tyrosine kinase rearranged during transfection (RET) can be oncogenically activated by gene fusions or point mutations. Multikinase inhibitors such as cabozantinib, lenvatinib and vandetanib have demonstrated activity in RET-dependent malignancies, and selective RET inhibitors (...
Main Authors: | , , , , , , , , , , , , , , , , , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
Elsevier
2020-10-01
|
Series: | ESMO Open |
Online Access: | https://esmoopen.bmj.com/content/5/5/e000799.full |
id |
doaj-c90d0d405f934390885cdc8e42bce7c6 |
---|---|
record_format |
Article |
spelling |
doaj-c90d0d405f934390885cdc8e42bce7c62021-04-02T20:44:56ZengElsevierESMO Open2059-70292020-10-015510.1136/esmoopen-2020-000799Responsiveness to immune checkpoint inhibitors versus other systemic therapies in RET-aberrant malignanciesJessica Lee0Vivek Subbiah1Shuang Liu2Jason Roszik3David Hong4Funda Meric-Bernstam5John Heymach6Ramona Dadu7Kenneth Hess8Le Huang9Aparna Hegde10Alexander Y Andreev-Drakhlin11Maria Cabanillas12Mimi I Hu13Naifa L Busaidy14Steven I Sherman15Elizabeth G Grubbs16Siraj M Ali17Yasir Y Elamin18George R Simon19George R Blumenschein, Jr20Vassiliki A Papadimitrakopoulou21Department of Clinical Development, Foundation Medicine Inc, Cambridge, Massachusetts, USAMD Anderson Cancer Center, Houston, TX, USADepartment of Investigational Cancer Therapeutics, UTMDACC, Houston, Texas, USADepartment of Melanoma Medical Oncology, UTMDACC, Houston, Texas, USA1MD Anderson Cancer Center, Houston, TX, USAMD Anderson Cancer Center, Houston, TX, USAThe University of Texas MD Anderson Cancer Center, Houston, TX, USADepartment of Endocrine Neoplasia and Hormonal Disorders, UTMDACC, Houston, Texas, USADepartment of Biostatistics, UTMDACC, Houston, Texas, USADepartment of Investigational Cancer Therapeutics, UTMDACC, Houston, Texas, USADepartment of Hematology Oncology, The University of Alabama at Birmingham, Birmingham, Alabama, USADepartment of Hematology Oncology, UTMDACC, Houston, Texas, USADepartment of Endocrine Neoplasia and Hormonal Disorders, UTMDACC, Houston, Texas, USADepartment of Endocrine Neoplasia and Hormonal Disorders, UTMDACC, Houston, Texas, USADepartment of Endocrine Neoplasia and Hormonal Disorders, UTMDACC, Houston, Texas, USADepartment of Endocrine Neoplasia and Hormonal Disorders, UTMDACC, Houston, Texas, USADepartment of Surgical Oncology, UTMDACC, Houston, Texas, USADepartment of Clinical Development, Foundation Medicine Inc, Cambridge, Massachusetts, USADepartment of Thoracic Head and Neck Medical Oncology, UTMDACC, Houston, Texas, USADepartment of Thoracic Head and Neck Medical Oncology, UTMDACC, Houston, Texas, USADepartment of Thoracic Head and Neck Medical Oncology, UTMDACC, Houston, Texas, USADepartment of Thoracic Head and Neck Medical Oncology, UTMDACC, Houston, Texas, USAPurpose The receptor tyrosine kinase rearranged during transfection (RET) can be oncogenically activated by gene fusions or point mutations. Multikinase inhibitors such as cabozantinib, lenvatinib and vandetanib have demonstrated activity in RET-dependent malignancies, and selective RET inhibitors (Selpercatinib and Pralsetinib) are in clinical trials. However, the responsiveness of RET-dependent malignancies to immune checkpoint inhibitors (ICIs) is unknown. We compared the time to treatment discontinuation (TTD) for ICI versus non-ICI therapy in patients with malignancies harbouring activating RET mutations or fusions (RET+).Methods A retrospective review of all RET+ patients who were referred to the phase I clinical trials programme at the University of Texas MD Anderson Cancer Center was conducted. TTD was estimated using Kaplan-Meier analysis. Multivariate analysis using the Cox proportional hazard model was performed to identify independent risk factors of treatment discontinuation.Results Of 70 patients who received systemic therapy for RET+ malignancies, 20 (28.6%) received ICI and 50 (71.4%) received non-ICI therapy. Non-ICI therapy was associated with decreased risk for treatment discontinuation compared with ICI in the overall population (HR=0.31; 95% CI 0.16–0.62; p=0.000834) and in patients with RET point mutations (HR=0.13; 95% CI 0.04–0.45; p=0.00134). In patients with RET fusions, non-ICI therapy was associated with a non-statistically significant decreased risk of treatment discontinuation (HR=0.59; 95% CI 0.25–1.4; p=0.24). ICI therapy and a diagnosis other than medullary thyroid cancer (MTC) were independent risk factors for treatment discontinuation.Conclusion Our study supports the prioritisation of non-ICI over ICI therapy in patients with RET+ tumours.https://esmoopen.bmj.com/content/5/5/e000799.full |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Jessica Lee Vivek Subbiah Shuang Liu Jason Roszik David Hong Funda Meric-Bernstam John Heymach Ramona Dadu Kenneth Hess Le Huang Aparna Hegde Alexander Y Andreev-Drakhlin Maria Cabanillas Mimi I Hu Naifa L Busaidy Steven I Sherman Elizabeth G Grubbs Siraj M Ali Yasir Y Elamin George R Simon George R Blumenschein, Jr Vassiliki A Papadimitrakopoulou |
spellingShingle |
Jessica Lee Vivek Subbiah Shuang Liu Jason Roszik David Hong Funda Meric-Bernstam John Heymach Ramona Dadu Kenneth Hess Le Huang Aparna Hegde Alexander Y Andreev-Drakhlin Maria Cabanillas Mimi I Hu Naifa L Busaidy Steven I Sherman Elizabeth G Grubbs Siraj M Ali Yasir Y Elamin George R Simon George R Blumenschein, Jr Vassiliki A Papadimitrakopoulou Responsiveness to immune checkpoint inhibitors versus other systemic therapies in RET-aberrant malignancies ESMO Open |
author_facet |
Jessica Lee Vivek Subbiah Shuang Liu Jason Roszik David Hong Funda Meric-Bernstam John Heymach Ramona Dadu Kenneth Hess Le Huang Aparna Hegde Alexander Y Andreev-Drakhlin Maria Cabanillas Mimi I Hu Naifa L Busaidy Steven I Sherman Elizabeth G Grubbs Siraj M Ali Yasir Y Elamin George R Simon George R Blumenschein, Jr Vassiliki A Papadimitrakopoulou |
author_sort |
Jessica Lee |
title |
Responsiveness to immune checkpoint inhibitors versus other systemic therapies in RET-aberrant malignancies |
title_short |
Responsiveness to immune checkpoint inhibitors versus other systemic therapies in RET-aberrant malignancies |
title_full |
Responsiveness to immune checkpoint inhibitors versus other systemic therapies in RET-aberrant malignancies |
title_fullStr |
Responsiveness to immune checkpoint inhibitors versus other systemic therapies in RET-aberrant malignancies |
title_full_unstemmed |
Responsiveness to immune checkpoint inhibitors versus other systemic therapies in RET-aberrant malignancies |
title_sort |
responsiveness to immune checkpoint inhibitors versus other systemic therapies in ret-aberrant malignancies |
publisher |
Elsevier |
series |
ESMO Open |
issn |
2059-7029 |
publishDate |
2020-10-01 |
description |
Purpose The receptor tyrosine kinase rearranged during transfection (RET) can be oncogenically activated by gene fusions or point mutations. Multikinase inhibitors such as cabozantinib, lenvatinib and vandetanib have demonstrated activity in RET-dependent malignancies, and selective RET inhibitors (Selpercatinib and Pralsetinib) are in clinical trials. However, the responsiveness of RET-dependent malignancies to immune checkpoint inhibitors (ICIs) is unknown. We compared the time to treatment discontinuation (TTD) for ICI versus non-ICI therapy in patients with malignancies harbouring activating RET mutations or fusions (RET+).Methods A retrospective review of all RET+ patients who were referred to the phase I clinical trials programme at the University of Texas MD Anderson Cancer Center was conducted. TTD was estimated using Kaplan-Meier analysis. Multivariate analysis using the Cox proportional hazard model was performed to identify independent risk factors of treatment discontinuation.Results Of 70 patients who received systemic therapy for RET+ malignancies, 20 (28.6%) received ICI and 50 (71.4%) received non-ICI therapy. Non-ICI therapy was associated with decreased risk for treatment discontinuation compared with ICI in the overall population (HR=0.31; 95% CI 0.16–0.62; p=0.000834) and in patients with RET point mutations (HR=0.13; 95% CI 0.04–0.45; p=0.00134). In patients with RET fusions, non-ICI therapy was associated with a non-statistically significant decreased risk of treatment discontinuation (HR=0.59; 95% CI 0.25–1.4; p=0.24). ICI therapy and a diagnosis other than medullary thyroid cancer (MTC) were independent risk factors for treatment discontinuation.Conclusion Our study supports the prioritisation of non-ICI over ICI therapy in patients with RET+ tumours. |
url |
https://esmoopen.bmj.com/content/5/5/e000799.full |
work_keys_str_mv |
AT jessicalee responsivenesstoimmunecheckpointinhibitorsversusothersystemictherapiesinretaberrantmalignancies AT viveksubbiah responsivenesstoimmunecheckpointinhibitorsversusothersystemictherapiesinretaberrantmalignancies AT shuangliu responsivenesstoimmunecheckpointinhibitorsversusothersystemictherapiesinretaberrantmalignancies AT jasonroszik responsivenesstoimmunecheckpointinhibitorsversusothersystemictherapiesinretaberrantmalignancies AT davidhong responsivenesstoimmunecheckpointinhibitorsversusothersystemictherapiesinretaberrantmalignancies AT fundamericbernstam responsivenesstoimmunecheckpointinhibitorsversusothersystemictherapiesinretaberrantmalignancies AT johnheymach responsivenesstoimmunecheckpointinhibitorsversusothersystemictherapiesinretaberrantmalignancies AT ramonadadu responsivenesstoimmunecheckpointinhibitorsversusothersystemictherapiesinretaberrantmalignancies AT kennethhess responsivenesstoimmunecheckpointinhibitorsversusothersystemictherapiesinretaberrantmalignancies AT lehuang responsivenesstoimmunecheckpointinhibitorsversusothersystemictherapiesinretaberrantmalignancies AT aparnahegde responsivenesstoimmunecheckpointinhibitorsversusothersystemictherapiesinretaberrantmalignancies AT alexanderyandreevdrakhlin responsivenesstoimmunecheckpointinhibitorsversusothersystemictherapiesinretaberrantmalignancies AT mariacabanillas responsivenesstoimmunecheckpointinhibitorsversusothersystemictherapiesinretaberrantmalignancies AT mimiihu responsivenesstoimmunecheckpointinhibitorsversusothersystemictherapiesinretaberrantmalignancies AT naifalbusaidy responsivenesstoimmunecheckpointinhibitorsversusothersystemictherapiesinretaberrantmalignancies AT stevenisherman responsivenesstoimmunecheckpointinhibitorsversusothersystemictherapiesinretaberrantmalignancies AT elizabethggrubbs responsivenesstoimmunecheckpointinhibitorsversusothersystemictherapiesinretaberrantmalignancies AT sirajmali responsivenesstoimmunecheckpointinhibitorsversusothersystemictherapiesinretaberrantmalignancies AT yasiryelamin responsivenesstoimmunecheckpointinhibitorsversusothersystemictherapiesinretaberrantmalignancies AT georgersimon responsivenesstoimmunecheckpointinhibitorsversusothersystemictherapiesinretaberrantmalignancies AT georgerblumenscheinjr responsivenesstoimmunecheckpointinhibitorsversusothersystemictherapiesinretaberrantmalignancies AT vassilikiapapadimitrakopoulou responsivenesstoimmunecheckpointinhibitorsversusothersystemictherapiesinretaberrantmalignancies |
_version_ |
1721546671252307968 |