A phase II study of combined therapy with a BRAF inhibitor (vemurafenib) and interleukin-2 (aldesleukin) in patients with metastatic melanoma
Background: Approximately 50% of melanomas harbor BRAF mutations. Treatment with BRAF +/− MEK inhibition is associated with favorable changes in the tumor microenvironment thus providing the rationale for combining targeted agents with immunotherapy. Methods: Patients with unresectable Stage III or...
Main Authors: | , , , , , , , , , , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
Taylor & Francis Group
2018-05-01
|
Series: | OncoImmunology |
Subjects: | |
Online Access: | http://dx.doi.org/10.1080/2162402X.2017.1423172 |
id |
doaj-3495f5ff5acd475a9e7884607e56d256 |
---|---|
record_format |
Article |
spelling |
doaj-3495f5ff5acd475a9e7884607e56d2562020-11-25T03:43:47ZengTaylor & Francis GroupOncoImmunology2162-402X2018-05-017510.1080/2162402X.2017.14231721423172A phase II study of combined therapy with a BRAF inhibitor (vemurafenib) and interleukin-2 (aldesleukin) in patients with metastatic melanomaMeghan J. Mooradian0Alexandre Reuben1Peter A. Prieto2Mehlika Hazar-Rethinam3Dennie T. Frederick4Brandon Nadres5Adriano Piris6Vikram Juneja7Zachary A. Cooper8Arlene H. Sharpe9Ryan B. Corcoran10Keith T. Flaherty11Donald P. Lawrence12Jennifer A. Wargo13Ryan J. Sullivan14Massachusetts General HospitalThe University of Texas MD Anderson Cancer CenterThe University of Texas MD Anderson Cancer CenterMassachusetts General HospitalMassachusetts General HospitalMassachusetts General HospitalHarvard Medical SchoolHarvard Medical SchoolThe University of Texas MD Anderson Cancer CenterHarvard Medical SchoolMassachusetts General HospitalMassachusetts General HospitalMassachusetts General HospitalThe University of Texas MD Anderson Cancer CenterMassachusetts General HospitalBackground: Approximately 50% of melanomas harbor BRAF mutations. Treatment with BRAF +/− MEK inhibition is associated with favorable changes in the tumor microenvironment thus providing the rationale for combining targeted agents with immunotherapy. Methods: Patients with unresectable Stage III or IV BRAFV600E mutant melanoma were enrolled in a single-center prospective study (n = 6). Patients were eligible to receive two courses of HD-IL-2 and vemurafenib twice daily. The primary endpoint was progression-free survival (PFS) with secondary objectives including overall survival (OS), response rates (RR), and safety of combination therapy as compared to historical controls. Immune profiling was performed in longitudinal tissue samples, when available. Results: Overall RR was 83.3% (95% CI: 36%–99%) and 66.6% at 12 weeks. All patients eventually progressed, with three progressing on treatment and three progressing after the vemurafenib continuation phase ended. Median PFS was 35.8 weeks (95% CI: 16–57 weeks). Median OS was not reached; however, the time at which 75% of patients were still alive was 104.4 weeks. Change in circulating BRAFV600E levels correlated with response. Though combination therapy was associated with enhanced CD8 T cell infiltrate, an increase in regulatory T cell frequency was seen with HD-IL-2 administration, suggesting a potential limitation in this strategy. Conclusion: Combination vemurafenib and HD-IL-2 is well tolerated and associated with treatment responses. However, the HD-IL-2 induced increase in Tregs may abrogate potential synergy. Given the efficacy of regimens targeting the PD-1 pathway, strategies combining these regimens with BRAF-targeted therapy are currently underway, and the role of combination vemurafenib and HD-IL-2 is uncertain. Trial Registration: Clinical trial information: NCT01754376; https://clinicaltrials.gov/show/NCT01754376http://dx.doi.org/10.1080/2162402X.2017.1423172melanomabrafil-2combination therapyvemurafenib |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Meghan J. Mooradian Alexandre Reuben Peter A. Prieto Mehlika Hazar-Rethinam Dennie T. Frederick Brandon Nadres Adriano Piris Vikram Juneja Zachary A. Cooper Arlene H. Sharpe Ryan B. Corcoran Keith T. Flaherty Donald P. Lawrence Jennifer A. Wargo Ryan J. Sullivan |
spellingShingle |
Meghan J. Mooradian Alexandre Reuben Peter A. Prieto Mehlika Hazar-Rethinam Dennie T. Frederick Brandon Nadres Adriano Piris Vikram Juneja Zachary A. Cooper Arlene H. Sharpe Ryan B. Corcoran Keith T. Flaherty Donald P. Lawrence Jennifer A. Wargo Ryan J. Sullivan A phase II study of combined therapy with a BRAF inhibitor (vemurafenib) and interleukin-2 (aldesleukin) in patients with metastatic melanoma OncoImmunology melanoma braf il-2 combination therapy vemurafenib |
author_facet |
Meghan J. Mooradian Alexandre Reuben Peter A. Prieto Mehlika Hazar-Rethinam Dennie T. Frederick Brandon Nadres Adriano Piris Vikram Juneja Zachary A. Cooper Arlene H. Sharpe Ryan B. Corcoran Keith T. Flaherty Donald P. Lawrence Jennifer A. Wargo Ryan J. Sullivan |
author_sort |
Meghan J. Mooradian |
title |
A phase II study of combined therapy with a BRAF inhibitor (vemurafenib) and interleukin-2 (aldesleukin) in patients with metastatic melanoma |
title_short |
A phase II study of combined therapy with a BRAF inhibitor (vemurafenib) and interleukin-2 (aldesleukin) in patients with metastatic melanoma |
title_full |
A phase II study of combined therapy with a BRAF inhibitor (vemurafenib) and interleukin-2 (aldesleukin) in patients with metastatic melanoma |
title_fullStr |
A phase II study of combined therapy with a BRAF inhibitor (vemurafenib) and interleukin-2 (aldesleukin) in patients with metastatic melanoma |
title_full_unstemmed |
A phase II study of combined therapy with a BRAF inhibitor (vemurafenib) and interleukin-2 (aldesleukin) in patients with metastatic melanoma |
title_sort |
phase ii study of combined therapy with a braf inhibitor (vemurafenib) and interleukin-2 (aldesleukin) in patients with metastatic melanoma |
publisher |
Taylor & Francis Group |
series |
OncoImmunology |
issn |
2162-402X |
publishDate |
2018-05-01 |
description |
Background: Approximately 50% of melanomas harbor BRAF mutations. Treatment with BRAF +/− MEK inhibition is associated with favorable changes in the tumor microenvironment thus providing the rationale for combining targeted agents with immunotherapy. Methods: Patients with unresectable Stage III or IV BRAFV600E mutant melanoma were enrolled in a single-center prospective study (n = 6). Patients were eligible to receive two courses of HD-IL-2 and vemurafenib twice daily. The primary endpoint was progression-free survival (PFS) with secondary objectives including overall survival (OS), response rates (RR), and safety of combination therapy as compared to historical controls. Immune profiling was performed in longitudinal tissue samples, when available. Results: Overall RR was 83.3% (95% CI: 36%–99%) and 66.6% at 12 weeks. All patients eventually progressed, with three progressing on treatment and three progressing after the vemurafenib continuation phase ended. Median PFS was 35.8 weeks (95% CI: 16–57 weeks). Median OS was not reached; however, the time at which 75% of patients were still alive was 104.4 weeks. Change in circulating BRAFV600E levels correlated with response. Though combination therapy was associated with enhanced CD8 T cell infiltrate, an increase in regulatory T cell frequency was seen with HD-IL-2 administration, suggesting a potential limitation in this strategy. Conclusion: Combination vemurafenib and HD-IL-2 is well tolerated and associated with treatment responses. However, the HD-IL-2 induced increase in Tregs may abrogate potential synergy. Given the efficacy of regimens targeting the PD-1 pathway, strategies combining these regimens with BRAF-targeted therapy are currently underway, and the role of combination vemurafenib and HD-IL-2 is uncertain. Trial Registration: Clinical trial information: NCT01754376; https://clinicaltrials.gov/show/NCT01754376 |
topic |
melanoma braf il-2 combination therapy vemurafenib |
url |
http://dx.doi.org/10.1080/2162402X.2017.1423172 |
work_keys_str_mv |
AT meghanjmooradian aphaseiistudyofcombinedtherapywithabrafinhibitorvemurafenibandinterleukin2aldesleukininpatientswithmetastaticmelanoma AT alexandrereuben aphaseiistudyofcombinedtherapywithabrafinhibitorvemurafenibandinterleukin2aldesleukininpatientswithmetastaticmelanoma AT peteraprieto aphaseiistudyofcombinedtherapywithabrafinhibitorvemurafenibandinterleukin2aldesleukininpatientswithmetastaticmelanoma AT mehlikahazarrethinam aphaseiistudyofcombinedtherapywithabrafinhibitorvemurafenibandinterleukin2aldesleukininpatientswithmetastaticmelanoma AT dennietfrederick aphaseiistudyofcombinedtherapywithabrafinhibitorvemurafenibandinterleukin2aldesleukininpatientswithmetastaticmelanoma AT brandonnadres aphaseiistudyofcombinedtherapywithabrafinhibitorvemurafenibandinterleukin2aldesleukininpatientswithmetastaticmelanoma AT adrianopiris aphaseiistudyofcombinedtherapywithabrafinhibitorvemurafenibandinterleukin2aldesleukininpatientswithmetastaticmelanoma AT vikramjuneja aphaseiistudyofcombinedtherapywithabrafinhibitorvemurafenibandinterleukin2aldesleukininpatientswithmetastaticmelanoma AT zacharyacooper aphaseiistudyofcombinedtherapywithabrafinhibitorvemurafenibandinterleukin2aldesleukininpatientswithmetastaticmelanoma AT arlenehsharpe aphaseiistudyofcombinedtherapywithabrafinhibitorvemurafenibandinterleukin2aldesleukininpatientswithmetastaticmelanoma AT ryanbcorcoran aphaseiistudyofcombinedtherapywithabrafinhibitorvemurafenibandinterleukin2aldesleukininpatientswithmetastaticmelanoma AT keithtflaherty aphaseiistudyofcombinedtherapywithabrafinhibitorvemurafenibandinterleukin2aldesleukininpatientswithmetastaticmelanoma AT donaldplawrence aphaseiistudyofcombinedtherapywithabrafinhibitorvemurafenibandinterleukin2aldesleukininpatientswithmetastaticmelanoma AT jenniferawargo aphaseiistudyofcombinedtherapywithabrafinhibitorvemurafenibandinterleukin2aldesleukininpatientswithmetastaticmelanoma AT ryanjsullivan aphaseiistudyofcombinedtherapywithabrafinhibitorvemurafenibandinterleukin2aldesleukininpatientswithmetastaticmelanoma AT meghanjmooradian phaseiistudyofcombinedtherapywithabrafinhibitorvemurafenibandinterleukin2aldesleukininpatientswithmetastaticmelanoma AT alexandrereuben phaseiistudyofcombinedtherapywithabrafinhibitorvemurafenibandinterleukin2aldesleukininpatientswithmetastaticmelanoma AT peteraprieto phaseiistudyofcombinedtherapywithabrafinhibitorvemurafenibandinterleukin2aldesleukininpatientswithmetastaticmelanoma AT mehlikahazarrethinam phaseiistudyofcombinedtherapywithabrafinhibitorvemurafenibandinterleukin2aldesleukininpatientswithmetastaticmelanoma AT dennietfrederick phaseiistudyofcombinedtherapywithabrafinhibitorvemurafenibandinterleukin2aldesleukininpatientswithmetastaticmelanoma AT brandonnadres phaseiistudyofcombinedtherapywithabrafinhibitorvemurafenibandinterleukin2aldesleukininpatientswithmetastaticmelanoma AT adrianopiris phaseiistudyofcombinedtherapywithabrafinhibitorvemurafenibandinterleukin2aldesleukininpatientswithmetastaticmelanoma AT vikramjuneja phaseiistudyofcombinedtherapywithabrafinhibitorvemurafenibandinterleukin2aldesleukininpatientswithmetastaticmelanoma AT zacharyacooper phaseiistudyofcombinedtherapywithabrafinhibitorvemurafenibandinterleukin2aldesleukininpatientswithmetastaticmelanoma AT arlenehsharpe phaseiistudyofcombinedtherapywithabrafinhibitorvemurafenibandinterleukin2aldesleukininpatientswithmetastaticmelanoma AT ryanbcorcoran phaseiistudyofcombinedtherapywithabrafinhibitorvemurafenibandinterleukin2aldesleukininpatientswithmetastaticmelanoma AT keithtflaherty phaseiistudyofcombinedtherapywithabrafinhibitorvemurafenibandinterleukin2aldesleukininpatientswithmetastaticmelanoma AT donaldplawrence phaseiistudyofcombinedtherapywithabrafinhibitorvemurafenibandinterleukin2aldesleukininpatientswithmetastaticmelanoma AT jenniferawargo phaseiistudyofcombinedtherapywithabrafinhibitorvemurafenibandinterleukin2aldesleukininpatientswithmetastaticmelanoma AT ryanjsullivan phaseiistudyofcombinedtherapywithabrafinhibitorvemurafenibandinterleukin2aldesleukininpatientswithmetastaticmelanoma |
_version_ |
1724518393442205696 |