TY - JOUR
T1 - Short-term treatment with multi-drug regimens combining BRAF/MEK-targeted therapy and immunotherapy results in durable responses in Braf-mutated melanoma
AU - White, Michael G.
AU - Szczepaniak Sloane, Robert
AU - Witt, Russell G.
AU - Reuben, Alexandre
AU - Gaudreau, Pierre Olivier
AU - Andrews, Miles C.
AU - Feng, Ningping
AU - Johnson, Sarah
AU - Class, Caleb A.
AU - Bristow, Christopher
AU - Wani, Khalida
AU - Hudgens, Courtney
AU - Nezi, Luigi
AU - Manzo, Teresa
AU - De Macedo, Mariana Pettaccia
AU - Hu, Jianhua
AU - Davis, Richard
AU - Jiang, Hong
AU - Prieto, Peter
AU - Burton, Elizabeth
AU - Hwu, Patrick
AU - Tawbi, Hussein
AU - Gershenwald, Jeffrey
AU - Lazar, Alexander J.
AU - Tetzlaff, Michael T.
AU - Overwijk, Willem
AU - Woodman, Scott E.
AU - Cooper, Zachary A.
AU - Marszalek, Joseph R.
AU - Davies, Michael A.
AU - Heffernan, Timothy P.
AU - Wargo, Jennifer A.
N1 - Funding Information:
MCA reports advisory board participation and honoraria from Merck Sharp and Dohme, outside the submitted work. MAD has been a consultant to Roche/Genentech, Array, Novartis, BMS, GlaxoSmithKline (GSK), Sanofi-Aventis, Vaccinex and Apexigen, and he has been the PI of research grants to UT MD Anderson by Roche/Genentech, GSK, Sanofi-Aventis, Merck, Myriad, and Oncothyreon. JEG reports advisory board participation with Merck, Regeneron, BMS, Novartis, and Syndax. AJL reports personal fees from BMS, Novartis, Genentech/Roche, and Merck; personal fees and non-financial support from ArcherDX and Beta-Cat; grants and non-financial support from Medimmune/AstraZeneca and Sanofi; grants, personal fees and non-financial support from Janssen, all outside the submitted work. MTT reports personal fees from Myriad Genetics, Seattle Genetics and Novartis, all outside the submitted work. ZAC is currently an employee of AstraZeneca outside the submitted work. JAW reports speaker fees from Imedex, Dava Oncology, Omniprex, Illumina, Gilead, MedImmune and BMS; consultant/advisor roles or advisory board membership for Roche-Genentech, Novartis, AstraZeneca, GSK, BMS, Merck/MSD, Biothera Pharma, and Microbiome DX; and receives clinical trial support from GSK, Roche-Genentech, BMS, and Novartis, all outside the current work. The remaining authors declare no competing interests.
Funding Information:
This work was supported by a grant from the Cancer Prevention Research Institute of Texas (CPRIT grant RP150030) and by the generous philanthropic contributions to The University of Texas MD Anderson Cancer Center Melanoma Moon Shots Program from the Lyda Hill Foundation. MAD is supported by the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation, the AIM at Melanoma Foundation, the NIH/NCI (1 P50 CA221703-02 and 1U54CA224070-03; MAD), the American Cancer Society and the Melanoma Research Alliance, Cancer Fighters of Houston, the Anne and John Mendelsohn Chair for Cancer Research, and philanthropic contributions to the Melanoma Moon Shots Program of MD Anderson. MCA is supported by a National Health and Medical Research Council of Australia CJ Martin Early Career Fellowship (#1148680; MCA). AR was supported by the Kimberley Clark Foundation Award for Scientific Achievement provided by MD Anderson’s Odyssey Fellowship Program. MGW is supported by National Institutes of Health T32 CA 009599 and the MD Anderson Cancer Center support grant (P30 CA016672). MGW was supported by National Institutes of Health (T32CA009599; MGW) and the MD Anderson Cancer Center support grant (P30 CA016672; MGW). POG was supported by the Fonds de Recherche Québec–Santé’s (FRQS) Resident Physician Health Research Career Training Program (32667; POG). J.A.W. is supported by the National Institutes of Health (1R01CA219896-01A1; JAW), the Melanoma Research Alliance (4022024), American Association for Cancer Research Stand Up To Cancer (SU2C-AACR-IRG-19-17; JAW), and the MD Anderson Melanoma Moonshot Program. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. Finally, the authors would like to thank Jennifer McQuade for her helpful discussions and input. TM
Funding Information:
This work was supported by the Cancer Prevention Research Institute of Texas [RP150030]; the American Association for Cancer Research [SU2C-AACR-IRG-19-17]; National Institutes of Health [T32CA009599]; National Institutes of Health [1R01CA219896-01A1]; National Institutes of Health [1U54CA224070-03]; National Institutes of Health [P30 CA016672]; National Institutes of Health [1 P50 CA221703-02]; Melanoma Research Alliance [4022024]; National Health and Medical Research Council of Australia [1148680]; Fonds de Recherche Qu?bec?Sant? [32667]; Dr. Miriam and Sheldon G. Adelson Medical Research Foundation, the AIM at Melanoma Foundation and the MD Anderson Moon Shots ProgramTM. This work was supported by a grant from the Cancer Prevention Research Institute of Texas (CPRIT grant RP150030) and by the generous philanthropic contributions to The University of Texas MD Anderson Cancer Center Melanoma Moon Shots ProgramTM from the Lyda Hill Foundation. MAD is supported by the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation, the AIM at Melanoma Foundation, the NIH/NCI (1 P50 CA221703-02 and 1U54CA224070-03; MAD), the American Cancer Society and the Melanoma Research Alliance, Cancer Fighters of Houston, the Anne and John Mendelsohn Chair for Cancer Research, and philanthropic contributions to the Melanoma Moon Shots Program of MD Anderson. MCA is supported by a National Health and Medical Research Council of Australia CJ Martin Early Career Fellowship (#1148680; MCA). AR was supported by the Kimberley Clark Foundation Award for Scientific Achievement provided by MD Anderson?s Odyssey Fellowship Program. MGW is supported by National Institutes of Health T32 CA 009599 and the MD Anderson Cancer Center support grant (P30 CA016672). MGW was supported by National Institutes of Health (T32CA009599; MGW) and the MD Anderson Cancer Center support grant (P30 CA016672; MGW). POG was supported by the Fonds de Recherche Qu?bec?Sant??s (FRQS) Resident Physician Health Research Career Training Program (32667; POG). J.A.W. is supported by the National Institutes of Health (1R01CA219896-01A1; JAW), the Melanoma Research Alliance (4022024), American Association for Cancer Research Stand Up To Cancer (SU2C-AACR-IRG-19-17; JAW), and the MD Anderson Melanoma Moonshot Program. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. Finally, the authors would like to thank Jennifer McQuade for her helpful discussions and input.
Publisher Copyright:
© 2021 The Author(s). Published with license by Taylor & Francis Group, LLC.
PY - 2021
Y1 - 2021
N2 - Targeted and immunotherapy regimens have revolutionized the treatment of advanced melanoma patients. Despite this, only a subset of patients respond durably. Recently, combination strategies of BRAF/MEK inhibitors with immune checkpoint inhibitor monotherapy (α-CTLA-4 or α-PD-1) have increased the rate of durable responses. Based on evidence from our group and others, these therapies appear synergistic, but at the cost of significant toxicity. We know from other treatment paradigms (e.g. hematologic malignancies) that combination strategies with multi-drug regimens (>4 drugs) are associated with more durable disease control. To better understand the mechanism of these improved outcomes, and to identify and prioritize new strategies for testing, we studied several multi-drug regimens combining BRAF/MEK targeted therapy and immunotherapy combinations in a Braf-mutant murine melanoma model (BrafV600E/Pten−/−). Short-term treatment with α-PD-1 and α-CTLA-4 monotherapies were relatively ineffective, while treatment with α-OX40 demonstrated some efficacy [17% of mice with no evidence of disease, (NED), at 60-days]. Outcomes were improved in the combined α-OX40/α-PD-1 group (42% NED). Short-term treatment with quadruplet therapy of immunotherapy doublets in combination with targeted therapy [dabrafenib and trametinib (DT)] was associated with excellent tumor control, with 100% of mice having NED after combined DT/α-CTLA-4/α-PD-1 or DT/α-OX40/α-PD-1. Notably, tumors from mice in these groups demonstrated a high proportion of effector memory T cells, and immunologic memory was maintained with tumor re-challenge. Together, these data provide important evidence regarding the potential utility of multi-drug therapy in treating advanced melanoma and suggest these models can be used to guide and prioritize combinatorial treatment strategies.
AB - Targeted and immunotherapy regimens have revolutionized the treatment of advanced melanoma patients. Despite this, only a subset of patients respond durably. Recently, combination strategies of BRAF/MEK inhibitors with immune checkpoint inhibitor monotherapy (α-CTLA-4 or α-PD-1) have increased the rate of durable responses. Based on evidence from our group and others, these therapies appear synergistic, but at the cost of significant toxicity. We know from other treatment paradigms (e.g. hematologic malignancies) that combination strategies with multi-drug regimens (>4 drugs) are associated with more durable disease control. To better understand the mechanism of these improved outcomes, and to identify and prioritize new strategies for testing, we studied several multi-drug regimens combining BRAF/MEK targeted therapy and immunotherapy combinations in a Braf-mutant murine melanoma model (BrafV600E/Pten−/−). Short-term treatment with α-PD-1 and α-CTLA-4 monotherapies were relatively ineffective, while treatment with α-OX40 demonstrated some efficacy [17% of mice with no evidence of disease, (NED), at 60-days]. Outcomes were improved in the combined α-OX40/α-PD-1 group (42% NED). Short-term treatment with quadruplet therapy of immunotherapy doublets in combination with targeted therapy [dabrafenib and trametinib (DT)] was associated with excellent tumor control, with 100% of mice having NED after combined DT/α-CTLA-4/α-PD-1 or DT/α-OX40/α-PD-1. Notably, tumors from mice in these groups demonstrated a high proportion of effector memory T cells, and immunologic memory was maintained with tumor re-challenge. Together, these data provide important evidence regarding the potential utility of multi-drug therapy in treating advanced melanoma and suggest these models can be used to guide and prioritize combinatorial treatment strategies.
KW - checkpoint blockade
KW - immunotherapy
KW - MAP-kinase
KW - Melanoma
KW - OX-40
KW - targeted therapy
KW - toxicity
UR - http://www.scopus.com/inward/record.url?scp=85118827164&partnerID=8YFLogxK
U2 - 10.1080/2162402X.2021.1992880
DO - 10.1080/2162402X.2021.1992880
M3 - Article
C2 - 34777916
AN - SCOPUS:85118827164
VL - 10
JO - OncoImmunology
JF - OncoImmunology
SN - 2162-402X
IS - 1
M1 - 1992880
ER -