TY - JOUR
T1 - A Phase 2 Trial of Enhancing Immune Checkpoint Blockade by Stereotactic Radiation and In Situ Virus Gene Therapy in Metastatic Triple-Negative Breast Cancer
AU - Sun, Kai
AU - Xu, Yitian
AU - Zhang, Licheng
AU - Niravath, Polly
AU - Darcourt, Jorge
AU - Patel, Tejal
AU - Teh, Bin S.
AU - Farach, Andrew M.
AU - Guerrero, Carlo
AU - Mathur, Sunil
AU - Sultenfuss, Mark A.
AU - Gupta, Nakul
AU - Schwartz, Mary R.
AU - Haley, Susan L.
AU - Nair, Sindhu
AU - Li, Xiaoxian
AU - Nguyen, Thi Truc Anh
AU - Butner, Joseph D.
AU - Ensor, Joe
AU - Mejia, Jaime A.
AU - Mei, Zhuyong
AU - Butler, E. Brian
AU - Chen, Shu Hsia
AU - Bernicker, Eric H.
AU - Chang, Jenny C.
N1 - Funding Information:
P. Niravath reports grants from Merck during the conduct of the study. N. Gupta reports grants and non-financial support from Siemens Healthineers, as well as personal fees and non-financial support from GE Healthcare outside the submitted work. J.A. Mejia reports grants from Merck Research Labs during the conduct of the study, as well as other support from Merck Research Labs outside the submitted work. E.H. Bernicker reports personal fees from Blueprint Medicine, as well as grants from Genentech outside the submitted work. J.C. Chang is the sole inventor on patent application no. 10420838 entitled “Methods for treating cancer using iNOS-inhibitory compositions” held by Houston Methodist Hospital. No disclosures were reported by the other authors.
Funding Information:
The clinical trial was supported by Merck Sharp & Dohme Corp. The authors would like to acknowledge Dr. Mary and Ron Neal for their generous financial support; Drs. H. Heslop and M. Brenner for their input in this research.
Publisher Copyright:
© 2022 The Authors.
PY - 2022/10/14
Y1 - 2022/10/14
N2 - PURPOSE: A Phase 2 trial of stereotactic radiotherapy and in situ cytotoxic virus therapy in patients with metastatic triple-negative breast cancer (mTNBC) followed by pembrolizumab (STOMP) was designed to evaluate dual approach of enhancing single-agent immune checkpoint blockade with adenovirus-mediated expression of herpes-simplex-virus thymidine-kinase (ADV/HSV-tk) plus valacyclovir gene therapy and stereotactic body radiotherapy (SBRT) in patients with mTNBC. PATIENTS AND METHODS: In this single-arm, open-label Phase 2 trial, patients with mTNBC were treated with ADV/HSV-tk [5 × 1011 virus particles (vp)] intratumoral injection, followed by SBRT to the injected tumor site, then pembrolizumab (200 mg, every 3 weeks). The primary endpoint was clinical benefit rate [CBR; complete response (CR), partial response (PR), or stable disease (SD) ≥ 24 weeks per RECIST version1.1 at non-irradiated site]. Secondary endpoints included duration on treatment (DoT), overall survival (OS), and safety. Exploratory endpoints included immune response to treatment assessed by correlative tissue and blood-based biomarkers. RESULTS: Twenty-eight patients were enrolled and treated. CBR was seen in 6 patients (21.4%), including 2 CR (7.1%), 1 PR (3.6%), and 3 SD (10.7%). Patients with clinical benefit had durable responses, with median DoT of 9.6 months and OS of 14.7 months. The median OS was 6.6 months in the total population. The combination was well tolerated. Correlative studies with Cytometry by Time of Flight (CyTOF) and imaging mass cytometry (IMC) revealed a significant increase of CD8 T cells in responders and of myeloid cells in non-responders. CONCLUSIONS: The median OS increased by more than 2-fold in patients with clinical benefit. The therapy is a well-tolerated treatment in heavily pretreated patients with mTNBC. Early detection of increased effector and effector memory CD8 T cells and myeloids correlate with response and non-response, respectively.
AB - PURPOSE: A Phase 2 trial of stereotactic radiotherapy and in situ cytotoxic virus therapy in patients with metastatic triple-negative breast cancer (mTNBC) followed by pembrolizumab (STOMP) was designed to evaluate dual approach of enhancing single-agent immune checkpoint blockade with adenovirus-mediated expression of herpes-simplex-virus thymidine-kinase (ADV/HSV-tk) plus valacyclovir gene therapy and stereotactic body radiotherapy (SBRT) in patients with mTNBC. PATIENTS AND METHODS: In this single-arm, open-label Phase 2 trial, patients with mTNBC were treated with ADV/HSV-tk [5 × 1011 virus particles (vp)] intratumoral injection, followed by SBRT to the injected tumor site, then pembrolizumab (200 mg, every 3 weeks). The primary endpoint was clinical benefit rate [CBR; complete response (CR), partial response (PR), or stable disease (SD) ≥ 24 weeks per RECIST version1.1 at non-irradiated site]. Secondary endpoints included duration on treatment (DoT), overall survival (OS), and safety. Exploratory endpoints included immune response to treatment assessed by correlative tissue and blood-based biomarkers. RESULTS: Twenty-eight patients were enrolled and treated. CBR was seen in 6 patients (21.4%), including 2 CR (7.1%), 1 PR (3.6%), and 3 SD (10.7%). Patients with clinical benefit had durable responses, with median DoT of 9.6 months and OS of 14.7 months. The median OS was 6.6 months in the total population. The combination was well tolerated. Correlative studies with Cytometry by Time of Flight (CyTOF) and imaging mass cytometry (IMC) revealed a significant increase of CD8 T cells in responders and of myeloid cells in non-responders. CONCLUSIONS: The median OS increased by more than 2-fold in patients with clinical benefit. The therapy is a well-tolerated treatment in heavily pretreated patients with mTNBC. Early detection of increased effector and effector memory CD8 T cells and myeloids correlate with response and non-response, respectively.
KW - Antineoplastic Combined Chemotherapy Protocols/therapeutic use
KW - Genetic Therapy
KW - Humans
KW - Immune Checkpoint Inhibitors
KW - Radiosurgery
KW - Thymidine/therapeutic use
KW - Thymidine Kinase/genetics
KW - Triple Negative Breast Neoplasms/drug therapy
KW - Valacyclovir/therapeutic use
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U2 - 10.1158/1078-0432.CCR-22-0622
DO - 10.1158/1078-0432.CCR-22-0622
M3 - Article
C2 - 35877117
AN - SCOPUS:85139880701
SN - 1078-0432
VL - 28
SP - 4392
EP - 4401
JO - Clinical cancer research : an official journal of the American Association for Cancer Research
JF - Clinical cancer research : an official journal of the American Association for Cancer Research
IS - 20
ER -