TY - JOUR
T1 - Pilot clinical trial of perioperative durvalumab and tremelimumab in the treatment of resectable colorectal cancer liver metastases
AU - Marie, Preeti Kanikarla
AU - Haymaker, Cara
AU - Parra, Edwin Roger
AU - Kim, Young Uk
AU - Lazcano, Rossana
AU - Gite, Swati
AU - Lorenzini, Daniele
AU - Wistuba, Ignacio I.
AU - Slack Tidwell, Rebecca S.
AU - Song, Xiaofei
AU - Foo, Wai Chin
AU - Maru, Dipen M.
AU - Chun, Yun Shin
AU - Futreal, Andy
AU - Kee, Bryan
AU - Menter, David
AU - Solis, Luisa
AU - Tzeng, Ching Wei
AU - Parseghian, Christine
AU - Raghav, Kanwal
AU - Morris, Van
AU - Chang, Chia Chi
AU - Jenq, Robert
AU - Tam, Alda
AU - Bernatchez, Chantale
AU - Kopetz, Scott
AU - Vauthey, Jean Nicolas
AU - Overman, Michael J.
N1 - Funding Information:
C. Haymaker reports other from AstraZeneca during the conduct of the study, as well as other from Briacell Therapeutics and Mesothelioma Applied Research Foundation outside the submitted work. I.I. Wistuba reports grants and personal fees from Genentech/Roche, Bayer, Astra Zeneca/MedImmune, Pfizer, HTG Molecular, Merck, and Guardant Health; personal fees from Bristol Myers Squibb, GlaxoSmithKline, Oncocyte, MSD, and Platform Health; and grants from Adaptive, Adaptimmune, EMD Serono, Takeda, 4D, Novartis, Amgen, Karus, Iovance, Akoya, and Johnson & Johnson outside the submitted work. R.S.S. Tidwell reports grants from NIH during the conduct of the study. B. Kee reports grants from MedImmune during the conduct of the study and ownership of Medtronic stock. K. Raghav reports personal fees from Bayer, Daiichi, and AstraZeneca outside the submitted work. V. Morris reports grants from Pfizer, Bristol Myers Squibb, and EMD Serono outside the submitted work. R.R. Jenq reports personal fees from Maat Pharma, Seres Therapeutics, Prolacta Bioscience, and LISCure Biosciences and grants and personal fees from Kaleido Bioscience outside the submitted work. A. Tam reports grants from Guerbet LLC, grants and personal fees from Boston Scientific, and personal fees from Cello Therapeutics and Endocare outside the submitted work. C. Bernatchez reports grants from Astra Zeneca during the conduct of the study, as well as other from Myst Therapeutics and grants and personal fees from Iovance Biotherapeutics outside the submitted work. S. Kopetz reports personal fees from Roche, Genentech, Merck, Karyopharm Therapeutics, Amal Therapeutics, Navire Pharma, Symphogen, Holy Stone, Biocartis, Amgen, Novartis, Lilly, Boehringer Ingelheim, Boston Biomedical, AstraZeneca/MedImmune, Bayer Health, Pierre Fabre, EMD Serono, Redx Pharma, Jacobio, Natera, Repare Therapeutics, Daiichi Sankyo, Lutris, Pfizer, Ipsen, and HalioDx outside the submitted work. M.J. Overman reports grants and personal fees from MedImmune during the conduct of the study. No disclosures were reported by the other authors.
Funding Information:
This work was supported through a Medimmune/AstraZeneca MD Anderson Cancer Center alliance, by the NCI through both the Cancer Center Support Grant P30CA16672 [Institutional Tissue Bank (ITB) and Research Histology Core Laboratory (RHCL)], and SPORE Grant P50CA221707, and supported by the generous philanthropic contributions to The University of Texas MD Anderson Cancer Center Moon Shots Program. Adaptive Patient-Oriented Longitudinal Learning and Optimization (APOLLO) Moonshot Program, Strategic Alliances and the Translational Molecular Pathology-Immunoprofiling lab (TMP-IL) at the Department of Translational Molecular Pathology, the University of Texas MD Anderson Cancer Center, and the NCI Cooperative Agreement U24CA224285 (to the MD Anderson Cancer Center CIMAC).
Publisher Copyright:
© 2021 American Association for Cancer Research.
PY - 2021/6/1
Y1 - 2021/6/1
N2 - Purpose: Despite the prognostic importance of immune infiltrate in colorectal cancer, immunotherapy has demonstrated limited clinical activity in refractory metastatic proficient mismatch-repair (pMMR) colorectal cancer. This study explores combining anti-CTLA-4 and an anti-PD-L1 therapy in the preoperative management of resectable colorectal cancer liver metastases with the intent to improve immune responses in this disease setting. Patients and Methods: Patients with resectable colorectal cancer liver-only metastases received one dose of tremelimumab and durvalumab preoperatively followed by single-agent durvalumab postoperatively. Primary objectives were to determine feasibility and safety. Results: A total of 24 patients were enrolled between November 2016 and November 2019. Twenty-three patients received treatment [21 pMMR and 2 deficient mismatch-repair (dMMR)] and subsequently 17 (74%; 95% CI: 53%-88%) underwent surgical resection. Grade 3/4 treatment-related immune toxicity and postoperative grade 3/4 toxicity were seen in 5/23 (22%; 95% CI: 10%-44%) and 2/17 (12%; 95% CI: 2%-38%) patients. The median relapse-free survival (RFS) was 9.7 (95% CI: 8.1-17.8) months, and overall survival was 24.5 (95% CI: 16.5-28.4) months. Four patients demonstrated complete pathologic response, two dMMR patients and two POLE mutation patients. Pre- and post-tumor tissue analysis by flow cytometry, immunofluorescence, and RNA sequencing revealed similar levels of T-cell infiltration, but did demonstrate evidence of CD8þ and CD4þ activation posttreatment. An increase in B-cell transcriptome signature and B-cell density was present in posttreatment samples from patients with prolonged RFS. Conclusions: This study demonstrates the safety of neoadjuvant combination tremelimumab and durvalumab prior to colorectal cancer liver resection. Evidence for T- and B-cell activation following this therapy was seen in pMMR metastatic colorectal cancer.
AB - Purpose: Despite the prognostic importance of immune infiltrate in colorectal cancer, immunotherapy has demonstrated limited clinical activity in refractory metastatic proficient mismatch-repair (pMMR) colorectal cancer. This study explores combining anti-CTLA-4 and an anti-PD-L1 therapy in the preoperative management of resectable colorectal cancer liver metastases with the intent to improve immune responses in this disease setting. Patients and Methods: Patients with resectable colorectal cancer liver-only metastases received one dose of tremelimumab and durvalumab preoperatively followed by single-agent durvalumab postoperatively. Primary objectives were to determine feasibility and safety. Results: A total of 24 patients were enrolled between November 2016 and November 2019. Twenty-three patients received treatment [21 pMMR and 2 deficient mismatch-repair (dMMR)] and subsequently 17 (74%; 95% CI: 53%-88%) underwent surgical resection. Grade 3/4 treatment-related immune toxicity and postoperative grade 3/4 toxicity were seen in 5/23 (22%; 95% CI: 10%-44%) and 2/17 (12%; 95% CI: 2%-38%) patients. The median relapse-free survival (RFS) was 9.7 (95% CI: 8.1-17.8) months, and overall survival was 24.5 (95% CI: 16.5-28.4) months. Four patients demonstrated complete pathologic response, two dMMR patients and two POLE mutation patients. Pre- and post-tumor tissue analysis by flow cytometry, immunofluorescence, and RNA sequencing revealed similar levels of T-cell infiltration, but did demonstrate evidence of CD8þ and CD4þ activation posttreatment. An increase in B-cell transcriptome signature and B-cell density was present in posttreatment samples from patients with prolonged RFS. Conclusions: This study demonstrates the safety of neoadjuvant combination tremelimumab and durvalumab prior to colorectal cancer liver resection. Evidence for T- and B-cell activation following this therapy was seen in pMMR metastatic colorectal cancer.
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U2 - 10.1158/1078-0432.CCR-21-0163
DO - 10.1158/1078-0432.CCR-21-0163
M3 - Article
C2 - 33811152
AN - SCOPUS:85107009910
SN - 1078-0432
VL - 27
SP - 3039
EP - 3049
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 11
ER -