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Pilot Clinical Trial of Perioperative Durvalumab and Tremelimumab in the Treatment of Resectable Colorectal Cancer Liver Metastases

2021; American Association for Cancer Research; Volume: 27; Issue: 11 Linguagem: Inglês

10.1158/1078-0432.ccr-21-0163

1557-3265

Preeti Kanikarla Marie, Cara Haymaker, Edwin R. Parra, Young Uk Kim, Rossana Lazcano, Swati Gite, Daniele Lorenzini, Ignacio I. Wistuba, Rebecca S. Tidwell, Xiaofei Song, Wai Chin Foo, Dipen M. Maru, Yun Shin Chun, Andy Futreal, Bryan K. Kee, David G. Menter, Luisa M. Solis, Ching‐Wei D. Tzeng, Christine M. Parseghian, Kanwal Raghav, Van K. Morris, Chia‐Chi Chang, Robert R. Jenq, Alda L. Tam, Chantale Bernatchez, Scott Kopetz, Jean‐Nicolas Vauthey, Michael J. Overman,

Colorectal Cancer Surgical Treatments

Abstract 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 CD8+ and CD4+ 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.