VSports注册入口 - Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The . gov means it’s official. Federal government websites often end in . gov or . mil VSports app下载. Before sharing sensitive information, make sure you’re on a federal government site. .

Https

The site is secure. The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely. V体育官网.

Clinical Trial
. 2021 Apr 15;27(8):2200-2208.
doi: 10.1158/1078-0432.CCR-20-2474. Epub 2021 Jan 27.

Phase II Single-arm Study of Durvalumab and Tremelimumab with Concurrent Radiotherapy in Patients with Mismatch Repair-proficient Metastatic Colorectal Cancer

Neil H Segal  1 , Andrea Cercek  2 , Geoffrey Ku  2   3 , Abraham J Wu  2 , Andreas Rimner  2 , Danny N Khalil  2 , Diane Reidy-Lagunes  2 , John Cuaron  2 , T Jonathan Yang  2 , Martin R Weiser  2 , Paul B Romesser  2 , Zsofia K Stadler  2   3 , Anna M Varghese  2 , Karuna Ganesh  2 , Rona Yaeger  2 , Louise C Connell  2 , David Faleck  2 , Ghassan K Abou-Alfa  2 , Kathleen C Mcauliffe  2 , Pamela Vaiskauskas  2 , Mark L Solter  2 , Martinique Ogle  2 , Matthew J Adamow  2 , Aliya Holland  2 , Pallavi Vedantam  2 , Phillip Wong  2 , Taha Merghoub  2 , Efsevia Vakiani  2 , Travis J Hollmann  2 , Krishna Juluru  2 , Joanne F Chou  2 , Marinela Capanu  2 , Joseph Erinjeri  2 , Stephen Solomon  2 , Yoshiya Yamada  2 , Nancy Kemeny  2 , Christopher H Crane  2 , Leonard B Saltz  2
Affiliations
Clinical Trial

Phase II Single-arm Study of Durvalumab and Tremelimumab with Concurrent Radiotherapy in Patients with Mismatch Repair-proficient Metastatic Colorectal Cancer

"VSports注册入口" Neil H Segal et al. Clin Cancer Res. .

Abstract

Purpose: Immune checkpoint inhibition (ICI) alone is not active in mismatch repair-proficient (MMR-P) metastatic colorectal cancer (mCRC), nor does radiotherapy alone result in objective systemic benefit. However, combined radiotherapy plus ICI can induce systemic antitumor immunity in preclinical and clinical models VSports手机版. .

Patients and methods: In this single-center, phase II study, patients with chemotherapy-refractory MMR-P mCRC received durvalumab 1,500 mg plus tremelimumab 75 mg every 4 weeks plus radiotherapy. The primary endpoint was objective response rate (ORR) in nonirradiated lesions V体育安卓版. Treatment and efficacy were correlated with peripheral immune cell profiles. .

Results: We enrolled 24 patients, and report outcomes after a median follow-up of 21. 8 (range: 15. 9-26. 3) months. The ORR was 8 V体育ios版. 3% (2 patients) [95% confidence interval (CI), 1. 0-27. 0]. The median progression-free survival was 1. 8 (95% CI, 1. 7-1. 9) months, median overall survival was 11. 4 (95% CI, 10. 1-17. 4) months. Twenty five percent of patients (n = 6) had treatment-related grade 3-4 adverse events. We observed increased circulating CD8+ T lymphocyte activation, differentiation, and proliferation in patients with objective response. .

Conclusions: This combination of radiotherapy plus ICI study did not meet the prespecified endpoint criteria to be considered worthwhile for further study. However, rare instances of systemic immune augmentation and regression in nonirradiated lesions were observed (an abscopal response). Combination durvalumab and tremelimumab plus radiotherapy is feasible in MMR-P mCRC with a manageable safety profile. Further studies of novel immunotherapy combinations, and identification of biomarkers predictive of abscopal response are warranted. VSports最新版本.

PubMed Disclaimer

Figures

Figure 1:
Figure 1:
Waterfall plot showing target lesion change Maximum percentage change from baseline in the size of tumors in all patients treated with durva/treme and RT (progression >100% was cut off at 100%). Two patients (right bars) achieved an objective response, one patient remains on treatment.
Figure 2:
Figure 2:
Treatment and response timeline for responding patient 1 The blue bar indicates study time line, and treatment with durva/treme (D/T) or durva alone (D). Panel A illustrates the RT field targeting a liver tumor, the purple outline is tumor. The green is the line corresponding to 100% of radiation dose (5,000 cGy/5 Fx), magenta is 50% and blue is 30% of the dose. Panels B and C demonstrate baseline imaging and representative lesion of RECIST-defined objective response in a non-radiated tumor at week 16 after starting durva/ treme (−45.8%).
Figure 3:
Figure 3:
Treatment and response timeline for responding patient 2 Mixed response and pseudoprogression in a patient achieving an objective response. The blue bar indicates study time line, and treatment with durva/treme (D/T) or durvalumab alone (D). Panel A illustrates the RT field (i.e. 2,000 cGy/5 Fx), targeting a retroperitoneal tumor, the tumor is in red, and the portal is the jagged yellow outline. Upper panels demonstrate radiographic change on treatment. Panel B illustrates two liver metastases observed on baseline imaging. Panel C illustrates response in a non-radiated liver lesion (blue circle) and pseudoprogression in a separate non-radiated lesion (red circle) at week 8 on treatment. Panel D illustrates a subsequent RECIST-defined objective response in both lesions at week 16 (−49.4%). Lower panels illustrate histopathology obtained pre-treatment (panel E), and 9 weeks post-treatment of the pseudoprogression lesion (panel F) and the responding lesion (panel G). Both lesions demonstrated replacement by necrosis and marked inflammatory infiltrate at week 9.
Figure 4:
Figure 4:
Peripheral blood flow cytometry showing population % positive and median values among responders and non-responders Flow cytometry analysis showing the percentage (y-axis) of CD4+ or CD8+ T cells positive for the indicated immune markers at pre-treatment baseline and at weeks 2, 4 and 8 after starting treatment. Symbols reflect unique patients. Two responding patients (blue) compared to non-responders (brown) showed higher frequencies of CD25+CD4+ T lymphocytes relative to most non-responders. Within the CD8+ T lymphocyte population, relatively higher increases in HLA-DR, Ki-67, PD-1, and effector memory cells were observed (L to R, panels A-E) along with more sustained increases in CD8 T cells co-expressing Ki-67, PD-1 and ICOS (panels F-H). More sustained increases were seen in proliferating Ki67+ Tem effector memory (CCR7-CD45RA-) CD8 T lymphocytes (panel I). T regulatory cells (FoxP3+CD4+ Treg) increased in frequency by week 2 in responders and non-responders, but were overall lower in frequency relative to most non-responders (panel J).
See this image and copyright information in PMC

VSports在线直播 - References

    1. Le DT, Uram JN, Wang H, Bartlett BR, Kemberling H, Eyring AD, et al. PD-1 Blockade in Tumors with Mismatch-Repair Deficiency. The New England journal of medicine. 2015;372(26):2509–20. - PMC - PubMed
    1. Eng C, Kim TW, Bendell J, Argilés G, Tebbutt NC, Di Bartolomeo M, et al. Atezolizumab with or without cobimetinib versus regorafenib in previously treated metastatic colorectal cancer (IMblaze370): a multicentre, open-label, phase 3, randomised, controlled trial. The lancet oncology. 2019;20(6):849–61. - PubMed
    1. O’Neil BH, Wallmark JM, Lorente D, Elez E, Raimbourg J, Gomez-Roca C, et al. Safety and antitumor activity of the anti-PD-1 antibody pembrolizumab in patients with advanced colorectal carcinoma. PloS one. 2017;12(12):e0189848. - PMC - PubMed
    1. Tang C, Wang X, Soh H, Seyedin S, Cortez MA, Krishnan S, et al. Combining radiation and immunotherapy: a new systemic therapy for solid tumors? Cancer Immunol Res. 2014;2(9):831–8. - PMC - PubMed
    1. Sharma A, Bode B, Studer G, Moch H, Okoniewski M, Knuth A, et al. Radiotherapy of human sarcoma promotes an intratumoral immune effector signature. Clinical cancer research : an official journal of the American Association for Cancer Research. 2013;19(17):4843–53. - V体育平台登录 - PubMed

Publication types

MeSH terms