Results of an Integrated Phase I/II Prospective Clinical Trial (NEXIS) for Neoadjuvant Anti-PD-L1 (Durvalumab) and Anti-CTLA-4 (Tremelimumab) With Radiation for High-Risk Soft-Tissue Sarcoma of the Trunk and Extremities.

Autor:	Ng VY; Department of Orthopedics, University of Maryland Medical Center, Baltimore, USA., Sahlani MN; Department of Orthopedics, University of Maryland Medical Center, Baltimore, USA., Fogel JD; Department of Orthopedics, University of Maryland Medical Center, Baltimore, USA., Chiu AK; Department of Orthopedics, University of Maryland Medical Center, Baltimore, USA., Kallen ME; Department of Pathology, University of Maryland School of Medicine, Baltimore, USA., Davis D; Department of Diagnostic Radiology, University of Maryland Medical Center, Baltimore, USA., Snider J; Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, USA., Regine W; Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, USA., Bentzen SM; Greenebaum Comprehensive Cancer Center and Department of Epidemiology and Public Health, University of Maryland School of Medicine, Baltimore, USA., Sausville E; Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, USA.
Jazyk:	angličtina
Zdroj:	Cureus [Cureus] 2024 Oct 22; Vol. 16 (10), pp. e72119. Date of Electronic Publication: 2024 Oct 22 (Print Publication: 2024).
DOI:	10.7759/cureus.72119
Abstrakt:	Background The current management of large, high-grade soft tissue sarcoma (STS) of the trunk and extremities includes radiation and surgical resection. The initial use of chemotherapy and targeted therapy are controversial and although most patients present with localized disease, many eventually develop incurable metastases. The results and analysis of the safety and antitumor activity of combined checkpoint inhibitor immunotherapy with neoadjuvant radiation for high-risk primary STS are presented here. Methods This was an integrated phase I/II prospective single-arm trial (Nutrition and Exercise in Critical Illness Trial (NEXIS) trial). Eligible patients were age ≥18 years with histologically confirmed intermediate or high-grade STS of the trunk or extremity ≥5 cm diameter and were Eastern Cooperative Oncology Group performance status 0-1. The treatment algorithm included neoadjuvant anti-PD-L1 (Durvalumab) and anti-CTLA-4 (Tremelimumab) for three cycles of four weeks/cycle along with external beam radiation for five weeks, followed by wide surgical resection, and adjuvant Durvalumab monotherapy for four cycles. High-grade toxicity was continually assessed for the first 12 patients in phase I and the primary endpoint for phase II was an excellent histological response (grade 0 or 1 score on a semi-quantitative assessment for tumor regression). This study was registered with ClinicalTrials.gov, number NCT03116529. Findings Between October 2017 and November 2021, 23 patients were enrolled. Five patients had progression of distant disease during neoadjuvant treatment and withdrew from the study before surgery. A total of 18 patients who completed at least the neoadjuvant immunotherapy, radiation and surgery were included for analysis. The most common tumor was undifferentiated pleomorphic sarcoma (n=9, 50%). The occurrence of any adverse event (AE) was recorded in 16 (88.9%) patients, and 3 (16.7%) patients had a serious AE. Eight out of 18 patients (44.4%) had disease-free survival at a median of 39.7 months. Four out of 18 patients (22.2%) were alive-with-disease at a median of 37.1 months from diagnosis of distant metastasis, and six out of 18 (33.3%) died of disease at a median of 20.8 months from diagnosis of distant metastasis. Local recurrence occurred in two patients (11.1%) and was concomitant with distant disease in each case. Based on Response Evaluation Criteria in Solid Tumors v1.1, a partial response was noted in five (27.8%) cases, stable disease in 10 (55.6%) cases, and progressive disease in three (16.7%) cases. Histological semiquantitative analysis revealed a "good" response in eight (44.4%) patients, a "moderate" response in four (22.2%) patients, and a "poor" response in six (33.3%) patients. The mean patient-reported outcome measures regarding fatigue, physical function, or physical interference demonstrated no significant differences between various timepoints before, during, or after treatment. Conclusion Neoadjuvant combined immunotherapy and radiation for high-risk STS was relatively well-tolerated. The histological, radiologic, and clinical outcome data in this novel trial were relatively similar to historical literature for non-immunotherapy treatment regimens. Competing Interests: Human subjects: Consent for treatment and open access publication was obtained or waived by all participants in this study. University of Maryland issued approval #HM-HP-00073356-25. ClinicalTrials.gov #: NCT03116529 Eligible patients will be approached for their consent to participate. All subjects must first read, understand, and sign the IRB/REB/IEC-approved ICF before any study-specific screening procedures are performed. The subject’s clinician will be involved in the consent conversation. Patients will be informed of the study goals and data to be collected. Additionally, patients and their families will be provided with written information describing the study, the risks and benefits of participation and what will be expected of them if they choose to participate. The consent form will describe the purpose of the study, the procedures to be followed, and the risks and benefits of participation. Copies of the signed consent forms will be given to the patient, and this fact will be documented in the patient’s record. Due to the high-risk nature of this study, no proxy (LAR) consent will be obtained. Prior to initiating the consent process, the participant’s treating physician will confirm that the participant has the ability to understand the relevant study information and communicate and maintain a choice. If the physician determines that the patient lacks the capacity to consent, the patient will be declared ineligible. Recognizing that consent is an ongoing process, the study team will encourage the participants to ask additional questions that may arise during the course of their participation in the study. The research staff will endeavor to answer all questions posed by the patient and his/her family to ensure their understanding of the protocol at all times. A limited number of questions will be asked of all patients after they are introduced to the study and have reviewed the consent form. These questions assess the person’s understanding of the study and what it means to participate, their appreciation of the consequences of participation, and their ability to consider alternatives to participation. A formal comprehension test may be utilized, or comprehension will be assessed by the person(s) obtaining the consent. The patient’s physician will ask the questions and determine the appropriateness of the responses. The study will not include children or prisoners. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: This study was supported by funds through the Maryland Department of Health’s Cigarette Restitution Fund Program (CH-649-CRF) and the National Cancer Institute Cancer Center Support Grant (CCSG) P30CA134274. The immunotherapy drugs were provided by the manufacturer, AstraZeneca. . Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work. (Copyright © 2024, Ng et al.)
Databáze:	MEDLINE
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