The Response Evaluation Criteria in Solid Tumors (RECIST) were developed and published in 2000, based on the original World Health Organization (WHO) guidelines first published in 1981. In 2009, revisions were made (RECIST 1.1) incorporating major changes, including a reduction in the number of lesions to be assessed, a new measurement method to classify lymph nodes as pathologic or normal, the clarification of the requirement to confirm a complete response (CR) or partial response (PR) and new methodologies for more appropriate measurement of disease progression. The purpose of this paper is to summarize the questions posed and the clarifications provided as an update to the 2009 publication.
PD-L1 immunohistochemistry correlates only moderately with patient survival and response to PD-(L)1 treatment. Heterogeneity of tumor PD-L1 expression might limit the predictive value of small biopsies. Here we show that tumor PD-L1 and PD-1 expression can be quantified non-invasively using PET-CT in patients with non-small-cell lung cancer. Whole body PD-(L)1 PET-CT reveals significant tumor tracer uptake heterogeneity both between patients, as well as within patients between different tumor lesions.
Radiologic imaging of disease sites plays a pivotal role in the management of patients with cancer. Response Evaluation Criteria in Solid Tumours (RECIST), introduced in 2000, and modified in 2009, has become the de facto standard for assessment of response in solid tumours in patients on clinical trials. The RECIST Working Group considers the ability of the global oncology community to implement and adopt updates to RECIST in a timely manner to be critical. Updates to RECIST must be tested, validated and implemented in a standardised, methodical manner in response to therapeutic and imaging technology advances as well as experience gained by users. This was the case with the development of RECIST 1.1, where an expanded data warehouse was developed to test and validate modifications. Similar initiatives are ongoing, testing RECIST in the evaluation of response to non-cytotoxic agents, immunotherapies, as well as in specific diseases. The RECIST Working Group has previously outlined the level of evidence considered necessary to formally and fully validate new imaging markers as an appropriate end-point for clinical trials. Achieving the optimal level of evidence desired is a difficult feat for phase III trials; this involves a meta-analysis of multiple prospective, randomised multicentre clinical trials. The rationale for modifications should also be considered; the modifications may be proposed to improve surrogacy, to provide a more mechanistic imaging technique, or be designed to improve reproducibility of the imaging biomarker. Here, we present the commonly described modifications of RECIST, each of which is associated with different levels of evidence and validation.
The programmed death protein (PD-1) and its ligand (PD-L1) play critical roles in a checkpoint pathway cancer cells exploit to evade the immune system. A same-day PET imaging agent for measuring PD-L1 status in primary and metastatic lesions could be important for optimizing drug therapy. Herein, we have evaluated the tumor targeting of an anti-PD-L1 adnectin after F-fluorine labeling. An anti-PD-L1 adnectin was labeled with F in 2 steps. This synthesis featured fluorination of a novel prosthetic group, followed by a copper-free click conjugation to a modified adnectin to generateF-BMS-986192. F-BMS-986192 was evaluated in tumors using in vitro autoradiography and PET with mice bearing bilateral PD-L1-negative (PD-L1(-)) and PD-L1-positive (PD-L1(+)) subcutaneous tumors.F-BMS-986192 was evaluated for distribution, binding, and radiation dosimetry in a healthy cynomolgus monkey. F-BMS-986192 bound to human and cynomolgus PD-L1 with a dissociation constant of less than 35 pM, as measured by surface plasmon resonance. This adnectin was labeled withF to yield a PET radioligand for assessing PD-L1 expression in vivo. F-BMS-986192 bound to tumor tissues as a function of PD-L1 expression determined by immunohistochemistry. Radioligand binding was blocked in a dose-dependent manner. In vivo PET imaging clearly visualized PD-L1 expression in mice implanted with PD-L1(+), L2987 xenograft tumors. Two hours after dosing, a 3.5-fold-higher uptake (2.41 ± 0.29 vs. 0.82 ± 0.11 percentage injected dose per gram, < 0.0001) was observed in L2987 than in control HT-29 (PD-L1(-)) tumors. Coadministration of 3 mg/kg ADX_5322_A02 anti-PD-L1 adnectin reduced tumor uptake at 2 h after injection by approximately 70%, whereas HT-29 uptake remained unchanged, demonstrating PD-L1-specific binding. Biodistribution in a nonhuman primate showed binding in the PD-L1-rich spleen, with rapid blood clearance through the kidneys and bladder. Binding in the PD-L1(+) spleen was reduced by coadministration of BMS-986192. Dosimetry estimates indicate that the kidney is the dose-limiting organ, with an estimated human absorbed dose of 2.20E-01 mSv/MBq. F-BMS-986192 demonstrated the feasibility of noninvasively imaging the PD-L1 status of tumors by small-animal PET studies. Clinical studies withF-BMS-986192 are under way to measure PD-L1 expression in human tumors.
18 F-FDG PET is often used to monitor tumor response in multicenter oncology clinical trials. This study assessed the repeatability of several semiquantitative standardized uptake values (mean SUV [SUV mean ], maximum SUV [SUV max ], peak SUV [SUV peak ], and the 3-dimensional isocontour at 70% of the maximum pixel value [SUV 70% ]) as measured by repeated baseline 18 F-FDG PET studies in a multicenter phase I oncology trial. Methods: Double-baseline 18 F-FDG PET studies were acquired for 62 sequentially enrolled patients. Tumor metabolic activity was assessed by SUV mean , SUV max , SUV peak , and SUV 70% . The effect on SUV repeatability of compliance with recommended image-acquisition guidelines and quality assurance (QA) standards was assessed. Summary statistics for absolute differences relative to the average of baseline values and repeatability analysis were performed for all patients and for a subgroup that passed QA, in both a multi-and a single-observer setting. Intrasubject precision of baseline measurements was assessed by repeatability coefficients, intrasubject coefficients of variation (CV), and confidence intervals on mean baseline differences for all SUV parameters. Results: The mean differences between the 2 SUV baseline measurements were small, varying from 22.1% to 1.9%, and the 95% confidence intervals for these mean differences had a maximum half-width of about 5.6% across the SUV parameters assessed. For SUV max , the intrasubject CV varied from 10.7% to 12.8% for the QA multiand single-observer datasets and was 16% for the full dataset. The 95% repeatability coefficients ranged from 228.4% to 39.6% for the QA datasets and up to 234.3% to 52.3% for the full dataset. Conclusion: Repeatability results of doublebaseline 18 F-FDG PET scans were similar for all SUV parameters assessed, for both the full and the QA datasets, in both the multi-and the single-observer settings. Centralized quality assurance and analysis of data improved intrasubject CV from 15.9% to 10.7% for averaged SUV max . Thresholds for metabolic response in the multicenter multiobserver non-QA settings were 234% and 52% and in the range of 226% to 39% with centralized QA. These results support the use of 18 F-FDG PET for tumor assessment in multicenter oncology clinical trials. PET,wi th the tracer 18 F-FDG, is used for tumor detection, staging, and follow-up studies for multiple neoplasms (1) and is increasingly becoming an integral part of multicenter clinical trials in oncology for the assessment of treatment effect. Accurate quantitative assessment of response as measured by changes in standardized uptake value (SUV) parameters over the course of treatment serves as an early surrogate for clinical benefit and facilitates drug development in oncology (2).For the accurate assessment of tumor response using 18 F-FDG PET, it is crucial to know the intrasubject variation in the measurement of semiquantitative parameters before the initiation of treatment (3). This study focused on the repeatability of 18 F-FDG PET in a mul...
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