Biomarkers for Clinical Benefit of Immune Checkpoint Inhibitor Treatment—A Review From the Melanoma Perspective and Beyond

The purpose of this article is to review the status and limitations of anatomic tumor response metrics including the World Health Organization (WHO) criteria, the Response Evaluation Criteria in Solid Tumors (RECIST), and RECIST 1.1. This article also reviews qualitative and quantitative approaches to metabolic tumor response assessment with (18)F-FDG PET and proposes a draft framework for PET Response Criteria in Solid Tumors (PERCIST), version 1.0. PubMed searches, including searches for the terms RECIST, positron, WHO, FDG, cancer (including specific types), treatment response, region of interest, and derivative references, were performed. Abstracts and articles judged most relevant to the goals of this report were reviewed with emphasis on limitations and strengths of the anatomic and PET approaches to treatment response assessment. On the basis of these data and the authors' experience, draft criteria were formulated for PET tumor response to treatment. Approximately 3,000 potentially relevant references were screened. Anatomic imaging alone using standard WHO, RECIST, and RECIST 1.1 criteria is widely applied but still has limitations in response assessments. For example, despite effective treatment, changes in tumor size can be minimal in tumors such as lymphomas, sarcoma, hepatomas, mesothelioma, and gastrointestinal stromal tumor. CT tumor density, contrast enhancement, or MRI characteristics appear more informative than size but are not yet routinely applied. RECIST criteria may show progression of tumor more slowly than WHO criteria. RECIST 1.1 criteria (assessing a maximum of 5 tumor foci, vs. 10 in RECIST) result in a higher complete response rate than the original RECIST criteria, at least in lymph nodes. Variability appears greater in assessing progression than in assessing response. Qualitative and quantitative approaches to (18)F-FDG PET response assessment have been applied and require a consistent PET methodology to allow quantitative assessments. Statistically significant changes in tumor standardized uptake value (SUV) occur in careful test-retest studies of high-SUV tumors, with a change of 20% in SUV of a region 1 cm or larger in diameter; however, medically relevant beneficial changes are often associated with a 30% or greater decline. The more extensive the therapy, the greater the decline in SUV with most effective treatments. Important components of the proposed PERCIST criteria include assessing normal reference tissue values in a 3-cm-diameter region of interest in the liver, using a consistent PET protocol, using a fixed small region of interest about 1 cm(3) in volume (1.2-cm diameter) in the most active region of metabolically active tumors to minimize statistical variability, assessing tumor size, treating SUV lean measurements in the 1 (up to 5 optional) most metabolically active tumor focus as a continuous variable, requiring a 30% decline in SUV for "response," and deferring to RECIST 1.1 in cases that do not have (18)F-FDG avidity or are technically unsuitable. Criteria to define progression of tumor-absent new lesions are uncertain but are proposed. Anatomic imaging alone using standard WHO, RECIST, and RECIST 1.1 criteria have limitations, particularly in assessing the activity of newer cancer therapies that stabilize disease, whereas (18)F-FDG PET appears particularly valuable in such cases. The proposed PERCIST 1.0 criteria should serve as a starting point for use in clinical trials and in structured quantitative clinical reporting. Undoubtedly, subsequent revisions and enhancements will be required as validation studies are undertaken in varying diseases and treatments.

Answer questions and earn CME/CNE To update the melanoma staging system of the American Joint Committee on Cancer (AJCC) a large database was assembled comprising >46,000 patients from 10 centers worldwide with stages I, II, and III melanoma diagnosed since 1998. Based on analyses of this new database, the existing seventh edition AJCC stage IV database, and contemporary clinical trial data, the AJCC Melanoma Expert Panel introduced several important changes to the Tumor, Nodes, Metastasis (TNM) classification and stage grouping criteria. Key changes in the eighth edition AJCC Cancer Staging Manual include: 1) tumor thickness measurements to be recorded to the nearest 0.1 mm, not 0.01 mm; 2) definitions of T1a and T1b are revised (T1a, <0.8 mm without ulceration; T1b, 0.8-1.0 mm with or without ulceration or <0.8 mm with ulceration), with mitotic rate no longer a T category criterion; 3) pathological (but not clinical) stage IA is revised to include T1b N0 M0 (formerly pathologic stage IB); 4) the N category descriptors "microscopic" and "macroscopic" for regional node metastasis are redefined as "clinically occult" and "clinically apparent"; 5) prognostic stage III groupings are based on N category criteria and T category criteria (ie, primary tumor thickness and ulceration) and increased from 3 to 4 subgroups (stages IIIA-IIID); 6) definitions of N subcategories are revised, with the presence of microsatellites, satellites, or in-transit metastases now categorized as N1c, N2c, or N3c based on the number of tumor-involved regional lymph nodes, if any; 7) descriptors are added to each M1 subcategory designation for lactate dehydrogenase (LDH) level (LDH elevation no longer upstages to M1c); and 8) a new M1d designation is added for central nervous system metastases. This evidence-based revision of the AJCC melanoma staging system will guide patient treatment, provide better prognostic estimates, and refine stratification of patients entering clinical trials. CA Cancer J Clin 2017;67:472-492. © 2017 American Cancer Society.

Ipilimumab, an immune checkpoint inhibitor targeting CTLA-4, prolongs survival in a subset of patients with metastatic melanoma (MM) but can induce immune-related adverse events, including enterocolitis. We hypothesized that baseline gut microbiota could predict ipilimumab anti-tumor response and/or intestinal toxicity.