Validation of biomarkers to predict response to immunotherapy in cancer: Volume II — clinical validation and regulatory considerations

Abstract

There is growing recognition that immunotherapy is likely to significantly improve health outcomes for cancer patients in the coming years. Currently, while a subset of patients experience substantial clinical benefit in response to different immunotherapeutic approaches, the majority of patients do not but are still exposed to the significant drug toxicities. Therefore, a growing need for the development and clinical use of predictive biomarkers exists in the field of cancer immunotherapy. Predictive cancer biomarkers can be used to identify the patients who are or who are not likely to derive benefit from specific therapeutic approaches. In order to be applicable in a clinical setting, predictive biomarkers must be carefully shepherded through a step-wise, highly regulated developmental process. Volume I of this two-volume document focused on the pre-analytical and analytical phases of the biomarker development process, by providing background, examples and “good practice” recommendations. In the current Volume II, the focus is on the clinical validation, validation of clinical utility and regulatory considerations for biomarker development. Together, this two volume series is meant to provide guidance on the entire biomarker development process, with a particular focus on the unique aspects of developing immune-based biomarkers. Specifically, knowledge about the challenges to clinical validation of predictive biomarkers, which has been gained from numerous successes and failures in other contexts, will be reviewed together with statistical methodological issues related to bias and overfitting. The different trial designs used for the clinical validation of biomarkers will also be discussed, as the selection of clinical metrics and endpoints becomes critical to establish the clinical utility of the biomarker during the clinical validation phase of the biomarker development. Finally, the regulatory aspects of submission of biomarker assays to the U.S. Food and Drug Administration as well as regulatory considerations in the European Union will be covered.Electronic supplementary materialThe online version of this article (doi:10.1186/s40425-016-0179-0) contains supplementary material, which is available to authorized users.

Assessing Tumor-infiltrating Lymphocytes in Solid Tumors: A Practical Review for Pathologists and Proposal for a Standardized Method From the International Immunooncology Biomarkers Working Group: Part 1: Assessing the Host Immune Response, TILs in Invasive Breast Carcinoma and Ductal Carcinoma In Situ, Metastatic Tumor Deposits and Areas for Further Research

“…Development of prognostic and predictive biomarkers in oncology requires robust assessment of the test’s analytical validity, clinical validity and clinical utility [6,7]. Evidence is accumulating to support the use of TILs scoring as a prognostic biomarker in various solid tumors and evidence for the predictive benefit of TILs is being investigated at present.…”

“…For example, semi-quantitative H&E based scores may suffer from low precision and poor inter-observer reproducibility if no clear guidance exists, while digital quantification of IHC stained sections may produce different results due to inaccurate measurement of the test variable without controlled calibration. Testing of the clinical validity of biomarkers involves determining the extent to which the biomarker predicts the clinical outcome of interest, that is, patient prognosis or response to treatment [7]. Assessment of the clinical validity of TILs scoring requires a standardized, reproducible method, which can be validated preferably in several independent populations.…”

Secreted Tumor Antigens – Immune Biomarkers for Diagnosis and Therapy

“…Several studies have looked for biomarkers that indicate a general activation or suppression of an immune response, such as the infiltration of tumor tissue with lymphocytes, production of cytokines, increase in activated immune cells, and expression of the immune inhibitor, PD‐L1, on tumor cells . More specific biomarker studies have included profiling the patient's T‐ and B‐cell receptor repertoire .…”

“…Biomarker‐driven patient selection has the potential to distinguish patients most likely to benefit from different immunotherapy approaches and define progression and resistance . Development of any biomarkers for clinical use can be more difficult than discovery and includes several steps in the validation process . The Society for Immunotherapy of Cancer (SITC) has established an ‘Immune Biomarker Taskforce’ to facilitate and coordinate biomarker discovery and validation (https://www.sitcancer.org/membership/volunteer/task-forces/biomarkers).…”

Biomarker classification, validation, and what to look for in 2017 and beyond

“… A BMJ case report discussed around the topic of simple biomarker nomenclature and classification . A comprehensive review of urinary biomarkers for bladder cancer . A validation study of a biomarker linked to sunitinib response in metastatic clear cell renal cancer . A review of immunotherapy in urological cancers . Two companion reviews of biomarker validation in immunotherapy . …”