The use of immunotherapy in oncology has rapidly evolved, altering the cancer treatment landscape and creating unique opportunities and challenges for biomarker identification and selection in clinical trial protocols. Biomarkers are defined by the National Institutes of Health as characteristics that can be objectively measured as indicators of normal biological processes, disease processes, or pharmacologic responses to therapy. Biomarkers provide an invaluable biologic context for the development and evaluation of immunotherapies and may enhance patient outcomes by matching novel agents to populations that will derive the most benefit from them. The Society for Immunotherapy of Cancer (SITC) recently issued a consensus statement to further advance biomarker-based strategies and help prioritize biomarkers for inclusion in novel clinical trial protocols.
With a focus on early-phase clinical trial design, SITC classifies biomarkers as essential, eligibility, and exploratory or emergent. Essential biomarkers are those that are clinically relevant in multiple tumor settings, either predictive of response to therapy or prognostic for survival endpoints (ie, disease-free, progression-free, or overall survival). Predictive biomarkers are often directly related to the mechanism of action of a particular cancer therapy and are used to identify patients who benefit from or whose tumors are resistant to specific therapies (eg, molecular targeted therapies or programmed cell death protein 1 [PD-1]/PD-1 ligand 1 [PD-L1] blockade). Prognostic biomarkers can be identified using various statistical and machine-learning tools and relate tumor and host variables to clinical outcomes independently of treatment (eg, tumor size, Eastern Cooperative Oncology Group performance status). Some biomarkers may be both predictive and prognostic (eg, the presence of estrogen and progesterone receptors serves as both a prognostic and predictive factor for the efficacy of hormonal therapy).
The essential biomarkers determined by SITC are limited to currently reimbursable tests performed in routine clinical practice. Examples include neutrophil-to-lymphocyte ratio, lactate dehydrogenase serum levels, albumin levels, PD-L1 expression on the tumor, and measurement of tumor mutational burden and microsatellite instability (high or low). Clinical outcome models based on these essential biomarkers are expected to be heavily employed in future trial designs, expedited by artificial intelligence and machine learning to support patient selection, stratification, and randomization.
The consensus includes rationale and considerations for eligibility biomarkers, which are a subset of essential biomarkers that are relevant in a particular trial context, such as tumor type or treatment-specific biomarkers. Criteria are also included to support evaluation of promising emergent biomarkers, such as circulating tumor DNA, major histocompatibility complex class I expression on the tumor, and CD8 and PD-1 expression within the tumor. It is expected that emergent biomarkers will be added as essential in future consensus updates once they have met the essential biomarker criteria.
Regarding data reporting, the panel suggests using the recommendations in the REMARK initiative (REporting recommendations for tumor MARKer Prognostic Studies). As research into biomarkers continues to evolve, there is an urgent need to establish a common database to allow comparison across trials.
High level
No common database currently exists, but SITC has called on informed scientists and clinicians to develop one in collaboration with life science companies and academic labs. Data sharing and collaboration will be critical to further advance characterization and standardization of essential biomarkers.
Ground level
Validated predictive biomarkers are pivotal to the effective delivery of personalized medicine. As their use increases, health literacy principles will need to be employed to ensure patients and their families fully understand the value of the information obtained with essential biomarkers and how it will be used to guide their care.