Why are biomarker studies important when evaluating RECIST criteria in early clinical trials?

The Response Evaluation Criteria In Solid Tumors (RECIST) serve as a pivotal framework for assessing tumor response to treatment in clinical trials involving patients with solid tumors. Developed initially in the late 1990s and later refined to RECIST 1.1 in 2009, these criteria provide a standardized method for measuring tumor size and evaluating changes over time. This standardization is crucial for objectively comparing the efficacy of treatments across different studies and treatment modalities.

What Are RECIST Criteria?

RECIST criteria focus primarily on the change in size of tumor lesions as a measure of treatment response. They categorize response into four main groups: complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD). These categories help clinicians and researchers standardize the assessment of tumor response to treatments:

• Complete Response (CR): Disappearance of all target lesions.

• Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.

• Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD.

• Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.

Historical Development and Iterations of RECIST

The initial RECIST guidelines, known as RECIST 1.0, were introduced in 2000 as a means to address the inconsistencies in the definitions and measurement of tumors in clinical trials. By providing a clear, reproducible assessment method, RECIST 1.0 helped harmonize the evaluation of oncologic therapies. Over time, however, feedback from various studies highlighted the need for updates to accommodate new imaging technologies and better address the realities of clinical practice.

In response, RECIST 1.1 was released, which made several key changes to the original guidelines:

• Reduction in the number of lesions to be measured, to simplify and expedite the assessment process.

• Clarification on what constitutes a measurable lesion, particularly with the advent of high-resolution imaging techniques.

• Introduction of lymph nodes as measurable targets, specifying that nodes must be over 15 mm in short axis to be considered measurable.

How RECIST Criteria Are Used in Clinical Trials

In clinical trials, RECIST criteria are employed to determine whether a treatment has a therapeutic effect on tumor growth. Trial investigators use these criteria to assess changes in tumor burden at various intervals throughout the study. This quantifiable measurement allows for the objective comparison of the tumor's response to the treatment against a control or against other treatments. Moreover, regulatory agencies often rely on RECIST-based assessments when considering drug approval, making these criteria central to drug development processes in oncology.

Correlation of Biomarkers with Clinical Outcomes

Incorporating biomarkers with RECIST criteria allows researchers to correlate biological changes within the tumor with visible changes in tumor size. This correlation is essential for understanding how variations in biomarker levels influence treatment response and disease progression. Such insights are crucial for developing targeted therapies that can more effectively treat various cancer subtypes based on their unique biomarker profiles.

Examples of Biomarkers Evaluated Using RECIST Criteria

Numerous studies have utilized RECIST criteria to evaluate the effectiveness of biomarker-driven therapies. For instance, the presence of a RET fusion was a candidate biomarker for responsiveness to RET inhibitors. Patients with tumors harboring RET fusions were enrolled in the LIBRETTO-001 phase 1 trial and the fusion partner for the RET fusion was assessed as a biomarker.

Waterfall plot for RET fusion partner assessment in the phase 1 trial of a RET inhibitor. Notice the dashed horizontal line on the graph that separates stable disease (above the line) from partial response (below the line).

RECIST criteria were used to monitor changes in tumor size and assess these with different RET fusion partners, thus showing that fusion with KIF5B could be a fusion partner that shows better responses. Ultimately, the use of RECIST criteria along with biomarker data enabled accelerated drug discovery efforts and regulatory approvals for this drug.

How biomarkers can help to improve responses in early trials where RECIST is being evaluated

An important part of biomarker study is evaluating the heterogeneity of the biomarker before the patient starts treatment. What may be considered a binary biomarker (present or absent) can be interpreted as a continuous biomarker (range of levels) in the context of a tumor with many cells.

In our example above the patients are interpreted as RET fusion-positive, and it is assumed that RET fusion-negative patients were not enrolled in the trial. However, each of these patients may have different levels of RET fusion present in their tumor. Some cells may be RET fusion positive and some RET fusion negative. As the targeted drug only affects cells with a RET fusion, it stands to reason that patients with more cells with RET fusions will have deeper responses in the waterfall plot.

To achieve a partial response by RECIST criteria, it is required to see at least a 30% decrease in tumor lesion size. A tumor with less than 30% of cells harboring a RET fusion is highly unlikely to show a partial response. Luckily, RET fusions, when present, are usually observed in a large proportion of the tumor. This fact ultimately contributed to the drug's success.

Future Potential

The integration of biomarkers with RECIST criteria holds immense potential for the future of drug development and patient management in oncology. As biomarker research continues to evolve, it may lead to the refinement of RECIST criteria themselves, incorporating biomarker-based endpoints to better capture the complexities of tumor biology and treatment response. This evolution could pave the way for more dynamic and responsive clinical trial designs that better reflect the real-world efficacy of cancer therapies.

A recent review by researchers at the Sarah Cannon Research Institute in Nashville provides insights into the use of ctDNA via liquid biopsy to forecast responses to therapy in solid tumors (Ann Oncol. 2023 Dec 23:S0923-7534(23)05114-1). The article points out the shortcomings of current methods that rely on imaging to measure changes in tumor size, advocating for a more standardized approach known as Liquid Biopsy RECIST (LB-RECIST). The proposed framework aims to standardize and harmonize ctDNA detection techniques and establish clear guidelines for defining ctDNA responses or disease progression in the context of precision oncology. These steps are crucial for integrating ctDNA response criteria into routine clinical practice.

As the field progresses, the ongoing refinement and expansion of these criteria are set to positively influence drug development and clinical outcomes. This will accelerate the introduction of more personalized and effective treatments into clinical practice, significantly benefiting patients.