iRECIST and Alliance trials
For decades, cancer treatments such as surgery, radiation therapy, and chemotherapy were evaluated largely by whether they reduced or eliminated visible tumors. The development of cancer immunotherapies introduced a different approach. Rather than directly targeting cancer cells, immunotherapies can activate a patient’s own immune system to recognize and attack cancer cells.
These treatments have produced durable responses for many patients, but they can also create new challenges for evaluating treatment response. Tumors may temporarily appear larger or new lesions may appear on imaging as immune cells enter the tumor and trigger inflammation. These changes can look similar to conventional disease progression, even when a treatment may ultimately be effective.
To help address these challenges in clinical trials, the international clinical research community developed iRECIST (Immune Response Evaluation Criteria in Solid Tumors), a standardized framework for assessing tumor response to immunotherapy.
Developed by the RECIST Working Group in 2017, iRECIST provides consensus guidelines for evaluating tumor response and progression in clinical trials of immunotherapies, including immune checkpoint inhibitors.
iRECIST is a modification of RECIST 1.1, the widely used standard for assessing changes in the size of tumors during cancer clinical trials. Under RECIST 1.1, a decrease in tumor size of at least 30% may qualify as a partial response, while an increase in the size of target lesions of at least 20%, or the appearance of new lesions, may indicate progressive disease.
RECIST 1.1 remains an important standard for evaluating cancer treatments, including immunotherapies. However, because immunotherapy can produce patterns of response that differ from those seen with conventional treatments, iRECIST provides an additional framework for interpreting these changes in the context of an immune response.
One of the challenges associated with immunotherapy is pseudoprogression, which is a temporary increase in the apparent size of a tumor or the appearance of new lesions that may occur as the immune system responds to the cancer.
When immunotherapy activates T-cells and other immune cells, these cells can accumulate within and around a tumor and cause inflammation. On an imaging scan, this immune-cell infiltration and inflammation can make a tumor appear larger, even cancer cells are being destroyed.
Under conventional response criteria, these findings may initially resemble disease progression, iRECIST provides a standardized way for clinical trials to distinguish unconfirmed progression from progression that has been subsequently confirmed.
iRECIST introduces additional response criteria categories to account for the possibility of an atypical immune response.
When imaging (or a scan) first shows progression, the finding may be classified as immune unconfirmed progressive disease (iUPD) rather than immediately being considered confirmed progression. In appropriate circumstances, and when permitted by the clinical trial protocol and the patient’s clinical condition, a follow-up assessment can help determine whether progression is confirmed.
If a second scan does not confirm progression (that the tumor has shrunk or stayed the same size), the initial finding may be reclassified according to iRECIST criteria. If additional scans confirm continued disease progression, the finding may be classified as immune confirmed progressive disease (iCPD).
This approach helps clinical researchers capture the full pattern of response to immunotherapy and reduces the risk of prematurely classifying an atypical response as treatment failure.
Importantly, iRECIST is a clinical trial response-assessment framework. Decisions about whether a patient should continue treatment after apparent progression are made by the treating team in accordance with the study protocol, the patient’s clinical condition, and applicable medical guidance.
The Alliance iRECIST resources are available to member clinicians through a secure, password-protected platform. The Alliance’s iRECIST activities are coordinated through the Immuno-Oncology Committee and the Statistics and Data Management Center (SDMC).
This centralized approach helps participating sites apply response-assessment criteria consistently and ensures that iRECIST data can be appropriately incorporated into Alliance clinical trial analyses.
The Alliance incorporates iRECIST into selected clinical trials evaluating immunotherapies when appropriate to the study design. Using iRECIST alongside conventional response criteria allows investigators to more fully characterize treatment response and atypical patterns of progression.
Examples include:
Alliance A031704 (PDIGREE): A phase III study evaluating nivolumab and ipilimumab followed by nivolumab or nivolumab plus cabozantinib in patients with advanced kidney cancer.
Alliance A031901 (IMAGINE): A study evaluating different durations of immune checkpoint therapy im patients with advanced cancer.
As immunotherapy continues to transform cancer treatment, accurately measuring treatment response is increasingly important. iRECIST gives clinical researchers a common framework for recognizing and documenting response patterns that may differ from those seen with conventional cancer treatments.