Immune-related dissociated response as a specific atypical response pattern in solid tumors with immune checkpoint blockade

Immune checkpoint blockade using immune checkpoint inhibitors, including cytotoxic T-lymphocyte-associated antigen-4 and programmed cell death protein-1/programmed cell death ligand-1 inhibitors, has revolutionized systematic treatment for advanced solid tumors, with unprecedented survival benefit and tolerable toxicity. Nivolumab, pembrolizumab, cemiplimab, avelumab, durvalumab, atezolizumab, and ipilimumab are currently approved standard treatment options for various human cancer types. The response rate to immune checkpoint inhibitors, however, is unsatisfactory, and unexpectedly, atypical radiological responses, including delayed responses, pseudoprogression, hyperprogression, and dissociated responses (DRs), are observed in a small subgroup of patients. The benefit of immunotherapy for advanced patients who exhibit atypical responses is underestimated according to the conventional response evaluation criteria in solid tumors (RECIST). In particular, DR is considered a mixed radiological or heterogeneous response pattern when responding and nonresponding lesions or new lesions coexist simultaneously. The rate of DR reported in different studies encompass a wide range of 3.3-47.8% based on diverse definition of DR. Although DR is also associated with treatment efficacy and a favorable prognosis, it is different from pseudoprogression, which has concordant progressive lesions and can be regularly captured by immune RECIST. This review article aims to comprehensively determine the frequency, definition, radiological evaluation, probable molecular mechanisms, prognosis, and clinical management of immune-related DR and help clinicians and radiologists objectively and correctly interpret this specific atypical response and better understand and manage cancer patients with immunotherapy and guarantee their best clinical benefit.

Automated summary

Immune checkpoint blockade with immune checkpoint inhibitors has revolutionized systematic treatment for advanced solid tumors. However, the response rate to these inhibitors is unsatisfactory, and atypical radiological responses, including delayed responses, pseudoprogression, hyperprogression, and dissociated responses, are observed in some patients. The conventional response evaluation criteria in solid tumors underestimate the benefit of immunotherapy for patients with atypical responses. This review aims to comprehensively analyze the frequency, definition, radiological evaluation, probable molecular mechanisms, prognosis, and clinical management of immune-related dissociated responses.