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

Abstract

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.

A preliminary study of optimal treatment response rates in patients undergoing hepatic arterial infusion chemotherapy combined with molecular targeting and immunotherapy

“…During the immunotherapy course with ICI, patients may exhibit atypical reaction patterns, including false progression, reaction separation, and delayed reaction. Notably, objective responses have been documented in non-small cell lung cancer patients up to 2 years following ICI treatment ( 37 , 38 ). The median apparent time for FOLFOX-HAIC is approximately 3–4 treatment cycles ( 8 , 39 ).…”

Dissociated Response to PD-1 Inhibitors Combined with Radiotherapy in Patients with Advanced Metastatic Solid Tumors

“…The incidence of this atypical reaction is unknown. Depending on the de nition, the incidence of DR varied between 3.3% and 47.8% in different histological subtypes [15]. However[16] studies on DR in immunotherapy combined with radiotherapy are rare.…”

Multi-Center Real-World Outcomes of Nivolumab Plus Ipilimumab and Chemotherapy in Patients with Metastatic Non-Small-Cell Lung Cancer

“…The explanation for this higher mPFS may be related to less stringent radiologic evaluation for treatments in the real-world clinical setting, especially in the era of IO, where RECISTs are not routinely used and, in many cases, have been replaced by the use of immune response evaluation criteria in solid tumors (iRECIST) [ 20 ]. The iRECIST is not a well-established method for routine clinical use in many medical centers, and in many cases, there is an overestimation of “atypical responses” like pseudoprogression or hyperprogression [ 21 , 22 ]. In addition, it is difficult to assess the mPFS in real-world retrospective trials because of intra-observer variation in radiologic response evaluation, especially once taking into account the clinical status of a patient.…”