Incidence of Pseudoprogression during Immune Checkpoint Inhibitor Therapy for Solid Tumors: A Systematic Review and Meta-Analysis

Abstract

I n the era of cancer immunotherapy, the number of clinical trials for immunotherapeutic agents has been growing. Immune checkpoint inhibitors (ICIs) that target cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and programmed cell death protein 1 (PD-1) or its ligand (PD-L1) have been studied in clinical trials and applied in clinical practice (1).A subset of patients treated with ICI manifest an atypical pattern of tumor response either after an increase of tumor burden or appearance of new lesions, a phenomenon termed pseudoprogression, which is classified as progressive disease by conventional response criteria (2,3). This triggered efforts to develop criteria including immune-related response criteria (irRC) in 2009, immune-related Response Evaluation Criteria in Solid Tumors (RECIST; irRECIST) in 2013, and iRECIST in 2017 (2,(4)(5)(6).Along with increasing recognition of pseudoprogression and its importance, several studies evaluated its incidence and patterns (7-9). But a unifying definition of pseudoprogression is lacking. Although studies have raised the need for robust data on pseudoprogression (10,11), to our knowledge, there is no evidence-based systematic summary of definitions and incidence of pseudoprogression.We performed a systematic review and meta-analysis of published clinical trial reports to determine the incidence of pseudoprogression during treatment with ICI and Purpose: To evaluate by systematic review and meta-analysis the incidence of pseudoprogression in cancer treatment with ICIs, and compare the incidence according to response criteria, tumor types, and immunotherapeutic agents. Materials and Methods:Medline and Embase were searched to identify relevant studies published before December 31, 2018. Clinical trials, post hoc analysis of clinical trials, and prospective studies on ICI treatment in patients with malignant solid tumors were included. Pooled incidence of pseudoprogression for all included studies, per definition of pseudoprogression, cancer type, and drug type, was obtained by random-effects models with inverse variance weighting model. Results:Seventeen studies with 3402 patients were analyzed. The pooled incidence of pseudoprogression was 6.0% (95% confidence interval: 5.0%, 7.0%). The definition of pseudoprogression were divided into four categories: progressive disease followed by partial response (PR) or complete response (CR) but not stable disease (SD) with Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 (six studies); progressive disease followed by SD or PR or CR with RECIST 1.1 (five studies); progressive disease followed by SD or PR or CR with RECIST 1.0 (three studies); and progressive disease followed by SD or PR or CR with immunerelated response criteria (irRC) (three studies). Incidence of pseudoprogression varied from 4.5% to 8.0% per definition, ranged from 5.0% to 7.0% per cancer type, and was 5.6% with the monotherapy of programmed cell death-1 inhibitor. Conclusion:The overall incidence of pseudoprogression was 6.0% and was less than 10% in...

Comparison of RECIST 1.1 and iRECIST in Patients Treated with Immune Checkpoint Inhibitors: A Systematic Review and Meta-Analysis

“…Likewise, the pooled incidence rate of PD date discordance (3.9%) between RECIST 1.1 and iRECIST was associated with the major concept of iRECIST, “resetting the bar,” which occurs if RECIST 1.1 defined PD is followed by tumor shrinkage [ 9 ]. These results are in line with the recent data that pseudoprogression is a rare phenomenon in ICI treatment [ 1 , 23 ]. Studies demonstrated that patients showing PD during ICI treatment may show a prolonged or delayed response or durable disease stabilization and it may impact the clinical outcome [ 24 ].…”

“…Although iRECIST captured the benefit of ICI treatment in a subset of patients which RECIST 1.1 did not, and significantly prolonged PFS compared to RECIST 1.1, the magnitude of benefit was modest (3.9% of patients with pseudoprogression and PFS prolongation by 0.46 months), and these results should be interpreted with caution concerning the benefit and drawbacks of iRECIST application in clinical trial and practice [ 20 , 23 ]. While the application of iRECIST is beneficial to fully investigate the atypical response such as pseudoprogression and treatment efficacy, it adds considerable burden in imaging interpretation, data management, statistical analysis, cost, and potential risk of maintaining futile treatment.…”

“…Thus, iRECIST reflects the pseudoprogression well. However, controversy remains as the incidence of pseudoprogression is low, less than 10% [ 23 ] Treatment beyond progression might have risks of continuing futile treatment and delaying switch to other treatment options in patients with true progression. Although recent studies demonstrated that treatment beyond progression can provide the benefit of overall survival [ 20 ], further studies are necessary to evaluate the survival benefit of treatment beyond progression based on iRECIST.…”

Molecular Imaging in Immunotherapy: A Systematic Review

“…In a recent meta-analysis on the incidence of pseudoprogression during ICIs for solid tumor, Park et al [144] reported that the incidence according to tumor types were similar for the three more representative ones (6.4% in melanoma, 5.0% in NSCLC, and 7.0% in genitourinary cancer). The incidence of pseudoprogression according to the agent types were also analyzed: the pooled incidence in the studies of PD-1/PD-L1 inhibitor monotherapy was 5.7% (5.6% for PD-1 and 6.8% for PD-L1), whereas one study of melanoma that used a CTLA-4 inhibitor showed higher incidence of pseudoprogression (9.7%).…”

The Future of Cancer Diagnosis, Treatment and Surveillance: A Systemic Review on Immunotherapy and Immuno-PET Radiotracers

“…In a recent meta-analysis on the incidence of pseudoprogression during ICIs for solid tumor, Park et al [ 143 ] reported that the incidence according to tumor types were similar for the three more representative ones (6.4% in melanoma, 5.0% in NSCLC, and 7.0% in genitourinary cancer). The incidence of pseudoprogression according to the agent types were also analyzed: the pooled incidence in the studies of PD-1/PD-L1 inhibitor monotherapy was 5.7% (5.6% for PD-1 and 6.8% for PD-L1), whereas one study of melanoma that used a CTLA-4 inhibitor showed higher incidence of pseudoprogression (9.7%).…”