What’s the difference between hyperprogressive disease and progressive disease for patients with treated immune checkpoint inhibitors?

Background Although the immune checkpoint inhibitors (ICIs) became a vital part of cancer care, many patients do not respond to treatment. Some of the patients in this group, which is considered to have hyperprogressive disease (HPD), have a shorter overall survival compared to progressive disease (PD). Therefore, biomarkers are needed to differentiate between HPD and PD. Here, we evaluated PILE score to differentiate HPD from PD in patients treated with ICI. Methods Ninety-five patients treated with anti-PD-1 or anti-PD-L1 inhibitors for any type of cancer with progression according to RECIST criteria in the first control imaging were included. HPD was defined according to Russo's work. The PILE scoring system was calculated, including PIV (< median vs. ≥ median), LDH (normal and > normal), and ECOG performance status (0 vs. ≥ 1). The relationship between PILE score and HPD was examined. Results The median follow-up was 6.6 months and the median OS of all cohort were 11.18 ± 1.36 months. The patients in the HPD group had decreased OS (4.77 ± 0.89 vs. 13.94 ± 1.80 months, p <0.001) and PFS (1.89 ± 0.11 vs. 3.16 ± 0.12 months, p <0.001) compared to PD group. The risk of HPD was higher than the risk of PD in patİents with a high PILE score (p:0.001). Conclusion In this study, we showed that patients treated with ICI with a higher PILE score are at greater risk for HPD. If prospective studies confirm our results, the PILE score may be a biomarker to differentiate HPD from PD.

Case Report: Tumor Microenvironment Characteristics in a Patient With HER2 Mutant Lung Squamous Cell Carcinoma Harboring High PD-L1 Expression Who Presented Hyperprogressive Disease

BackgroundHigh PD-L1 expression in non-small cell lung cancer (NSCLC) is evident to predict elevated immunotherapy efficacy, to which NSCLC with onco-driver gene mutations is probed with poor responsiveness. Thus, it is of great interest to investigate how effective immune monotherapy is in the presence of concurrent high PD-L1 expression and driving gene mutation.Patients and methodsWe present a case of squamous lung cancer with high PD-L1 expression and HER2 exon 20 insertion (20Ins) who presented hyperprogressive disease (HPD) after being treated with PD-1 inhibitor.ResultsA 71-year-old female was diagnosed with advanced squamous lung cancer with 98% tumor proportion score of PD-1 and 20ins. She benefited from first-line docetaxel cisplatin followed by 2 months second-line afatinib. Third-line pembrolizumab monotherapy was then given. Unfortunately, she rapidly progressed with dramatically enlarged primary site as well as mediastinal lymph nodes and pleural effusion only 2 weeks later, presenting severe dyspnea and dysphagia. Re-biopsy was conducted, and we found that compared with the baseline, CD8+ T cells were largely recruited only in tumor stroma but not in tumor parenchyma. Tumor-associated macrophages were notably increased in both tumor stroma and parenchyma. Concomitantly, CD56dim NK cells in tumor parenchyma were decreased.ConclusionsApplication of immune monotherapy in patients with positive driver genes demands extreme caution, even harboring high PD-L1 expression. Abnormality of tumor microenvironment might be critically involved in immune checkpoint inhibitor-induced HPD. Further study in greater depth is required.

A case of successful pembrolizumab monotherapy in a patient with advanced lung adenocarcinoma: Use of multiple biomarkers in combination for clinical practice

Clinical treatment is challenging for elderly patients with lung cancer who cannot tolerate chemotherapy, do not have cancer driver genes, and have low expression of PD-L1. Since these patients are usually excluded from clinical studies, evidence-based medicine supporting the use of immunotherapy is lacking. Considering the potentially limited clinical benefits and high associated risk of hyperprogressive disease, determining an appropriate treatment is an urgent clinical challenge. We report a 71 year-old male patient diagnosed with advanced lung adenocarcinoma lacking key driving genes (EGFR, ALK, and ROS-1), and low expression of PD-L1 on tumor cells (10–15%). The tumor tissue showed a low level of microsatellite instability, low tumor mutational burden, and no DNA mismatch repair deficiency on whole-exome sequencing (WES). However, a high blood tumor mutational burden was detected. After considering the biomarkers of therapeutic effect and ruling out the risk of hyperprogressive disease, pembrolizumab 200 mg was administered every 3 weeks for a year (17 cycles). The disease remained stable for >39 months, and adverse effects were mild and well-tolerated. Therefore, a comprehensive biomarker evaluation, especially in elderly patients lacking driving genes, is essential. Liquid biopsy technology and WES may be useful for overcoming the limitations of tissue biopsy.

Evaluation of Response to Immune Checkpoint Inhibitors Using a Radiomics, Lesion-Level Approach

Conventional methods to determine the response to immune checkpoint inhibitors (ICIs) are limited by the unique responses to an ICI. We performed a radiomics approach for all measurable lesions to identify radiomic variables that could distinguish hyperprogressive disease (HPD) on baseline CT scans and classify a dissociated response (DR). One hundred and ninety-six patients with advanced lung cancer, treated with ICI monotherapy, who underwent at least three CT scans, were retrospectively enrolled. For all 621 measurable lesions, HPDv was determined from baseline CT scans using the tumor growth kinetics (TGK) ratio, and radiomics features were extracted. Multivariable logistic regression analysis of radiomics features was performed to discriminate DR. Radiomics features that significantly discriminated HPDv on baseline CT differed according to organ. Of the 196 patients, 54 (27.6%) had a DR and 142 (72.4%) did not have a DR. Overall survival in the group with a DR was significantly inferior to that in the group without a DR (log rank test, p = 0.04). Our study shows that lesion-level analysis using radiomics features has great potential for discriminating HPDv and understanding heterogeneous tumor progression, including a DR, after ICI treatment.

Redefine Hyperprogressive Disease During Treatment With Immune-Checkpoint Inhibitors in Patients With Gastrointestinal Cancer

ObjectiveEmerging evidence showed that immune checkpoint inhibitors (ICIs) lead to hyperprogressive disease (HPD) in a small proportion of patients. There is no well-recognized standard for the evaluation of HPD. Comprehensive exploration of HPD definition system in gastrointestinal cancer treated with ICI is lacking to date.MethodsA total of 126 patients with advanced or metastatic gastrointestinal cancer treated with ICI monotherapy were analyzed. Seven definitions of HPD were defined with tumor growth kinetics (TGK) or tumor growth rate (TGR) by including new lesions or not, and with different cutoffs. Incidence and performance of different criteria were compared. Clinicopathologic characteristics and baseline genomic variations associated with HPD were also explored.ResultsTumor growth kinetics ratio of more than two fold that incorporated new lesions into calculation of HPD outperformed other definitions by successfully stratifying 14 patients (11.1%) with both accelerated disease progression (median PFS, 1.62 versus 1.93 months; hazard ratio, 1.85; 95% CI, 0.98 to 3.48; P = 0.059) and worse overall survival (median OS, 3.97 versus 10.23 months; hazard ratio, 2.30; 95% CI, 1.11 to 4.78; P = 0.021). Baseline genomic alterations in circulating tumor DNA, including SMARCA2, MSH6, APC signaling pathway, and Wnt signaling pathway, might be associated with the risk of HPD.ConclusionIncorporating new lesions emerging during the treatment was shown to be reliable for the assessment of TGK. TGK serves as a more convenient way to reflect tumor growth acceleration compared with TGR. Genomic alterations were suggested to be associated with the occurrence of HPD.

Case Report: Immune and Genomic Characteristics Associated With Hyperprogression in a Patient With Metastatic Deficient Mismatch Repair Gastrointestinal Cancer Treated With Anti-PD-1 Antibody

Microsatellite instability-high/deficient mismatch repair (MSI-H/dMMR) status of tumors is a distinct predictive biomarker of immune checkpoint inhibitors (ICIs) for colorectal and non-colorectal cancer populations. The overall response rate (ORR) varies from approximately 40% to 60%, indicating that nearly half of MSI-H tumors do not respond to ICIs. The mechanism of response heterogeneity in MSI-H/dMMR cancers is unclear. Some patients who have been treated with ICIs have developed a novel pattern of progression called hyperprogression, which is defined as unexpected accelerated tumor growth. No case of MSI-H/dMMR immunotherapy-associated hyperprogression has been reported in the literature. Here, we present the case of a patient with dMMR gastrointestinal cancer who suffered hyperprogressive disease (HPD) after treatment with nivolumab. We explored the potential mechanisms of HPD by clinical, immune, and genomic characteristics. Extremely high levels of serum LDH, low TMB and TILs, and the disruption of TGFβ signaling, may be related to hyperprogression.

Hyperprogressive Disease After Combined Anti-PD-L1 and Anti-CTLA-4 Immunotherapy for MSI-H/dMMR Gastric Cancer: A Case Report

Immune checkpoint inhibitors (ICI) have been developed in gastric adenocarcinomas and approved in first-line metastatic setting (in combination with chemotherapy) as well as in pretreated patients. Microsatellite instability-high (MSI-H) tumors are predicted to derive high benefit from ICI but data in gastric locations are limited. Here, we describe the case of a 68-year old patient with stage IV MSI-H gastric adenocarcinoma, referred to our center to receive immunotherapy after failure of standard of care (surgery with perioperative platin-based chemotherapy and paclitaxel plus ramucirumab at disease progression). The patient received one injection of durvalumab and tremelimumab and was hospitalized eighteen days after because of occlusive syndrome. The CT scan showed hyperprogression of the lymph nodes and hepatic lesions, compressing the gastric stump. He died few days later. Molecular analyses did not explain this outcome. To our knowledge, this is one of the first reported cases of hyperprogressive disease after combined ICI for a patient with MSI-H tumor. We review the potential causes and discuss the emerging literature regarding predictive factors of hyperprogression in the particular subset of MSI-H patients. If some data were available in retrospective studies, validation of strong predictive factors is needed to avoid such dramatic evolutions.