Hyperprogressive Disease Research Articles

P14.25 Immune Cell Profiling of Hyperprogressive Disease in Patients with Non-Small Cell Lung Cancer Treated with Anti-PD-1/PD-L1 Antibodies

P14.25 Immune Cell Profiling of Hyperprogressive Disease in Patients with Non-Small Cell Lung Cancer Treated with Anti-PD-1/PD-L1 Antibodies

Tumor infiltrated immune cell types support distinct immune checkpoint inhibitor outcomes in patients with advanced non-small cell lung cancer.

The evaluation of PD‐L1 expression alone has limitations in predicting clinical outcome in immune‐checkpoint inhibitors (ICI). This study aimed to evaluate the predictive and prognostic effects of the presence of various immune cells in pretreatment tissue samples and to identify determinants associated with response in patients with advanced non‐small cell lung cancer (NSCLC) treated with PD‐1 blockade. Immune cell distribution was heterogeneous and the most dominant immune cell type was T cells. Patients with durable clinical benefit (DCB) showed significantly higher PD‐L1 expression. The ratio of tumor/stroma region of T cell, B cell, and macrophage was significantly higher in patient with DCB. High intratumoral T‐ and B‐cell density (≥median) was associated with DCB in the low PD‐L1 expression (<50%) group. In univariate analyses, the overall survival (OS) benefit was shown according to intratumoral B‐cell density (p = 0.0337). The incidence of hyperprogressive disease (HPD) was 13.0%. The Chi‐square test revealed that HPD was significantly associated with intratumoral B‐cell density but not T‐cell or macrophage density. Our results demonstrate different predictive and prognostic values for infiltrating immune cells in tumor tissue, which may help in selecting patients for ICI.

Squamous differentiation is a potential biomarker predicting tumor progression in patients treated with pembrolizumab for urothelial carcinoma

Immune checkpoint inhibitor (ICI) is widely used and highly effective for some cancer patients but may result in disease progression in others. Hyperprogressive disease in particular is characterized by an acceleration of tumor growth during ICI therapy and has been reported in patients including those with urothelial carcinoma. Biomarkers predicting treatment efficacy are crucial to avoid tumor progression and unnecessary adverse effects. This study aims to clarify the predictors of disease progression for ICI treatment in patients with urothelial carcinoma. We analyzed the response pattern of 23 urothelial carcinomas treated with pembrolizumab and its association with pathological features and potential immunohistochemical markers including EGFR, MDM2, p53, p16, and programmed cell death ligand-1 (PD-L1) expression and CD8- and CD204-positive cell infiltration. During ICI therapy, 13 (57 %) patients showed progressive disease including 6 (26 %) with hyperprogressive disease. Notably, squamous differentiation combined with MAC387 expression was observed exclusively in cases with progressive disease (6 of 13, 46 %); it was not present in cases with stable disease or partial/complete response (0 of 10, p = 0.0019). All tumors with squamous differentiation showed positive staining for EGFR. Additionally, the loss of p16 expression occurred more frequently in cases with progressive disease (8 of 13, 62 %) than in other cases (3 of 10, 30 %), but this finding did not reach statistical significance. Squamous differentiation was also significantly associated with shorter overall survival. Based on our observations, squamous differentiation may be a novel biomarker for predicting disease progression in patients with urothelial carcinoma who receive pembrolizumab.

Characterization of hyperprogressive disease in patients with advanced biliary tract cancer treated with anti-PD-1 inhibitor: A multicenter retrospective study.

339 Background: Immunotherapy, including anti-PD-1 inhibitor, represents a promising breakthrough treatment in poor prognostic cancers such as biliary tract cancer (BTC). However, subset of pts suffer from unexpected acceleration of tumor growth following the initiation of immunotherapy, termed hyperprogressive disease (HPD). We assessed HPD in BTC pts treated with anti-PD-1 inhibitor in association with clinicopathologic features. Methods: This retrospective study included pts with BTC who were treated with pembrolizumab 200mg IV as palliative second or third line treatment in 4 tertiary hospitals in South Korea. Previous proposed tumor dynamic parameters including time to treatment failure (TTF), tumor growth kinetics (TGK) and tumor growth rate (TGR) were calculated per RECIST v1.1. Neural network modeling technique was adopted to find clinicopathologic features that can predict HPD. Results: Total of 223 pts with BTC were treated with palliative second or third line pembrolizumab between December 2015 to August 2020. ORR was 11.2% (n=1 for CR, n=24 for PR, n=70 for SD, n=118 for PD, and 10 pts not evaluable). Among patients with best response as PD (n=118), 41 patients (18.4% from total pts) met the criteria for HPD definition (&gt;2-fold increase in both TGK and TGR in the experimental period compared to the reference period). HPD pts had worse prognosis compared to non-HPD pts in terms of TTF (median 1.4 vs 2.7 months, P =&lt;0.0001) and OS (median 3.57 vs 5.27 months, P =0.03). Clinicopathologic features including age, ECOG performance status, primary tumor site, pathology, metastatic organ, previous treatment history (surgery or radiotherapy), pretreatment PD-L1 score, tumor markers, and baseline laboratory results (LDH, albumin, or neutrophil-to-lymphocyte ratio) did not predict HPD (compared to non-HPD pts or PD without HPD pts). By neural network modeling and plotting with hidden vectors, we could define HPD-high-risk cluster (n=37) and HPD-lower-risk cluster (n=80). Higher CA 19-9-to-lymphocyte ratio ( P =0.0004) or higher platelet-to-PD-L1 CPS (combined positivity score) ratio ( P =0.002) predicted HPD-high-risk-cluster. HPD pts (n=41) tend to have progression due to liver (73.2% vs 45.6%, P =0.0026) or peritoneum (53.7% vs 21.4%, P=&lt;0.0001) metastases, compared to non-HPD pts (n=182). Conclusions: This study for the first time describe the clinicopathologic features of HPD among pembrolizumab treated BTC pts. Baseline pathology and laboratory tests may help optimal patient selection for immunotherapy to avoid HPD in BTC pts. Further validation of BTC-specific HPD predictive features and definition (TGK or TGR ratio cut-off) will be presented after comparison with clinicopathologic features among second line 5FU-based chemotherapy treated BTC pts.

IFN-γ and CD38 in Hyperprogressive Cancer Development.

Simple SummaryHyperprogressive disease (HPD) is a pattern of paradoxical tumor progression that has been reported in patients treated with immune checkpoint inhibitors (ICIs). Although a large number of studies have investigated HPD and several associated factors have been reported, the mechanisms that drive the acceleration of tumor growth remain unknown. In this review, we discuss the possible role of IFN-γ and CD38 in the development of HPD, and we report the main findings in the scientific literature on the signaling pathways in which these factors take part, and their involvement in response and resistance to ICI therapy.Immune checkpoint inhibitors (ICIs) improve the survival of patients with multiple types of cancer. However, low response rates and atypical responses limit their success in clinical applications. The paradoxical acceleration of tumor growth after treatment, defined as hyperprogressive disease (HPD), is the most difficult problem facing clinicians and patients alike. The mechanisms that underlie hyperprogression (HP) are still unclear and controversial, although different factors are associated with the phenomenon. In this review, we propose two factors that have not yet been demonstrated to be directly associated with HP, but upon which it is important to focus attention. IFN-γ is a key cytokine in antitumor response and its levels increase during ICI therapy, whereas CD38 is an alternative immune checkpoint that is involved in immunosuppressive responses. As both factors are associated with resistance to ICI therapy, we have discussed their possible involvement in HPD with the conclusion that IFN-γ may contribute to HP onset through the activation of the inflammasome pathway, immunosuppressive enzyme IDO1 and activation-induced cell death (AICD) in effector T cells, while the role of CD38 in HP may be associated with the activation of adenosine receptors, hypoxia pathways and AICD-dependent T-cell depletion.

The implications of clinical risk factors, CAR index, and compositional changes of immune cells on hyperprogressive disease in non-small cell lung cancer patients receiving immunotherapy

BackgroundImmune checkpoint blockades (ICBs) are characterized by a durable clinical response and better tolerability in patients with a variety of advanced solid tumors. However, we not infrequently encounter patients with hyperprogressive disease (HPD) exhibiting paradoxically accelerated tumor growth with poor clinical outcomes. This study aimed to investigate implications of clinical factors and immune cell composition on different tumor responses to immunotherapy in patients with non-small cell lung cancer (NSCLC).MethodsThis study evaluated 231 NSCLC patients receiving ICBs between January 2014 and May 2018. HPD was defined as a > 2-fold tumor growth kinetics ratio during ICB therapy and time-to-treatment failure of ≤2 months. We analyzed clinical data, imaging studies, periodic serologic indexes, and immune cell compositions in tumors and stromata using multiplex immunohistochemistry.ResultsOf 231 NSCLC patients, PR/CR and SD were observed in 50 (21.6%) and 79 (34.2%) patients, respectively and 26 (11.3%) patients met the criteria for HPD. Median overall survival in poor response groups (HPD and non-HPD PD) was extremely shorter than disease-controlled group (SD and PR/CR) (5.5 and 6.1 months vs. 16.2 and 18.3 months, respectively, P = 0.000). In multivariate analysis, HPD were significantly associated with heavy smoker (p = 0.0072), PD-L1 expression ≤1% (p = 0.0355), and number of metastatic site ≥3 (p = 0.0297). Among the serologic indexes including NLR, PLR, CAR, and LDH, only CAR had constantly significant correlations with HPD at the beginning of prior treatment and immunotherapy, and at the 1st tumor assessment. The number of CD4+ effector T cells and CD8+ cytotoxic T cells, and CD8+/PD-1+ tumor-infiltrating lymphocytes (TIL) tended to be smaller, especially in stromata of HPD group. More M2-type macrophages expressing CD14, CD68 and CD163 in the stromal area and markedly fewer CD56+ NK cells in the intratumoral area were observed in HPD group.ConclusionsOur study suggests that not only clinical factors including heavy smoker, very low PD-L1 expression, multiple metastasis, and CAR index, but also fewer CD8+/PD-1+ TIL and more M2 macrophages in the tumor microenvironment are significantly associated with the occurrence of HPD in the patients with advanced/metastatic NSCLC receiving immunotherapy.

Rare Nivolumab-associated Super Hyper Progressive Disease in Patients With Advanced Gastric Cancer.

Rapid tumor growth after administration of immune checkpoint inhibitors is designated hyper progressive disease (HPD). In this study, besides the conventional HPD category, we proposed the "super HPD" category where the disease is naturally rapidly growing. Patients treated for advanced gastric cancer with irinotecan or nivolumab as a third-line treatment were retrospectively compared. Eighteen and 26 patients were treated with irinotecan or nivolumab, respectively. There were 3 HPD cases (16.7%) in the irinotecan group, 6 cases (23.1%) in the nivolumab group, and the frequency of HPD was not significantly different. Two cases satisfied the super HPD definition only in the nivolumab group. When one of them was analyzed immunologically, the number of regulatory T cells was found to be increased, resulting in a low neutrophil-to-lymphocyte ratio. Our proposed super HPD was likely to represent a true HPD, with a frequency of 7.7%.

A case of hyperprogressive disease following atezolizumab therapy for pulmonary pleomorphic carcinoma with epidermal growth factor receptor mutation

A 66-year old man with non-smoking history was diagnosed with pulmonary pleomorphic carcinoma of the right lower lobe. The carcinoma metastasized to the brain, lungs, pleura, and mediastinal lymph nodes. It was positive for epidermal growth factor receptor (EGFR) L858R mutation, and tumor cells highly expressed programmed death-ligand 1(PD-L1). Atezolizumab was initiated as the fourth treatment. After three days, he developed cardiac tamponade and immediately underwent pericardial drainage. Computed tomography showed bilateral ground-glass opacity (GGO), significant worsening of multiple lung metastases, and increased size of metastatic lesions. Newly developed metastasis was noted in the lung, and the patient's respiratory condition rapidly deteriorated. He died of respiratory failure on day 13 after atezolizumab administration. The autopsy showed widespread metastasis in all lobes of the bilateral lungs, cardiac tamponade due to carcinomatous pericarditis, carcinomatous lymphangiopathy, and multiple lung metastases, which were thought to be comprehensively the cause of death. These symptoms suggested hyperprogressive disease (HPD). Hence, we report the first case of HPD following atezolizumab therapy for pulmonary pleomorphic carcinoma with EGFR mutation.

Lung Adenocarcinoma with Paraneoplastic Hyper-Eosinophilia Not Responding To Pembrolizumab

Background:Paraneoplastic hyper-eosinophilia associated with metastatic lung adenocarcinoma is a rare finding and has been associated with a poor prognosis when present. Early hyper-eosinophilia appearing following non-small cell lung cancer (NSCLC) treatment with immune checkpoint inhibitors (ICI) has been previously reported with contradictory outcomes.Case summary:We present the case of an elderly man with newly diagnosed metastatic lung adenocarcinoma and baseline hyper-eosinophilia, treated with pembrolizumab, and showing evidence of significant and rapid disease progression suggestive of hyper-progressive disease, worsening baseline hyper-eosinophilia, and a fatal outcome within 1 month of therapy initiation.Conclusion:Pre-treatment hyper-eosinophilia could represent a predictive factor of an unfavorable response to ICI treatment in cases of NSCLC. Additional similar cases are needed to draw a more conclusive relationship.

Immune checkpoint inhibitor-associated hypercalcaemia.

Immune checkpoint inhibitors (CPIs) have recently become a cornerstone for the treatment of different advanced cancers. These drugs have the ability to reactivate the immune system against tumour cells but can also trigger a myriad of side effects, termed immune-related adverse events (irAEs). Although there are numerous reports of CPI-related endocrinopathies, hypercalcaemia as a suspected irAE is not well documented. The mechanisms of CPI hypercalcaemia are not clearly established. However, in our review, four distinct causes emerged: endocrine disease-related, sarcoid-like granuloma, humoral hypercalcaemia due to parathyroid-related hormone and hyperprogressive disease following CPI initiation. Prompt recognition of hypercalcaemia and the institution of therapy can be lifesaving, affording the opportunity to address the underlying aetiology. In this review we discuss the incidence, diagnosis and management of immune-related hypercalcaemia in oncological patients receiving CPI agents.

Hyper-Progressive Disease: The Potential Role and Consequences of T-Regulatory Cells Foiling Anti-PD-1 Cancer Immunotherapy.

Simple SummarySince immune cells were found to attack cancer cells, strategies have been developed to sustain anti-cancer immune functions to prevent them from becoming exhausted in the midst of war. Immune checkpoint blockade therapy has gained significant traction with its ability to fast-track activation of immune cells as well as revive dormant immune cells. A prominent target for such treatment is programmed cell death protein 1 (PD-1). The natural role of PD-1 is in regulating the activity of immune cells, hence the term ‘checkpoint’. Blocking PD-1 can be effective especially when immune cells have easy access to cancer tissues. However, the immune cell population also contains cells that protect cancer cells from anti-cancer immune cells. One of these is the regulatory T-cell (Treg) subset, which is also regulated by PD-1. In this article, we review the downside of blocking PD-1 in Tregs when using PD-1 blockade therapy to treat cancer.Antibody-mediated disruption of the programmed cell death protein 1 (PD-1) pathway has brought much success to the fight against cancer. Nevertheless, a significant proportion of patients respond poorly to anti-PD-1 treatment. Cases of accelerated and more aggressive forms of cancer following therapy have also been reported. Termed hyper-progressive disease (HPD), this phenomenon often results in fatality, thus requires urgent attention. Among possible causes of HPD, regulatory T-cells (Tregs) are of suspect due to their high expression of PD-1, which modulates Treg activity. Tregs are a subset of CD4+ T-cells that play a non-redundant role in the prevention of autoimmunity and is functionally dependent on the X chromosome-linked transcription factor FoxP3. In cancer, CD4+FoxP3+ Tregs migrate to tumors to suppress anti-tumor immune responses, allowing cancer cells to persist. Hence, Treg accumulation in tumors is associated with poor prognosis. In mice, the anti-tumor efficacy of anti-PD-1 can be enhanced by depleting Tregs. This suggests Tregs pose resistance to anti-PD-1 therapy. In this article, we review the relevant Treg functions that suppress tumor immunity and the potential effects anti-PD-1 could have on Tregs which are counter-productive to the treatment of cancer, occasionally causing HPD.

Anti-PD1 checkpoint inhibitor with or without chemotherapy for patients with recurrent and metastatic nasopharyngeal carcinoma

PurposeTo compare the efficacy and safety of anti-PD1 checkpoint inhibitor plus chemotherapy with anti-PD1 checkpoint inhibitor alone in recurrent and metastatic nasopharyngeal carcinoma (R/M NPC) progressing after first or subsequent-line therapy. Methods and materialsA total of 67 patients with recurrent and metastatic nasopharyngeal carcinoma from our hospital were included. All patients were sorted into two arms: anti-PD1 checkpoint inhibitor+ chemotherapy arm and anti-PD1 checkpoint inhibitor arm. We retrospectively estimated objective response rate (ORR), progression-free survival (PFS) and overall survival (OS) in patients of both arms. Chi-square test and Kaplan–Meier methodology were used to analyze. ResultsFrom September 2018 to March 2020, this research included 67 patients. For anti-PD1 checkpoint inhibitor+ chemotherapy arm, partial response and stable disease were observed in fourteen and 11 patients, respectively, for an ORR of 53.8%. For anti-PD1 checkpoint inhibitor arm, complete response and partial response were observed in one and 5 patients, respectively, for an ORR of 14.6%. The incidence of hyperprogressive disease was higher in the anti-PD1 checkpoint inhibitor group compared with anti-PD1 checkpoint inhibitor+ chemotherapy group (39.0% vs 3.8%, p<0.05). Univariable analyses discovered that 6-month PFS and OS benefits were observed for anti-PD1 checkpoint inhibitor+ chemotherapy arm compared to anti-PD1 checkpoint inhibitor arm (65.4% vs. 28.6%, P = 0.001; 100.0% vs. 73.5%, P = 0.014). ConclusionIn present study, we revealed that adding chemotherapy to anti-PD1 checkpoint inhibitor significantly improved 6-month PFS and OS for patients with R/M NPC progressing after first-line therapy. It warrants further study.

Hyperprogressive disease: A distinct pattern of progression to immune checkpoint inhibitors.

Hyperprogressive disease (HPD) is a novel pattern of progression attributed to immune checkpoint inhibitor (ICI) treatment and characterized by a dramatic tumor surge and poor survival. The concept of HPD is still controversial, while the definition varies widely across studies. Although HPD has been associated with multiple clinicopathological and molecular features, there is no biomarker to predict this detrimental effect of immunotherapy and the underlying mechanism remains unknown. The aim of this comprehensive review is to summarize current data on HPD and present the controversies and clinical care management challenges for oncologists treating patients with ICIs.

Predicting hyperprogressive disease in patients with advanced hepatocellular carcinoma treated with anti-programmed cell death 1 therapy.

BackgroundHyperprogressive disease (HPD) is a new progressive pattern in patients with advanced hepatocellular carcinoma (HCC) treated with programmed cell death 1 (PD-1) inhibitors. We aimed to investigate risk factors associated with HPD in advanced HCC patients undergoing anti-PD-1 therapy.MethodsA total of 69 patients treated with anti-PD-1 therapy between March 2017 and January 2020 were included. HPD was determined according to the time to treatment failure, tumour growth rate, and tumour growth rate ratio. Univariate and multivariate analyses were performed to identify clinical variables significantly associated with HPD. A risk model was constructed based on clinical variables with prognostic significance for HPD.FindingsOverall, 10 (14·49%) had HPD. Haemoglobin level, portal vein tumour thrombus, and Child-Pugh score were significantly associated with HPD. The risk model had an area under the curve of 0·931 (95% confidence interval, 0·844–1·000). Patients with HPD had a significantly shorter overall survival (OS) than that of the patients with non-HPD (p < 0·001). However, there was no significant difference in OS between PD (progressive disease) patients with and without HPD (p = 0·05).InterpretationWe identified three clinical variables as risk factors for HPD, providing an opportunity to aid the pre-treatment evaluation of the risk of HPD in patients treated with immunotherapy.FundingThis study was funded by the National Natural Science Foundation of China (81571664, 81871323, and 81801665); National Natural Science Foundation of Guangdong Province (2018B030311024); Scientific Research General Project of Guangzhou Science Technology and Innovation Commission (201707010,328); and China Postdoctoral Science Foundation (2016M600145).

Comparison of Fast-Progression, Hyperprogressive Disease, and Early Deaths in Advanced Non-Small-Cell Lung Cancer Treated With PD-1/PD-L1 Inhibitors or Chemotherapy.

Hyperprogressive disease (HPD), fast progression (FP), and early death (ED) have been described in 13.8%, 4.7%, and 5.6% and in 5.1%, 2.8%, and 6.8%, respectively, of patients with non-small-cell lung cancer (NSCLC) treated with single-agent programmed cell death ligand 1 inhibitors (ICI) or chemotherapy, respectively. Whether FP/ED and HPD represent overlapping patterns is unknown. FP, ED, and HPD were retrospectively assessed in patients with NSCLC treated with single-agent ICI or chemotherapy. Eligibility required 2 computed tomography (CT) scans before and 1 CT scan during treatment. (1) HPD, (2) FP, (3) ED were defined as (1) RECIST version 1.1 progression at first CT scan and tumor growth rate variation per month > 50%, (2) ≥ 50% increase in the sum of the longest diameters of target lesions within 6 weeks from baseline, and (3) death as a result of radiologic progression within 12 weeks from baseline CT scan, respectively. Of 406 ICI-treated NSCLC, 56 patients (13.8%), 9 patients (2.2%), and 36 patients (8.8%) were HPD, FP, and ED, respectively. Eight (14.2%) and 20 (35.7%) of 56 patients with HPD were also FP and ED. ED significantly correlated with baseline Eastern Cooperative Oncology Group performance status ≥ 2 compared with HPD (33% v 13%, P = .02). Overall survival was significantly longer for HPD (3.4 months [95% CI, 2.7 to 4.0 months]) compared with FP (0.7 months [95% CI, 0.6 to 0.8 months]); HR, 0.18 [95% CI, 0.08 to 0.42]; P < .0001) and ED (1.4 months [95% CI, 1.3 to 1.6 months]); HR, 0.19 [95% CI, 0.11 to 0.34]); P < .0001), whereas it did not differ between FP and ED (HR, 1.3 [95% CI, 0.56 to 3.0]; P = .55). Of 59 patients with NSCLC treated with single-agent chemotherapy, the HPD, FP, and ED rates were 5.1%, 1.7%, and 6.7%, respectively. FP, ED, and HPD represent distinct progression patterns with limited overlap and different survival outcomes.

Clinical outcome and toxicity for immunotherapy treatment in metastatic cancer patients.

Immunotherapy (IO) is known to improve survival and outcome in various types of solid tumours. However, nonspecific activation of the immune system also affects various organ systems leading to the immune-related adverse events (irAEs). Systematic reviews of IO trials show that the actual incidence of irAEs may be higher than expected. Little is known about the impact of these irAEs on patients' clinical outcome, palliative care (PC) needs and hospice service use. This is a single centre, retrospective review study of metastatic cancer patients between June 2016 to June 2017 who consecutively received immune checkpoint inhibitors with anti-PD1 in our institution. The computerized medical record, body weight chart, blood test results and in-patient assessment records were reviewed. The study was approved by the Institutional Review Board of the University of Hong Kong/ Hospital Authority Hong Kong West Cluster and conducted in compliance with the Declaration of Helsinki. Fifty patients received immune checkpoint inhibitors with anti-PD1 consecutively between June 2016 to June 2017 were retrospectively reviewed. The median age was 64 years old (range: 22 to 87 years old). Thirty-three of them were male (66%) patients. Twenty-five patients (50%) experienced any grade irAE. Ten patients (20%) experienced grade III/IV irAE among which 7 patients (14%) discontinued IO treatment permanently and 2 patients (4%) died due to grade III/IV toxicity. The development of grade III/ IV irAE required in-patient management, with a median duration of hospitalization of 6.5 days (range: 1 to 38 days). The response rate was 36% vs. 4% (P=0.01), median PFS (15.8 vs. 6.2 months, P=0.26), median OS (21.0 vs. 12.9 months, P=0.05) for patients with or without irAEs, respectively. The occurrence of any grade irAE was associated with a trend of improved overall survival (OS) on IO (P=0.05). Five patients (10%) developed hyper-progressive disease and received only one course of treatment before they died. Only 2 patients (4%) developed pseudo-progressive disease during treatment. Thirty-five mortalities (70%) occurred at the time of assessment of the study, of which 18 patients (36%) received PC consultations and 12 patients (24%) received hospice care before they passed away. Our study underscored the need for enhanced selection criteria to identify patient subgroups which benefit most from IO, and the need to involve PC and hospice services early for those non-responders or unlikely responders. Patient education and a dedicated multi-disciplinary team approach is needed to identify and treat irAE timely to prevent severe morbidities and mortalities.

Comparison of Different Methods for Defining Hyperprogressive Disease in NSCLC

IntroductionHyperprogressive disease (HPD) as a consequence of immune checkpoint inhibitors in NSCLC has been reported in multiple studies. However, inconsistent results in incidence and survival outcomes within studies, together with different assessment methods, have led to increasing controversy regarding the concept of HPD. MethodsConsecutive patients treated with nivolumab (N = 42) or docetaxel (N = 37) were evaluated. HPD was quantified by applying three different methods (tumor growth rate [TGR], tumor growth kinetics [TGK], and Response Evaluation Criteria in Solid Tumors version 1.1 [RECIST 1.1]). HPD rates were compared between and within both cohorts using the different methods. ResultsUsing TGR, TGK, and RECIST 1.1, we identified seven (16.7%), seven (16.7%), and six (14.3%) patients with HPD in the nivolumab cohort and three (8.1%), four (10.8%), and five (13.6%) in the docetaxel cohort, respectively. We observed a higher concordance between TGR and TGK (90.1%) compared with RECIST 1.1 (31.3% and 37.5% with TGR and TGK, respectively). We found no significant differences in the overall survival between patients with progressive disease and HPD in either cohort. ConclusionsTGR and TGK revealed high concordance rates for identifying patients with HPD in NSCLC. The incidence of HPD was numerically higher in patients treated with immune checkpoint inhibitors. Standardization of methods for measuring HPD and its exploration in larger studies are needed to establish its clinical meaning in NSCLC.

Predicting Hyperprogressive Disease in Patients with Advanced Hepatocellular Carcinoma Treated with Anti-Programmed Cell Death 1 Therapy

Predicting Hyperprogressive Disease in Patients with Advanced Hepatocellular Carcinoma Treated with Anti-Programmed Cell Death 1 Therapy

Immunotherapy for Ovarian Cancer: Adjuvant, Combination, and Neoadjuvant.

Ovarian cancer is the most lethal gynecologic malignancy. Surgery and chemotherapy are the primary treatments for ovarian cancer; however, patients often succumb to recurrence with chemotherapeutic resistance within several years after the initial treatment. In the past two decades, immunotherapy has rapidly developed, and has revolutionized the treatment of various types of cancer. Despite the fact that immunotherapy response rates among ovarian cancer patients remain modest, treatment with immune checkpoint inhibitors (ICIs), chimeric antigen receptor (CAR)- and TCR-engineered T cells is rapidly developing. Therapeutic efficiency could be improved significantly if immunotherapy is included as an adjuvant therapy, in combination with chemotherapy, radiation therapy, and the use of anti-angiogenesis drugs, and poly ADP ribose polymerase inhibitors (PARPi). Newly developed technologies that identify therapeutic targets, predict treatment efficacy, rapidly screen potential immunotherapy drugs, provide neoadjuvant immunotherapy, and utilize nanomedicine technology provide new opportunities for the treatment of ovarian cancer, and have the potential to prolong patient survival. However, important issues that may hinder the efficacy of such approaches, including hyperprogressive disease (HPD), immunotherapy-resistance, and toxicity of the treatments, including neurotoxicity, must be taken into account and addressed for these therapies to be effective.

Factors predicting hyperprogression in patients with advanced ovarian cancer receiving anti-programmed cell death 1-therapy

Objective: Hyperprogressive disease (HPD) is one of the unconventional responses to immunotherapy. It is associated with a rapid increase in tumor growth rate following immune checkpoint inhibitor (ICI) therapy. Targeted programmed cell death-1 (PD-1) inhibitors (e.g., pembrolizumab and nivolumab) have recently been approved for use in patients with advanced ovarian cancer. HPD has also been observed in this group of patients and is reportedly related to a worse outcome compared with the so-called “conventional” progression. Therefore, it is important to identify factors that predict HPD and select appropriate patients before starting ICI therapy.