Incidence Of Hyperprogressive Disease Research Articles

Predominance of hyperprogression in mucosal melanoma during anti-PD-1 monotherapy treatment.

A minority subset of immunotherapy patients manifests hyperprogressive disease (HPD), with the disparity in melanoma subtypes yet to be reported. This study aimed to delineate the proportion and prognosis of HPD in patients receiving anti-PD-1 monotherapy and to identify patient with HPD clinical characteristics across melanoma subtypes to inform clinical decision making. Utilizing 4 established HPD definitions, the incidence of HPD in patients with advanced melanoma on anti-PD-1 monotherapy was determined. The incidence rates and prognostic abilities of various HPD definitions were compared to elect the most effective one. This facilitated a comparative analysis of subtypes and clinical features between patients with HPD and traditional progression. A total of 262 patients with advanced melanoma treated with anti-PD-1 monotherapy from 5 prospectively registered clinical trials were included in the study. The objective response rate (ORR) and disease control rate (DCR) was 21% and 58%, respectively, with 42% showcasing progression disease. The HPD incidences by 4 definitions were 13.2%, 16.8%, 10.8%, and 28.2%. All definitions effectively segregated HPD patients, with significantly poorer outcome than other progressive patients. The Delta TGR > 100 definition was the most indicative of a reduced overall survival, corroborated by the highest hazard ratio and statistical significance. The number of metastatic organs over 2 is a risk factor for HPD (OR = 4.18, P = .0103). Mucosal melanoma was the HPD prevalent subtype (OR = 3.13, P = .0489) in multivariable analysis, which is also indicated by RECIST criteria (P = .005). A delta TGR exceeding 100 best identified HPD patients in the advanced melanoma population treated with anti-PD-1 monotherapy. Hyperprogression was notably prevalent in mucosal melanoma patients with multiple metastatic organs. Caution against HPD is warranted when applying anti-PD-1 monotherapy in mucosal subtype.

Predictive Nomogram for Hyperprogressive Disease During Anti-PD-1/PD-L1 Treatment in Patients with Advanced Non-Small Cell Lung Cancer.

Various studies have reported that anti-PD-1/PD-L1 treatment may lead to the rapid development of tumors called hyperprogressive disease (HPD). A nomogram for HPD prediction in NSCLC patients is urgently needed. This retrospective cohort study included 176 cases for establishing a model of HPD prediction and 85 cases for validation in advanced NSCLC patients treated with PD-1/PD-L1 inhibitors. HPD was defined as tumor growth rate (TGR, ≥ 2), tumor growth kinetics (TGK, ≥ 2) or time to treatment failure (TTF, ≤ 2 months). Univariate and multivariate logistic regression were used to estimate the specified factors associated with HPD. Then, the nomogram was developed and validated. Anti-PD-1/PD-L1 therapy resulted in a 9.66% (17/176) incidence of HPD in advanced NSCLC. The overall survival (OS) and progression-free survival (PFS) in patients with HPD were significantly shorter than those in patients without HPD (OS: 7.00 vs 12.00 months, P<0.01; PFS: 2.00 vs 5.00 months, P<0.001, respectively). The HPD prediction nomogram included APTT (P<0.01), CD4+ CD25+ CD127-low cells (Treg cells) (P<0.01), the presence of liver metastasis (P<0.05), and more than two metastatic sites (P<0.05). Then, patients were divided into two groups by the "HPD score" calculated by the nomogram. The C-index was 0.845, while the area under the curve (AUC) was 0.830 (sensitivity 75.00%, specificity 91.70%). The calibration plot of HPD probability showed an optimal agreement between the actual observation and prediction by the nomogram. In the validation cohort, the AUC was up to 0.960 (sensitivity 88.70%, specificity 89.80%). The nomogram was constructed with the presence of liver metastasis, more than two metastatic sites, lengthened APTT and a high level of Treg cells, which could be used to predict HPD risk.

Abstract 5200: The incidence and risk factors of hyperprogressive disease(HPD) in non-small cell lung cancer(NSCLC) treated with immune checkpoint inhibitors(ICI)

Abstract Background: HPD is an unexpected rapid acceleration of tumor growth reported for patients treated with ICI. The definition of HPD is not fully established and risk factors are uncertain. Our aim in this study was to find the incidence of HPD as well as its significant clinical and genetic risk factors. Method: A total of 203 patients with NSCLC who received ICI at Northwestern Memorial Hospital during 2008-2020 were included. Tumor growth kinetics (TGK) on immunotherapy and TGK pre-immunotherapy were collected and TGK ratio (TGKR) was calculated. HPD was defined as TGKR≥2. Result: HPD was observed in 16% (n=33) of patients. HPD was significantly associated with high ECOG (3-4 vs 1-2) [OR = 4.52, 95% CI = 1.31 to 16.29, P = 0.01], presence of bone metastasis [OR = 2.51, 95% CI = 1.10 to 5.28, P = 0.01], neutrophils/lymphocyte ratio(NLR) ≥5 [OR = 2.68, 95% CI = 1.24 to 5.81 P = 0.01], thrombocytosis (platelet count &amp;gt;450k) [OR = 5.31, 95% CI = 2.07 to 14.70, P=0.0003], and treatment with PD-L1 inhibitor vs PD-1 inhibitor [OR = 2.14, 95% CI= 0.97 to 4.68, P= 0.068]. HPD was inversely associated with positive PD-L1 expression [OR = 0.34, 95% CI = 0.13 to 0.86, P = 0.01], ICI combined with chemotherapy vs ICI monotherapy [OR = 0.24, 95% CI = 0.055 to 0.97, P=0.04], and positive TTF-1 expression [OR = 0.46, 95% CI = 0.21 to 1.02, P=0.057]. HPD was not associated with histology of NSCLC (adenocarcinoma, squamous cell carcinoma, large cell carcinoma, and large cell neuroendocrine carcinoma), age(&amp;lt;70, ≥70), sex, smoking history, number of metastatic lesions (&amp;lt;3, ≥3), brain metastasis, liver metastasis, brain metastasis before treatment initiation, EGFR mutation, TP53 mutation, BRAF mutation, and TNM staging. Conclusion: The incidence of HPD in NSCLC treated with ICI was consistent with current literature. High NLR and platelet count are suggestive of an immunosuppressive environment that could contribute to the rapid growth of tumors. To our knowledge, this is the first study to report an inverse correlation of PD-L1 expression and TTF-1 expression with HPD. The strength of our study lies in a large number of patients. Further studies on validating risk factors of HPD and exploring their associated mechanisms are warranted. Citation Format: Hyeonseon Kim, Yeun Ho Lee, Chiwoo Song, Leeseul Kim, Min Jeong Kim, Horyun Choi, Jinah Kim, Young Kwang Chae. The incidence and risk factors of hyperprogressive disease(HPD) in non-small cell lung cancer(NSCLC) treated with immune checkpoint inhibitors(ICI) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5200.

Abstract 5209: Hyperprogression in various solid cancers treated with immune checkpoint inhibitors in the real world

Abstract Purpose: Immune checkpoint inhibitors (ICIs) have revolutionized the cancer prognosis in various cancer types. However, ICIs may trigger accelerated tumor progression, regarded as hyperprogressive disease (HPD), in certain patients, and it is still challenging to define HPD. We aimed to investigate the landscape of HPD and the prognostic value of its different definitions in advanced solid cancer patients treated with ICIs. Methods: We conducted a multicenter, prospective cohort study for solid cancer patients receiving ICIs. Among them, only unresectable or metastatic cancer patients were included in this analysis. Tumor response was evaluated according to RECIST 1.1. In patients who showed progressive disease (PD) by RECIST 1.1 at the first tumor evaluation, HPD was defined according to the following three criteria: A) tumor growth kinetics (TGK) ratio (TGKpost-ICI/TGKpre-ICI &amp;gt;=2, B) &amp;gt;=10mm increase in sum of target lesion (SUMtarget)and at least one of the following two criteria - 1) &amp;gt;=40% increase in SUMtarget or 2) &amp;gt;=20% increase in SUMtarget and the appearance of new lesions in at least two different organs, C) TGK ratio &amp;gt;=2 and &amp;gt;50% increase in SUMtarget. The discriminatory ability of three definitions in terms of overall survival (OS) were evaluated by the chi-square, C-statistics, and prediction error with integrated Brier score. Results: A total of 427 patients were included; head and neck (n=22, 5.2%), lung (n=173, 40.5%), breast (n=8, 1.9%), gastrointestinal tract (n=99, 23.2%), hepatobiliary pancreas (n=57, 13.3%), genitourinary (n=56, 13.1%), melanoma (n=5, 1.2%), and others (n=7, 1.6%). Incidences of HPD were 4.9%, 14.8%, and 11.5% in definition A, B, C, respectively. The incidence of HPD was relatively low (2.7%-9.5%) in non-small cell lung cancer compared to other cancer types (10.1%-21.5% in esophagogastric cancer, 3.9%-21.6% in hepatobiliary pancreas cancer, and 5.5%-22.5% in genitourinary cancer). Median OS was the worst for patients with HPD, which ranged from 4.8 months to 4.9 months according to definition A-C. After multivariate analysis adjusting for cancer types, ICIs types, and the number of prior anti-cancer therapy, each definition remained a significant factor for OS (P&amp;lt;0.001, respectively). Both chi-square and C-statistics of definition B were higher than those of definition A and C, although prediction error with integrated brier scores was similar between three definitions. Conclusions: Incidences of HPD appear to be various according to its definitions and cancer types. Given that the RECIST-based definition B not requiring pre-ICI imaging, showed similar discriminatory ability to predict dismal OS compared to TGK-based ones, it may be the most feasible and convenient measure to capture HPD in daily clinical practice. Citation Format: Jwa Hoon Kim, Soohyeon Lee, Min Hee Hong, Jee Hyun Kim, Eun Joo Kang, Tae-Yong Kim, Yeon Hee Park, Ji-Youn Han, Il-Hwan Kim, Sang-We Kim, Dae Ho Lee, Jae Lyun Lee, Jae Cheol Lee, Chang-Min Choi, Changhoon Yoo, Shinkyo Yoon, Jae Ho Jeong, Seyoung Seo, Sun Young Kim, Jin-Hee Ahn, Sook Ryun Park. Hyperprogression in various solid cancers treated with immune checkpoint inhibitors in the real world [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5209.

The incidence and predictive factors of hyperprogressive disease (HPD) in non-small cell lung cancer (NSCLC) treated with immune checkpoint inhibitors (ICI).

e21025 Background: HPD is an unexpected and rapid acceleration of tumor growth in patients following treatment with ICI. The definition of HPD is not fully established and risk factors are uncertain. Our aim in this study was to find the incidence of HPD as well as its significant clinicopathological and genetic predictive factors. Methods: A total of 203 patients with NSCLC treated with ICI at Northwestern Memorial Hospital during 2015-2020 were included. Clinicopathological data were retrospectively gathered and analyzed. Tumor growth kinetics (TGK) of pre-immunotherapy and post-immunotherapy were collected and TGK ratio (TGKr) was calculated. HPD was defined as TGKr≥2. Results: HPD was observed in 16% (33/203) of patients. There was a statistically significant difference in overall survival(OS) between the two groups (non-HPD vs. HPD) [OR = 2.39, P &lt; 0.01]. The progression-free survival(PFS) also showed a statistically significant difference in patients (non-HPD vs HPD) [OR = 3.4, P &lt; 0.01]. The median OS and PFS of patients with HPD were 13.57 months and 2.2 months respectively. The median OS and PFS of patients without HPD were 30.67 months and 7.3 months respectively. HPD was significantly associated with performance status (3-4 vs. 1-2) [OR = 4.52, P = 0.01], presence of bone metastasis [OR = 2.51, P = 0.01], neutrophils/lymphocyte ratio(NLR) ≥5 [OR = 2.68, P = 0.01], thrombocytosis (platelet count &gt; 450k) [OR = 5.31, P &lt; 0.01], and treatment with PD-L1 inhibitor vs. PD-1 inhibitor [OR = 2.14, P = 0.06]. HPD was inversely associated with positive PD-L1 expression [OR = 0.34, P = 0.01], ICI combined with chemotherapy vs. ICI monotherapy [OR = 0.24, P = 0.04], and positive TTF-1 expression [OR = 0.46, P = 0.06]. HPD was not associated with histological subtypes of NSCLC, age(&lt; 70, ≥70), sex, smoking history, number of metastatic lesions (&lt; 3, ≥3), brain metastasis, liver metastasis, brain metastasis before treatment initiation, EGFR mutation, TP53 mutation, BRAF mutation, TNM staging, tumor mutational burden (TMB) (&lt; 10, ≥10), microsatellite stability index (MSI), human leukocyte antigen-1 (HLA-1) heterozygosity, hemoglobin(≤12, &gt; 12), albumin(≤3.5, &gt; 3.5), and LDH(≤240, &gt; 240). Conclusions: The incidence of HPD, 16%, was consistent with current literature. NLR ≥5, platelet count &gt; 450k, poor performance status, presence of bone metastasis, treatment with PD-L1 inhibitor, negative PD-L1 expression, negative TTF-1 expression, and ICI monotherapy were predictors of HPD. To our knowledge, this is the first study to report an inverse correlation of TTF-1 expression, and non correlation of HLA-1 heterozygosity with HPD. The strength of our study is that we analyzed recently emerging next-generation sequencing (NGS) data to find novel predictors of HPD. Further studies on validating risk factors of HPD and exploring their associated mechanisms are warranted.

The association of chromosome 11q13 amplification with the hyperprogressive disease in unresectable hepatocellular carcinoma patients underwent the immunotherapy.

e16156 Background: Hyperprogressive disease (HPD) is characterized by an acceleration of tumor growth during systemic therapy, which usually refers to immunotherapy. The incidence of HPD in patients with hepatocellular carcinoma (HCC) is reported to be 12.7%. Amplification of the chromosome 11q13 locus, including cyclin D1 (CCND1), FGF3, FGF4 and FGF19, is frequent in many cancers and correlates with inferior outcomes with immunotherapy. However, little is known about the association between chromosome 11q13 amplification and HPD of HCC. Methods: 58 HCC patients who underwent the next-generation sequencing (NGS) in our institution from September 2017 to April 2018 were enrolled in this study. Among them, 30 patients had unresectable advanced or recurrent HCC and received anti-tumoral therapy, including 18 cases (Group 1) receiving programmed cell death-1 (PD-1) monoclonal antibody immunotherapy (with or without tyrosine kinase inhibitors, TKIs) and 12 cases (Group 2) receiving local regional therapy (with or without TKIs). Based on radiological surveillance, HPD was defined as: 1. Tumor growth kinetics (TGK) or tumor growth rate (TGR) &gt; 2; 2. Time to treatment failure &lt; 2 months. Results: In our dataset, chromosome 11q13 amplification (11q13 Amp) was seen in 11 patients (19.0%). 11q13 Amp was associated with worse clinical baseline, with a significant concentration in patients with BCLC C stage, tumor numbers of ≥ 3 and ECOG 1 score. Group 1 had an objective response rate (ORR) of 50.0% and Group 2 had an ORR of 54.5%. There was no significant difference in progression-free survival (PFS) between these two groups. 3 patients showed HPD in Group 1, all of whom carried 11q13 Amp. Compared to non-11q13 Amp patients, patients with 11q13 Amp had worse PFS (log-rank P= 0.001) in Group 1. While there was no significant difference of PFS between 11q13 Amp and non-11q13 Amp patients in Group 2. We further investigated the efficacy of different treatment strategies based on 11q13 Amp status. These 11q13 Amp patients in Group 1 showed worse PFS, compared to Group 2 (log-rank P= 0.025). However, patients with non-11q13 Amp showed similar outcomes between these two groups (log-rank P= 0.70). Conclusions: Our findings suggested that 11q13 Amp was associated with HPD of HCC. PD-1 monoclonal antibody showed poor efficacy in patients with 11q13 Amp, therefore targeted treatment strategies might be more suitable for such patients. Meanwhile, the role of 11q13 Amp as putative predictive biomarkers of HPD needs further validation in larger cohorts.

Mechanism underlying the immune checkpoint inhibitor-induced hyper-progressive state of cancer.

Immune checkpoint inhibitors (ICIs) are gradually replacing chemotherapy as the cornerstone of the treatment of advanced malignant tumors because of their long-lasting and significant effect in different tumor types and greatly prolonging the survival time of patients. However, not all patients can respond to ICIs, and even rapid tumor growth after treatment with ICI has been observed in a number of clinical studies. This rapid progression phenomenon is called hyper-progressive disease (HPD). The occurrence of HPD is not uncommon. Past statistics show that the incidence of HPD is 4%-29% in different tumor types, and the progression-free survival and overall survival of patients with HPD are significantly shorter than those of the non-HPD progressor group. With the deepening of the study of HPD, we have established a preliminary understanding of HPD, but the diagnostic criteria of HPD are still not unified, and the addition of biomarkers may break this dilemma. In addition, quite a few immune cells have been found to be involved in the occurrence and development of HPD in the tumor microenvironment, indicating that the molecular mechanism of HPD may be triggered by a variety of ongoing events at the same time. In this review, we summarize past findings, including case reports, clinical trials, and fundamental research; compare the diagnostic criteria, incidence, and clinical prognostic indicators of HPD in different studies; and explore the molecular mechanism and future research direction of HPD.

Long-term Follow-up and Patterns of Response, Progression, and Hyperprogression in Patients after PD-1 Blockade in Advanced Sarcoma.

Programmed cell death protein 1 (PD-1) blockade can mediate objective responses in advanced sarcomas, but their durability has not been established and it is unclear if hyperprogressive disease (HPD) occurs in sarcomas treated with PD-1 inhibitors. We pooled patients who were treated prospectively with nivolumab or pembrolizumab as monotherapy or with bempegaldesleukin, epacadostat, ipilimumab, or talimogene laherparepvec. We did a new independent assessment for HPD and analyzed clinical, pathologic, and genomic data from baseline tumor biopsies. Our primary endpoint was the incidence of HPD; secondary endpoints were clinical or genomic correlates of response or HPD. We treated 134 patients with advanced sarcoma from 2015 to 2019. Twenty-one patients (16%) had a complete or partial response (CR/PR), and 30% of responses were durable for over 2 years. Forty-eight (36%) patients had stable disease (SD), 45 (34%) had progressive disease without HPD (PD), and 15 (11%) had HPD. Five patients (4%) were not evaluable for HPD. The sarcoma subtypes, sites of metastasis, clinical course, and genomic alterations in patients with PD and HPD were similar, except HPD tumors were smaller at baseline. In patients with advanced sarcoma, PD-1 blockade can mediate durable responses. HPD occurs in sarcoma at an incidence that is similar to what has been reported in other solid tumors, but patients with HPD were clinically and biologically similar to those who had PD. Further research is required to establish whether HPD is a biologically distinct phenomenon and whether a theoretical risk of HPD should influence patient management.

1527MO Biomarkers of response and hyperprogression in patients with sarcoma treated with checkpoint blockade

Checkpoint blockade with antibodies against PD-1 can mediate objective responses in selected sarcomas. There are few established predictors of response, and the incidence of hyperprogressive disease (HPD) is unknown.

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.

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.

Hyperprogression on immune checkpoint inhibitors: A single institution, real-world retrospective analysis.

e15143 Background: Hyper progressive disease (HPD) refers to the paradoxical acceleration of tumor growth following immune-checkpoint inhibitor (ICI) therapy. We aimed to evaluate the factors associated with HPD and its impact on overall survival (OS) in patients treated with ICI in our institution. Methods: We retrospectively reviewed the charts of 104 patients with solid tumors diagnosed from 04/01/2011 to 06/30/2018 who received ICI at John H. Stroger Jr. Hospital of Cook County, Chicago, IL. The OS, incidence of HPD and their demographic, clinical and laboratory correlates were recorded. HPD was defined as tumor growth ratio &gt; = 2 on CT imaging after treatment with at least 2 cycles. The Log-rank method survival analysis was done to compare survival of patients with and without HPD. Results: Majority of patients were treated with either nivolumab (71.1%) or pembrolizumab (21.2%) in the second (50%) or third line (29.8%) setting. After excluding two patients without follow up scans, 14 out of 102 patients (13.7%) had HPD during the course of study. The patients with small cell lung cancer had higher incidence of HPD (4 out of 9). Patients who had evidence of HPD had significantly shorter OS (22.21±16.23 months versus 37.52±230.8 months, P value = 0.01). The variables associated with HPD were liver metastasis (Pearson Chi squared = 18.68, P value &lt; 0.001) and persistently high LDH ( &gt; 240 IU/L) during therapy (Pearson Chi squared = 16.85, P value &lt; 0.001). Other variables that were significantly associated with HPD on univariate analysis, but not on multivariate analysis are as below. Conclusions: Although the etiopathogenesis of HPD is incompletely understood, the correlation of LDH to HPD is intriguing and warrants further studies as possible predictive marker of HPD. [Table: see text]

Hyperprogressive disease during treatment with immune checkpoint inhibitors in patients with advanced non-small cell lung cancer (NSCLC).

e21664 Background: Hyperprogressive disease (HPD) is a new pattern of progressión during immunotherapy and is described as an acceleration of tumor growth during treatment with immune checkpoint inhibitors (ICI). The rate of HPD in advanced solid tumors remains unknown, but it has been reported in 9% to 29% of patients in two recent series. Our aim was to study prognostic factors of HPD. Methods: We collected data of 104 patients diagnosed of advanced NSCLC and treated with ICI in monotherapy at our institution between December 2015 and December 2019. Several variables as clinical, tumour-related and therapeutical were included in the analysis. The variables were compared by chi-square and Fisher test, then we performed a multivariate logistic regression model to analyse the effects of the covariates, and finally we performed a Kaplan Meier survival analysis. We described HPD as disease progression at first evaluation with an increase in tumor growth rate exceeding 50%, according to Gustave Roussy criteria previously reported. Results: Cohort of 84 men and 20 women, median age of 67 years and 86% with Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1. 89% were active or ex-smokers and 11% had never smoked. 60% of patients had adenocarcinoma histology, 39% scamous and 1% had not otherwise specified (NOS) carcinoma histology. 3% of patients had III-B stage at the moment of start of immunotherapy, 37% M1a, 30% M1b and 30% M1c. 2 patients had driver mutations in EGFR gene. 41% of patients had unknown PDL1 status; 14% had no PDL1 expression, 14% low expression and 31% high expression. 78% of patients had progressed to prior line of treatment, while 22% were treatment-naive. Nine of 104 patients (8.7%) in our population developed HPD during treatment with ICI. HPD occured within the first two months of treatment in all 9 patients, and was associated with worse overall survival in the multivariate analysis by Cox regression (12.6 vs 2.6 months; HR 13.94, p &lt; 0.001). The presence of 2 or more metastatic sites was related to the development of HPD in the multivariate analysis (HR 8.59, p = 0.026). Conclusions: The incidence of HPD in our population is concordant with previous report about this topic. As previously described by Ferrara et al, HPD was significantly associated with a high number of metastatic sites before start treatment with ICI and correlated with poor outcomes in patients with advanced NSCLC.

EP1.01-55 Neoantigen Deletion Leads to Hyperprogressive Disease (HPD) in Non-Small Cell Lung Cancer (NSCLC) Treated with PD-1/PD-L1 Inhibitors

Hyperprogressive disease (HPD) is a distinct pattern of progression described in patients with cancer treated with PD-1/PD-L1 inhibitors. The incidence of HPD is reported to be 13.8% in advanced NSCLC. Recently multiple characteristics have been recognized to predict the risk of HPD, however the mechanism underlying have not been systemically studied. We report a Chinese patient who developed hyperprogressive disease after 4 cycles of PD-1 blockade treatment. Clinical and demographic data was collected from electronic records. Whole exome sequencing (WES) of the primary tumor was performed to identify tumor mutation burden (TMB) and tumor neoantigen burden (TNB) following the restricted pipeline. Liquid biopsy targeting ctDNA and T cell receptor (TCR) was constructed to monitor the efficacy of immunotherapy. A 70-year-old male with smoking history underwent chest CT scan in February 2018 and was found to have a right upper lobe mass with intrapulmonary metastasis in different lobes and multiple lymph nodes. Resection of right lower lung by video-assisted thoracic surgery (VATS) revealed poorly differentiated, squamous cell carcinoma. In July 2018, he progressed after two cycle of chemotherapy and radiation therapy targeting newly bone metastasis of lumbar spine, then he was screened to start Nivolumab at dose of 240mg daily/2 weeks. After four cycle of Nivolumab, he obtained PD and was assigned to palliative thoracic radiation therapy. The PD-L1 expression level of our patient was 1%≤TC<5%, next generation sequencing (NGS) didn’t show alteration in genes related to HPD, such as MDM2/MDM4 or EGFR. Blood sample retrieved before and after immunotherapy revealed the increase in bTMB (from 7.70 Muts/Mb to 18.00 Muts/Mb), however TNB truly expressed as neoantigens were rather lower compared to TMB, indicating the low immunogenicity of tumor. We also found a sharp fluctuate in the detection of driver genes mutations in ctDNA (TP53,CDKN2A,ERBB3,FBXW7), and the majority of high-frequency TCR dropped significantly during immunotharapy. It is reported that NSCLC with a high tumor mutation burden (TMB) may benefit from PD-1/PD-L1 inhibitors treatment, and TMB is considered as the surrogate of tumor neoantigen burden (TNB). However the deletion of neoantigen may occur at different level, including copy number variation at the DNA level, down-regulation of transcription level and inherited variation at the epigenetic level, resulting in the low immunogenicity of primary tumor. Deletion of neoantigen may provide a mechanism of immune evasion which leads to the resistance to PD-1/PD-L1 inhibitors. In this case, treatment of checkpoint inhibitors may activate certain signaling pathway of driver genes to support the hyperprogression disease (HPD). This case report focusing on neoantigen provides a new approach to predict the presence of hyperprogressive disease (HPD) before immunotherapy, and explains the potential mechanism of HPD.

Hyperprogressive Disease in Patients With Urothelial Carcinoma or Renal Cell Carcinoma Treated With PD-1/PD-L1 Inhibitors.

A rapid progression pattern called hyperprogressive disease (HPD) has been observed during early cycles of programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitor therapy. Data regarding HPD in patients with genitourinary cancer are limited. We included 203 patients with genitourinary cancer treated with PD-1/PD-L1 inhibitors between February 2015 and June 2018. HPD was defined as a greater than 50% increase in tumor burden, greater than 2-fold increase in tumor growth rate, or development of extensive (10 or more) new lesions. Patients (n= 102) with renal cell carcinoma (RCC) and patients (n= 101) with urothelial carcinoma (UC) were included. HPD was observed in 13 (6.4%) patients. The median overall survival for patients with progressive disease and HPD was 7.3 months and 3.5 months, respectively. HPD occurred more frequently in patients with UC than in those with RCC (11.9% vs. 0.9%; P= .01). Multivariate analysis showed that UC and creatinine above 1.2 mg/dL were independent predictive factors for HPD. A 30% increase in lymphocyte number following PD-1/PD-L1 inhibitor treatment was a negative predictor of HPD. The incidence of HPD in patients with UC treated with paclitaxel-based chemotherapy was one-third of those treated with PD-1/PD-L1 inhibitors. HPD developed predominantly in patients with UC, and the incidence of HPD in patients with RCC was negligible. Treatment with PD-1/PD-L1 inhibitors should be prescribed with caution in patients with UC and creatinine above 1.2 mg/dL.

Hyperprogressive disease on immune checkpoint therapy in advanced solid malignancies: A systematic review.

154 Background: Immune checkpoint therapy has changed the treatment landscape for many malignancies. As these agents are rapidly being incorporated into clinical practice, a subset of patients appear to have an accelerated tumor growth rate (TGR) after treatment initiation, a phenomenon termed hyperprogressive disease (HPD). Methods: A systematic search of original articles published between January 2000 and June 2018 was performed using PubMed, Embase, and Web of Science. Studies were eligible for inclusion if they reported on HPD in adult patients with advanced solid malignancies treated with checkpoint inhibitors and provided a specific HPD definition. Abstracts from ASCO, ESMO, and IASLC meetings were also included. Prespecified outcomes of interest included criteria used to define HPD, incidence of HPD, and association between HPD with baseline clinical or molecular characteristics and survival outcomes. Results: Of 700 studies screened, 12 retrospective studies were eligible, 3 of which evaluated patients treated in the context of clinical trials. Lung cancer and melanoma were the most common of the diverse histologies represented. The most common treatment was anti-PD1/PD-L1 monotherapy. A variety of criteria were utilized to define HPD, including TGR, RECIST progression, and time to treatment failure. HPD incidence ranged from 2% to 29%, and the only clinical factor significantly associated with HPD in more than one study was increased age. MDM2/4 and EGFR alterations appear to be associated with a higher incidence of HPD. HPD was significantly associated with poor overall survival in 3 studies. Conclusions: It remains unclear whether HPD reflects worsening disease caused by immunotherapy or is simply a manifestation of unfavorable, treatment unresponsive disease biology. There is a need to establish a consensus definition for HPD, and to examine HPD in prospective cohorts with appropriate comparison arms.

Hyperprogressive disease (HPD) in genitourinary (GU) cancer patients treated with PD-1/PD-L1 inhibitors.

369 Background: Post immunotherapy response and disease progression pattern are still under investigation. In terms of progression, rapid progression pattern called HPD has been observed during the early cycles of PD-1/PD-L1 inhibitors therapy in patients with various cancers. Data of HPD in patients with GU cancer are limited. Methods: This study included 203 patients with GU cancer treated with PD-1/PD-L1 inhibitors between February 2015 and June 2018. HPD was defined as greater than 50% increase in tumor burden compared with before-treatment computed tomography (CT) scan and greater than 2-fold increase in tumor growth rate (TGR) compared with previous TGR. Development of extensive new lesions were also regarded as HPD. Response was evaluated by RECIST v1.1 on at least two consecutive CT scan before the initiation of PD-1/PD-L1 inhibitors and one CT scan within 2 months after initiation of PD-1/PD-L1 inhibitors. Results: 102 patients with renal cell carcinoma (RCC) and 101 patients with urothelial cell carcinoma (UCC) were included. Median age was 64 years (range 56-71) and 141 patients (70%) were male. The most common metastatic site was lymph node (66%), followed by lung (51%) and bone (34%). HPD was observed in 13 out of 230 patients (5.7%; 95% CI, 5.0-6.3). Median OS for patients with progressive disease and HPD were 7.3 months and 3.5 months, respectively ( p=0.09). HPD was more frequently found in patients with UCC than RCC (11% vs. 0.9%, p=0.01). In multivariate analysis, patients of UCC ( p &lt;0.001), presence of liver metastasis ( p=0.002), elevated LDH level (&gt; upper normal limit, p=0.01), and hypoalbumimemia (&lt; 3.5 gm/dL, p&lt;0.001) were independent predictive factors for HPD. Conclusions: The incidence of HPD in GU cancer patients seems to be low compared to previous studies (9-10%). The majority of HPD developed in UCC and the incidence in RCC is negligible. Cares should be taken when treating patients with PD-1/PD-L1 inhibitors, especially when patients have UCC and liver metastases, elevated LDH and hypoalbuminemia.