bluuebunny/crossref_metadata_2025_split huggingface dataset:
Inter-reader reliability of immune-specific response criteria (irRECIST & iRECIST).
Authors: Ruchalski Kathleen , Kim Hyun J. , Dewan Rohit , Douek Michael , Sai Victor , Villegas Bianca , Wong Koon-Pong , Lisberg Aaron E. , Goldman Jonathan W. , Goldin Jonathan , Garon Edward B. , Aberle Denise R. 
Published: June 2022

e21108 Background: RECIST 1.1 can underestimate treatment benefits of immunotherapy, with irRECIST and iRECIST accounting for atypical responses. Inter-reader discordances are known to occur in a dual reader paradigm. Our objective is to compare inter-reader reliability between RECIST 1.1, irRECIST, and iRECIST. Methods: This is a retrospective analysis of advanced NSCLC patients treated with pembrolizumab at our institution as part of the KEYNOTE-001 study. All trial imaging was interpreted by two radiologists. RECIST 1.1, irRECIST, and iRECIST categorical responses and agreement for progressive disease (PD) was compared by kappa statistic. Time to progression (TTP) or time to censor was compared between readers by paired t test. Relationship to disease progression and overall survival (OS) was assessed by log rank. Results: Of 98 patients, 77 had baseline and subsequent imaging available for 5.8 mean timepoints with 42.9 weeks of follow up. From this group, 45 patients had imaging beyond iUPD for confirmation and were analyzed. PD occurred by reader 1, reader 2 in 34, 33 patients by RECIST 1.1 (k = 0.591, CI = 0.320-0.863), 31, 29 patients by irRECIST (k = 0.501, CI = 0.234-0.768), and 27, 22 patients by iRECIST iCPD (confirmed-PD) (k = 0.690, CI = 0.485-0.896). There was no significant difference in reader agreement by RECIST 1.1, irRECIST, iRECIST (p = 0.38, 0.60, 0.26). There was a significant difference in time to progression between RECIST 1.1, irRECIST and iRECIST, with median PFS 3.4 months (2.6-4.6), 4.7 (3.5-6.8) and 8.7 (6.9-14.5) (p < 0.0001). PD by any criteria was not significantly correlated with OS. Conclusions: PD confirmation by iRECIST resulted in substantial reader agreement compared to moderate reader agreement by RECIST 1.1 and irRECIST. There were significant differences in TTP between the criteria, with iRECIST having the longest TTP. PD by each criteria did not correlate with a significant difference in OS.[Table: see text]
Immune-suppressive microenvironment was revealed from NSCLC patients with hyperprogressive disease (HPD) from immunotherapy.
Authors: Wei Zhigong , Yu Min , Wang Weiya , Chen Lin , Yang Qidong , Xiao Mingzhe , Qi Chuang , Xi Wenjing , Luo Shifu , Peng Xingchen 
Published: June 2022

e21109 Background: Immune checkpoint inhibitors (ICIs) demonstrated clear survival benefit in advanced non-small cell lung cancer (NSCLC) and was considered as a standard treatment. However, 10%-20% of ICI treated patients presented hyper-progressive disease (HPD) and shortened OS (< 5 months). In this study, we analyzed the tumor immune microenvironment (TME) of HPD and non-HPD NSCLC patients, aiming to reveal their discrepancies. Methods: Advanced NSCLC patients treated with ICIs in West China Hospital from March 2015 to January 2020 were retrospectively analyzed. HPD was defined as: 1) RECIST progression at first response evaluation, or time-to-treatment failure (TTF) < 2 months; 2) increase in tumor volume > 50%; 3) tumor growth rate (TGR) > 2-fold. Total cellular RNA was extracted from FFPE samples and subjected to gene expression evaluation using NanoString nCounter. A customized code set consisting of a 289-gene panel related to the tumor, immune regulation, and tumor microenvironment was used. Results: A total of 296 patients were screened, including 26 (8.8%) HPD and 272 (91.2%) non-HPD patients. A total of 52 specimens were subjected to TME analysis. At last, data from 27 (8 HPD and 19 non-HPD) samples were suitable for final analysis. We revealed 22 differential expressed genes (DEGs) (fold change > = 2, FDR < 0.05) in the HPD group using DESeq2, including 14 up-regulated genes and 8 down-regulated genes. Gene ontology (GO) enrichment analysis revealed that the DEGs were significantly enriched in leukocyte migration, leukocyte chemotaxis, and neutrophil migration. The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis results revealed that the DEGs were significantly enriched in IL-17 signaling pathway. Levels and proportions of 16 immune cell types, tumor-infiltrating lymphocytes (TILs) score, cytolytic activity (CYT) score, cytotoxic T lymphocytes (CTL) level, IFN-γ signature, T cell markers, teff score and 18-gene T cell-inflamed GEP score were estimated using characteristic gene expression signatures. We found that immune cells had a lower tendency in the HPD group, and B-cells, CD45, cytotoxic cells, T-cells, and Th1-cells reached significantly lower levels. Further analysis revealed that the HPD group had significantly lower total TILs score, Teff score, and T cell-inflamed GEP score. Conclusions: HPD patients in NSCLC had immune-suppressive TME which were significantly different from non-HPD patients. Patients with low TILs score, Teff score, and T cell-inflamed GEP score may develop HPD and have a poor prognosis after receiving ICIs therapy. The TME signatures in the tissues before ICIs treatment might become a predictive biomarker of HPD risk.
The predictive values of POTEE mutations for response to immune checkpoint inhibitors in lung adenocarcinoma.
Authors: Yang Yi , Ren Fuqiang , Wang Yuan , Yang Qidong , Zhao Lele , Chen Lin , Liu Yaqin , Xiao Mingzhe 
Published: June 2022

e21110 Background: Precise selection of patients who could benefit from immune checkpoint inhibitors (ICIs)is an important challenge for immunotherapy in lung cancer. POTEE is a member of one primate-specific gene family which have been identified as cancer-related antigens and potential target for immunotherapy of cancer. Here, we investigated the correlation between POTEE mutation and the clinical outcomes of ICIs treatment in lung adenocarcinoma (LUAD). Methods: We merged three independent cohorts from publicly accessible data, the Miao(n = 47), Rizvi (n = 29) and Hellmann (n = 59), to explore the associations between POTEE mutations ( POTEE-mut) and ICIs efficacy. Then we explored the relationship between POTEE mutation and tumor mutational burden (TMB) and PD-L1 expression in the merged cohort. Further, gene set enrichment analyses (GSEA) was used to explore the potential molecular mechanism in The Cancer Genome Atlas (TCGA)-LUAD cohort. Results: In merged cohort, the mutation frequency of POTEE was 7.41% (10 in 135). POTEE-mut group had a significantly higher objective response rate (ORR) (100% vs 27.2%; Fisher’s exact test; P < 0.001) compared to POTEE wildtype group. Kaplan-Meier analysis revealed that POTEE-mut was significantly associated with longer progression-free survival (PFS) (not reached vs 6.1 months, P = 0.001). And at multivariable analysis adjusted by cohort, age, smoking status, line of immunotherapy, PD-L1 expression and TMB, POTEE-mut group showed significant improved PFS with a HR of 0.09(95% CI 0.01-0.71, P = 0.022). Then we explored the association of POTEE alterations with TMB and PD-L1 expression. In merged cohort significantly higher TMB were found in LUAD patient with POTEE mutation (Mann-Whitney U test; p < 0.001). However, there was no association between POTEE mutation and PD-L1 expression. We further explored the potential mechanism of POTTE mutation affecting immunotherapy response using TCGA-LUAD data. GSEA analysis revealed prominent enrichment of signatures related to DNA repair in patients with POTEE mutation (P < 0.001). In detail, four DNA damage response (DDR) pathways, homologous recombination repair (HRR) (NES = 2.108, P < 0.001), translesion DNA synthesis (NES = 1.587, P = 0.01), checkpoint factors (NES = 1.865, P < 0.001) and base excision repair (NES = 1.737, P = 0.002), were all significantly enriched in POTEE-mut tumor. Conclusions: Our data indicated that POTEE mutations were associated with the better response for immunotherapy of LUAD, implying that it can be used as a biomarker for predicting the efficacy of LUAD immunotherapy. POTEE mutation was associated with higher TMB and changed the activity of DNA repair related pathways in LUAD. These may be the underlying mechanisms for POTEE mutations to affect the prognosis of immunotherapy.
Outcomes of sintilimab plus pemetrexed and platinum (SPP) according to stage of disease in patients (pts) with locally advanced or metastatic nonsquamous NSCLC (AMnsqNSCLC) in the phase 3 ORIENT-11 study.
Authors: Yang Yunpeng , Wang Zhehai , Fang Jian , Yu Qitao , Han Baohui , Cang Shundong , Chen Gongyan , Mei Xiaodong , Yang Zhixiong , Stefaniak Victoria Jennifer , Ferry David Raymond , Zhao Yumin , Wang Shuyan , Wang Yan , Sun Luyao , Zhang Li 
Published: June 2022

e21157 Background: In ORIENT-11, first-line (1L) SPP improved progression-free survival (PFS), overall survival (OS), objective response rate (ORR) and duration of response (DoR) compared with placebo plus pemetrexed-platinum (PPP) in pts with AMnsqNSCLC. We report outcomes from ORIENT-11 (NCT03607539) for pts treated with SPP with stage III (b & c) compared with stage IV disease. Methods: Pts with treatment-naïve locally AMnsqNSCLC without sensitizing EGFR/ALK alterations were randomly assigned to SPP (n = 266) or PPP (n = 131), stratified by PD-L1 expression, platinum-chemotherapy and sex. Primary endpoint was PFS (RECIST v1.1). Secondary endpoints included OS, ORR, DoR and safety. Kaplan-Meier method was used to analyze median PFS, OS and DoR. Stratified Cox model was used to analyze the hazard ratio (HR) of SPP vs. PPP. Clopper-Pearson method was used to calculate the 95% confidence intervals (CI) of ORR for each group. Miettinen-Nurminen method was used to analyze 95% CI of ORR difference between SPP and PPP. Data cutoff for OS data was September 15, 2021, providing a median follow-up of 30.8 months. Cutoff for other data was November 15, 2019, providing a median follow-up of 8.9 months. Results: 21 pts (7.9%) receiving SPP had stage III disease and 245 pts (92.1%) had stage IV disease. Baseline sex, age and PD-L1 expression ≥1% were similar between subgroups (Table). There were differences between subgroups in number of pts receiving carboplatin and ECOG performance status at baseline. PFS, OS, ORR and DoR outcomes were comparable between pts with stage III and stage IV disease based on the ad-hoc analyses. Any-grade adverse events (AEs) (100.0% vs. 99.6%) and AEs of Grade ≥3 (57.1% vs. 62.0%) were similar in pts with stage III and stage IV disease. Conclusions: In ORIENT-11, outcomes for pts receiving SPP as 1L therapy in AMnsqNSCLC with stage III and stage IV disease were comparable. Clinical trial information: NCT03607539. [Table: see text]
Relevance of detection of RAF fusion in pan-negative melanoma in routine practice.
Authors: Jamme Philippe , Delzenne Guillaume , Mortier Laurent , Farchi Olivier , Boileau Marie 
Published: June 2022

e21500 Background: Pan-negative melanomas (i.e. without MAPK kinase pathway alteration and C-kit wild type) account for 30% of melanomas (according to the AACR GENIE database). In case of immunotherapy failure, therapeutic options are limited. Oncogene fusions represent a target of interest in many solid cancers (NSCLC, Cholangiocarcinoma, Glioma, GIST, pancreatic acinar carcinoma, thyroid, and prostate cancers). In melanoma, the frequency of oncogene fusion is not well documented and not routinely investigated. Methods: We conducted a single-center retrospective study. The objective was to determine the frequency of oncogene fusion detected by RNA sequencing (Archer Fusion pLex) performed in routine practice, in patients with advanced or metastatic pan negative melanoma. Data on clinical, pathological, and molecular characteristics and patient outcomes were collected. Analysis was carried out on the genetic material available for the diagnosis of the disease except for 1 patient who benefited from a new anatomopathological sample during an unfavorable evolution. In parallel, an extended molecular alteration search was performed using extended targeted NGS (OncoMine Comprehensive Assay panel). Results: We identified 48 patients with an advanced pan negative melanoma between January 2021 and January 2022 with a median age at diagnosis of 63 years. It was a cutaneous melanoma in 72,9 % (35/48) of the cases, a mucous melanoma in 14,5% (7/48) of the cases and a melanoma of unknown primary site in 12,5% (6/48) of the cases. The detection of fusion transcript was made in 89,5 % (43/48) of the cases. We identified 6 patients with a RAF fusion, including 4 BRAF gene fusion (MKLN1-BRAF, AGK-BRAF, SNX29-BRAF, PTPRJ-BRAF) and 2 RAF1 fusion (MAP4-RAF1, EFCC1-RAF1). Of the other molecular alterations, NF1 mutation was the most frequent molecular alteration identified (25 % (12/48) of patients). At lower frequencies, 6,8 % (3/48) of patients had a PI3K mutation, and 8,3 % (4/48) of patients had NOTCH, PTCH1, GNAQ mutations. Among the 6 patients with RAF fusions, all the patients initially received treatment with anti-PD1+/- anti-CTLA4 immunotherapy. After immunotherapy failure, 4 patients benefited from second-line targeted therapy (2 with BRAF and MEK inhibitors combination, 2 MEK inhibitors alone). One patient presented an objective imaging response, the other three patients have not yet benefited from reassessment imaging. Conclusions: In a population of pan negative melanoma, we detected 12,5 % (6/48) of RAF fusion. Fusion detection allowed the introduction of a second line of targeted therapy, in the absence of a validated therapeutic option in 66,6 % (4/6) of cases This study suggests the relevance of detecting RAF fusion in a selected population.
B7H3 CAR-T therapy in relation to tumor growth in skin tumor.
Authors: Hu Gang , Liang Yunsheng , Li Guangchao , Ding Wen , luo min 
Published: June 2022

e21502 Background: Exciting progress has been recently witnessed on the development of chimeric antigen receipt T cell (CAR-T) therapy for hematopoietic malignancies. The biological principles of CAR-T therapy are applicable to solid tumors but very little success has been achieved due to various challenges intrinsic to solid tumors. The development of new solid tumor targets is particularly important. CD276 (B7H3) is one of the most promising therapeutic targets for solid tumors and has been extensively tested in preclinical trials. However, no clinical trials have been reported on its efficacy and safety. In this study, we report a case of relapsed basal cell carcinoma (BCC) patient treated with B7H3 CAR-T cells through direct intra-tumor injection. Trial registration number: ChiCTR2100044386. Methods: We have generated a 2nd generation of B7H3 CAR-T, the extracellular scFv was derived from a humanized B7H3 monoclonal antibody, which was generated by hybridoma technology. Autologous CAR-T cells were manufactured in a cGMP facility. CAR-T cells were given by three dose-escalated intra-tumor injections without lymphodepletion conditioning. Results: A 65-year-old man was initially diagnosed with multiple BCC, the disease relapsed and spread to all over the body. Immunohistochemical staining of the tumor tissue showed positive for B7H3 (80%, ++̃+++). The patient received autologous anti-B7H3 CAR-T therapy cells through intra-tumor injection three times with dose escalation on day 1, day 14 and day 62. There were two different tumor sites that were treated in this patient (site 1 for abdominal tumor 1.8 cm × 0.6 cm; site 2 for forehead tumor 6 cm × 6 cm). For the adverse events, the patient’s AST/ALT levels slightly increased about two fold after the first infusion. However, we did not observe increases of AST/ALT levels after the second and third infusion, even with much higher dose. After three infusions, the volume of original lesion in the abdomen decreased 40% (1.8cm × 0.6cm to 1.3cm × 0.5cm), shrinking from bulging to flat. The large lesion in the forehead became dry from original ulcer and bleeding. We further performed surgery to remove the remained tumor in the abdomen after the third infusion. IHC analysis demonstrated that the percentage of B7H3 positive cells decreased from 80% to about 40%, and the intensity also decreased from ++̃+++ to +. Meanwhile, CD3 T cells increased in the tumor site, but failed to efficiently infiltrate into neighboring tumor areas, which was marked by high level of TGF-β. Conclusions: In this case, we reported for the first time that a patient with skin tumor achieved a partial response after receiving repeated intra-tumor injections of anti-B7H3 CAR-T cells. This study demonstrated that B7-H3 CAR-T cell therapy is a safe and promising treatment for relapsed skin tumor. Combination with other strategies to improve CAR-T cell infiltration in the tumor site may help to further improve the clinical response. Clinical trial information: ChiCTR2100044386.
Recombinant human adenovirus 5 injection plus toripalimab therapy in patients with advanced and refractory melanoma: A single arm, single-center, prospective study.
Authors: Zhao Huaxin , Guo Xianling , Liu Zhuqing , Xu Qing 
Published: June 2022

e21503 Background: Treatment options are limited for patients with advanced melanoma and refractory melenoma, especially for acral and mucosal melanoma. Previous data showed that the objective response rate (ORR) of second-line PD1 monotherapy for acral and mucosal melanoma were 14-15.8% and 0-13.3%, respectively. We evaluate the safety and efficacy of recombinant human adenovirus 5 injection (oncolytic virus) plus toripalimab (PD-1 antibody) for patients who have progressed on checkpoint inhibitors, chemotherapy and anti-angiogenesis. Preliminary analysis of efficacy- related factors. Methods: Patients received the recombinant human adenovirus 5 injection (2ml) local lesions plus toripalimab 240mg systemic therapy every 2 weeks until progression or intolerable toxicity. The primary objective was safety and ORR. Secondary objective included progression-free survival (PFS) and disease control rate (DCR). Efficacy assessments were performed every 2 months according to RECIST v1.1 criteria. Blood samples were collected from patients prospectively. Serum interleukin (IL)-2, IL-4, IL-6, IL-8, IL-10, Tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ) were measured at baseline and after two cycles of treatment via flow cytometry. The peripheral blood neutrophils and lymphocytes were collected simultaneously. Results: Ten cases of patients were enrolled from November 2020 to January 2022. Baseline character:primary site (1 cutaneous melanoma; 5 acral melanoma; 4 mucosal melanoma), prior therapy (anti-PD1 100%; anti-angiogenesis 60%; chemotherapy 60%; second line and above 40%), 50% liver/bone lesions. All patients evaluated received at least 2 cycles of the combination regimen. The treatment-related adverse event was fever, accounting for 80%, and there were no other adverse events. The ORR was 20% (2PR) and the DCR was 70% (2PR, 5SD, 3PD). The 2-month PFS was 70%, and the median PFS has not yet been reached. Disease progression in 3 patients including liver and bone lesion. Higher baseline lymphocyte levels and lower neutrophil-to-lymphocyte ratio (NLR) values were found in the respongders compared with non-responders. The serum IL-6, IL-8, IL-10, and TNF-α levels were significantly increased in the responders after 2 cycles of treatment. Conclusions: The preliminary data showed that the combination of recombinant human adenovirus 5 injection plus toripalimab demonstrated acceptable toxicity and promising antitumor efficacy in patients with advanced and refractory melanoma, and promoted favorable changes in serum IL-6, IL-8, IL-10 and TNF-α levels in clinical responders. High baseline lymphocyte and low NLR values may be predictors of treatment response. Long-term survival data remain to continue with follow-up. It is worth to further validate the efficacy in a randomized prospective trial. Clinical trial information: 2000033959.
Comparing overall survival of patients with metastatic uveal melanoma by sequence of Tebentafusp versus combination immune checkpoint inhibitors.
Authors: Shikdar Sufana , Day Silas , Ikeguchi Alexandra , Ying Yuan 
Published: June 2022

e21505 Background: Uveal melanoma is a rare melanoma subtype with poor outcome from immune checkpoint inhibition (ICI) compared to cutaneous melanoma. UM expresses high levels of Glycoprotein 100 (Gp-100) implicating potential sensitivity to tebentafusp (tebe), a novel immune-mobilizing monoclonal T cell receptor therapy. A recent phase 3 study compared tebe to investigator chosen standard of care (SOC) with crossover at progression. SOC regimens were single agent pembrolizumab, ipilimumab and Dacarbazine with 82% of SOC patients receiving pembrolizumab1. Other single arm studies suggest that survival with combination ICI is superior to single agent. We sought to compare overall survival (OS) of first or second line tebe in relation to combination ICI. Methods: Retrospective chart review at a single institution was conducted on patients with metastatic UM (mUM) treated with tebe on clinical trial between June 2018 and December 2021, either in first [NCT03070392] or second line [NCT02570308] setting. Patients were included if they received ipilimumab plus nivolumab either before or after tebe. Data including patient demographics and factors demonstrated in the phase 2 and 3 trials to correlate with survival including lactate dehydrogenase (LDH), size of largest liver lesion and early onset of rash with tebe were extracted. OS was the main outcome measure and was calculated as the time interval between the date of diagnosis of metastatic disease and date of death. Results: Six patients were identified in our data set as having received both ICI and Tebe, three in each sequence order. Mean characteristics were included in table. OS trended towards improvement in the cohort of patients who received tebe first in sequence both in OS in time from UM diagnosis (42.1 vs 63.5 months) (p = 0.21) and in OS in time from detection of mUM (29.8 vs 42.0 months) (p = 0.28), although neither difference was statistically significant given the small sample size. Conclusions: Our limited data demonstrate longer OS with tebe followed by combination ICI on progression compared to the reverse sequence. This comparison of patients at a single institution is underpowered to show a statistically significant OS difference but does demonstrate a trend in favor of first line tebe similar to the conclusive comparison of tebe and single agent ICI in the randomized trial. Reference: 1. Orloff, Marlana et al. Overall survival in patients who received checkpoint inhibitors after completing tebentafusp in phase 3 randomized trial of first-line metastatic uveal melanoma. (2021): 9526-9526.[Table: see text]