bluuebunny/crossref_metadata_2025 huggingface dataset:
Efficacy and safety of dostarlimab in patients (pts) with mismatch repair deficient (dMMR) solid tumors: Analysis of 2 cohorts in the GARNET study.
Authors: Andre Thierry , Berton Dominique , Curigliano Giuseppe , Jimenez-Rodriguez Begona , Ellard Susan , Gravina Adriano , Miller Rowan , Tinker Anna , Jewell Andrea , Pikiel Joanna , Oaknin Ana , Duan Tao , Zildjian Sybil , Zografos Eleftherios , Veneris Jennifer Taylor , Banerjee Susana N.
Published: June 2022

2587

Background: Dostarlimab is a programmed death 1 (PD-1) inhibitor approved in the US as a monotherapy in pts with dMMR solid tumors that have progressed on or after prior treatment, with no satisfactory alternative treatment options; or dMMR advanced/recurrent (AR) endometrial cancer (EC) that has progressed on or after treatment with a platinum-based chemo; and in the EU as a monotherapy in pts with dMMR/ microsatellite instabilityhigh (MSI-H) AR EC that has progressed on or after treatment with a platinum-based chemo. Here we report on efficacy and safety in 2 expansion cohorts that enrolled pts with dMMR solid tumors. Methods: GARNET is a multicenter, open-label, single-arm phase 1 study. Cohort A1 enrolled pts with dMMR/MSI-H AR EC; cohort F enrolled pts with dMMR/MSI-H/POLε-mut non-EC solid tumors. Pts received 500 mg of IV dostarlimab Q3W for 4 cycles, then 1000 mg Q6W until PD, discontinuation, or withdrawal. Primary endpoints were ORR and DOR by BICR per RECIST v1.1. Biomarker status was based on local assessment. Results: For this third interim analysis, 153 pts with dMMR/MSI-H EC and 210 pts with dMMR/MSI-H/POLε-mut non-EC solid tumors (56% colorectal cancer, 11% gastric) were enrolled and treated. Efficacy analysis was performed for 143 dMMR/MSI-H EC and 204 dMMR/MSI-H/POLε-mut non-EC pts who had measurable disease at baseline and ≥6 mo of follow-up. ORRs were 45.5% (dMMR/MSI-H EC) and 43.1% (dMMR/POLε-mut non-EC solid tumors; Table). Probability of PFS at 6, 9, and 12 mo was 49.5%, 48.0%, and 46.4% in dMMR/MSI-H EC and 51.8%, 48.1%, and 46.4% in dMMR/MSI-H/POLε-mut non-EC. Median (m) DOR and mOS were not reached for either cohort. A total of 13 pts (8.5%) with dMMR/MSI-H EC and 12 pts (5.7%) with dMMR/MSI-H/POLε-mut non-EC solid tumors discontinued owing to a treatment-related adverse event (TRAE). TRAEs occurring in ≥12% of pts were diarrhea, asthenia, fatigue, nausea, and pruritis (dMMR/MSI-H EC) and diarrhea, asthenia, and pruritus (dMMR/MSI-H/POLε-mut non-EC solid tumors). 2 deaths (1 hepatic ischemia, 1 suicide) were attributed by investigators to dostarlimab in pts with non-EC solid tumors. Conclusions: Dostarlimab demonstrated durable antitumor activity across 16 tumor types in pts with dMMR solid tumors, confirming efficacy in a larger sample size with extended follow-up. The safety profile was acceptable, with manageable toxicities. Clinical trial information: NCT02715284. [Table: see text]
Cisplatin (Cis) combined with sintilimab (Sint) and niraparib (Nir) in advanced solid tumors: Updated results.
Authors: Haitao TAO , Wang Lijie , Liu Zhefeng , Wang Jinliang , Zhang Guoqing , Ma Junxun , Hu Yi
Published: June 2022

2599

Background: PARP inhibitors or chemotherapy combined with PD1/PDL1 inhibitors resulting in enhanced antitumor activity. We previously reported the part 1 result of a phase Ⅰb study exploring the safety and efficacy of Cis plus Sint and Nir. Here we presented the updated survival and safety data. Methods: Eligible pts will receive Sint and Cis on D1, plus Nir on D1-21, every 21-day for up to 4 cycles, following Sint and Nir until disease progression or intolerable toxicity. Part 1 was dose escalation phase followed 3+3 model, and part 2 was dose expansion phase enrolled more patients based on part 1. The primary objective was to determine maximum tolerated dose (MTD)/ recommended part 2 dose (RP2D). Secondary endpoints include objective response rate (ORR) per RECIST v1.1, and safety based on CTCAE v5.0. Results: PR2D of Cis and Nir were 60 mg/m2 and 100 mg, respectively when combined with sint 200mg. From 7/2019 to 9/2021, 22 pts (13 pts in part2) were enrolled, including 12 small cell lung cancer (SCLC), 7 lung squamous cell carcinoma (LUSC), 2 ovarian cancer (OC) and 1 cervical squamous cell carcinoma (CSCC). Most were male (77.3%, n=17), ECOG=1 (63.6%, n=14), current smoker(68.2%, n=15) and PDL1＜1(50%, n=11). 36.4% (8/22) and 27.3% (6/22) had brain and liver metastasis at baseline, separately. Median follow-up was 6.2 months (range 2.5-10.8). ORR was 27.3% (6/22), DCR was 59.1% (13/22). Median progression-free survival (PFS) was 3.3 months (95%CI 1.9-3.9), and PFS rates at 6 months and 12 months were 28.8% and 10.8%. Median overall survival (OS) was 8.0 months (95%CI 4.9-14.1), 12 months OS rates was 28.5%. Median treatment duration was 4.7 months (range 1.9-15.1). The most common treatment-related adverse events included anemia (90.9%, 20/22, [5 Grade 3/4]), fatigue (77.3%, 17/22, [1 Grade 3/4), γ-glutamyl transpeptidase increased (72.7%, 16/22, [0 Grade 3/4]), leukopenia (68.2%, n=15, [4 Grade 3/4]) and neutropenia (59.1%, n=13, [5 Grade 3/4]). Conclusions: In this updated analysis, Cis combined with Sint and Nir showed clinically meaningful efficacy and an adequate safety profile in previously treated advanced solid tumors. Data need longer follow-up. Clinical trial information: ChiCTR1900024488.
Resistance to anti-PD-1/anti-PD-L1: GB1211 reverses galectin-3 induced blockade of pembrolizumab and atezolizumab binding to PD-1/PD-L1.
Authors: Mabbitt Joseph , Roper James A. , Slack Robert John
Published: June 2022

2607

Background: Galectin-3 (Gal-3) is a β-galactoside binding lectin highly expressed across many cancers (Li et al. Biomedicines, 2021) with high expression associated with poor response to the PD-1 inhibitor pembrolizumab (Capalbo et al., Int J Mol Sci, 2019). In addition, it has also been shown preclinically in in vivo mouse non-small cell lung carcinoma (NSCLC) models that inhibition of Gal-3 enhances the performance of checkpoint inhibitors targeting the PD-1/PD-L1 axis (Vuong et al., Cancer Res, 2019; Zhang et al., FEBS Open Bio, 2020). The mechanism by which Gal-3 negatively impacts the effect of PD-1/PD-L1 based checkpoint inhibitors is not fully understood. We investigated the hypothesis that anti-PD1/anti-PDL1 is induced by direct binding and blockade of Gal-3 to the PD-1/PD-L1 complex itself. Methods: SPR was used to investigate the effect of recombinant hGal-3 in combination with a Gal-3 inhibitor (GB1211) on the binding of recombinant hPD-L1 to hPD-1 in the absence and presence of either pembrolizumab or atezolizumab. SPR analysis was performed with a BIAcore (Cytiva, USA). hPD-1 was immobilized onto a CM5 Series S sensorchip via amine coupling and proteins, antibodies or small molecules flowed over in various combinations. Observations made at the protein level were further confirmed in cell binding assays using flow cytometry measuring pembrolizumab and atezolizumab binding to cells lines over expressing high levels of either PD-1 (Jurkat cells) or PD-L1 (RAJI-hPD-L1 cells), respectively. Results: Gal-3 potentiated the binding of PD-L1 to PD-1 with a 3-fold increase in its KD observed and the efficiency of pembrolizumab and atezolizumab binding to and blocking the PD-1/PD-L1 axis was reduced. A 6-fold reduction in KD of pembrolizumab for the PD-1/PD-L1 complex was observed in the presence of Gal-3. In addition, atezolizumab PD-L1 blockade was reversed in the presence of Gal-3 and dramatically improved by GB1211. Similarly, in cell systems expressing high levels of PD-1 or PD-L1, Gal-3 reduced the binding of pembrolizumab and atezolizumab to their respective targets on cell surfaces that was also reversed by GB1211. Conclusions: Gal-3 was shown to vastly reduce the binding of the checkpoint inhibitors pembrolizumab and atezolizumab, by potentiating the interaction between PD-1 and PD-L1. GB1211 restored the binding of the anti-PD1/anti-PDL1 therapeutics and may thus reduce tumor resistance to these agents. These findings harmonize excellently with in vivo and clinical data showing an association between Gal-3 expression and lack of efficacy of PD-1/PD-L1 targeted checkpoint inhibitors. Galecto is now investigating the safety and efficacy of GB1211 in combination with atezolizumab in NSCLC.
Safety of dual checkpoint-blockade with PSB205, an anti-PD-1/CTLA4 monoclonal antibody combination, manufactured and dispensed as a single product: A phase 1 study.
Authors: Chugh Rashmi , Wang Judy S. , Olszanski Anthony J. , Wilky Breelyn A. , Algate Paul , Plato Leah , Spira Alexander I. , Korchin Borys , Kylstra Jelle W.
Published: June 2022

2611

Background: PSB205 is a new biological agent consisting of two engineered monoclonal antibodies (anti-PD-1 IgG4 and anti-CTLA-4 IgG1) expressed in a fixed ratio (2:1) from a single cell-line, manufactured as one product and dispensed from a single vial. PSB205 was designed to optimally balance efficacy and safety through differential target coverage of PD-1 and CTLA-4: the anti-CTLA-4 antibody was engineered to have a shorter half-life to modulate exposure and lower risk of immune-related adverse events (irAEs). Methods: We report safety data from a first-in-human study, conducted in standard 3+3 Phase 1 dose escalation format, enrolling subjects with refractory solid tumors with mixed histologies, who had exhausted available standard treatments. Primary objectives were safety (including Dose Limiting Toxicities), tolerability and selection of a Phase 2 dose. Secondary objectives were PK and preliminary evaluation of effectiveness. Treatment was Q3 wks. Inclusive the 1st week following the 2nd infusion, the DLT-period was 28 days. Results:Nine US-centers enrolled 27 subjects, representing 19 tumor histologies, in 5 ascending dose cohorts ranging from 0.1 mg/kg to 5 mg/kg; an additional N = 49 pts were dosed in expansion cohorts at 5 mg/kg and 400 mg (fixed dose). Median number of prior systemic treatments for metastatic disease was 4. No DLT was observed at any of dose level evaluated. The most frequent Treatment-Related Adverse Events (TRAE) reported were diarrhea (9%), Infusion-Related Reaction (IRR) (5%) and fatigue (4%). Among the subset (N = 33) who completed at least 4 cycles of treatment, the most common TRAE were diarrhea (21%), IRR (12%), Fatigue (9%), and irAEs, specifically colitis, rash and arthralgia (6% each symptom). Most TRAEs were Grade 1 /2, with just 1 case each of diarrhea and colitis Graded as G 3/4. Tumor responses (all PRs) were observed at dose levels of 3 mg/kg and 5 mg/kg in 4 pts - 1 each with with RCC, SCLC, HNSCC and gastric cancer. Conclusions: PSB205 provides dual checkpoint blockade with a very tolerable side effect profile, with less AEs than typically noted in published studies of anti-PD1 and anti-CTLA-4 combination therapy. Further studies are ongoing to confirm this observation. Dose levels of 5 mg/kg and 400 mg fixed were selected for Phase 2, which has commenced enrollment. Clinical trial information: NCT03986606.
A pan-cancer analysis of P21 activated kinase (PAK) family genes as potential biomarkers for immune checkpoint therapy.
Authors: Gang Sun , Guo Wenjia , Qiao Lei , Sun Tonghui , Tan Yuan , Zhang Qin , Duan Qianqian , Sun Tingting , Qi Chuang
Published: June 2022

2614

Background: PAK (P21 activated kinase) is a family of serine threonine kinases, that consist of 6 members, PAKs 1-6, which are positioned at an intersection of multiple signaling pathways implicated in oncogenesis. Recent studies have found relationship between mutations of some PAK family genes and antitumor immunity. Here, we explored the associations of PAK family gene mutations with ICI response based on multidimensional data from multiple solid tumors. Methods: An immunotherapy cohort (Broad/Dana-Farber, Nat Genet 2018, N = 249) within 7 types of tumors as discovery stage, was used to explore the association of PAK family genes mutations with tumor mutation burden (TMB) and efficacy of immunotherapy. To further validate the predictive value of PAK family genes, we employed another ICI-treated cohort, MSKCC cohort (Samstein, Nat Genet 2019, n = 1661), as a validation cohort. TMB was calculated as the total count of nonsynonymous mutations in coding sequence. Results: In discovery cohort, compared to that in the PAK-Wt group, longer OS was observed in the PAK-Mut group (mOS: 31.3 vs 15.4 months, HR = 0.59, 95% CI: 0.36 to 0.96, P= 0.03). In addition, PAK-Mut group had higher TMB ( P< 0.001). Median TMB in PAK-Mut group and PAK-Wt group is 17.79 (IQR, 7.45-36.55) Mut/Mb and 5.47 (IQR, 2.46-9.09) Mut/Mb, separately. In validation cohort, PAK-Mut patients also achieved significant improved OS compared with PAK-Wt patients (mOS: 44.0 vs 17.0 months, HR = 0.51, 95% CI: 0.37 to 0.69, P< 0.001). Moreover, multivariable analysis of validation cohort demonstrated that PAK-Mut was associated with better OS (HR = 0.71; 95%CI, 0.52-0.98; P = 0.036), after adjusting for Age, Gender, Metastasis, Treatment, TMB, Cancer type. Compared with PAK-Wt group (median [IQR]: 5.90 [2.95-10.04]), PAK-Mut group (median [IQR]: 21.19 [11.81-43.29]) also had higher TMB ( P< 0.001). Conclusions: The results indicated that PAK family genes mutation was associated with a higher TMB both discovery and validation cohort. Analysis of discover and validation immunotherapy cohort data showed PAK family was associated with better OS. These findings indicate that these genes mutation may serve as a potential predictive biomarker for ICI in solid tumor patients.
WDR49 mutation as a novel predictive biomarker in patients with non–small cell lung cancer with immune checkpoint inhibitors.
Authors: Shi Zhihui , Liu Yaqin , Zhao Lele , Chen Lin , Yang Qidong , Xiao Mingzhe
Published: June 2022

2615

Background: Application of Immune Checkpoint Inhibitors (ICIs) has become the first-line therapy for advanced or metastatic non-small cell lung cancer (NSCLC). WDR49 gene belongs to the WDR (WD40-repeat) protein family which participates in a wide range of biological processes, including DNA damage repair and immune regulation, etc. However, the correlation between WDR49 mutation and immune efficacy is unclear. Methods: A total of three independent cohorts of NSCLC patients treated with immunotherapy were analyzed in this study: the Miao cohort (n = 56), the Rizvi cohort (n = 34), the Hellmann cohort (n = 75). Survival was estimated by Kaplan-Meier curves, with the p value determined by a log-rank test. HR was determined through the univariable and multivariable Cox regression. The CIBERSORT analysis relied on RNA-seq data in The Cancer Genome Atlas (TCGA) database. Two-sided P value < 0.05 was considered statistically significant. All the statistical analyses were conducted with R version 4.0.3. Results: In this merged cohort, the frequency of WDR49 mutation ( WDR49-mut) was 10.30% (17 in 165), and most patients with WDR49 mutation were lung adenocarcinoma (LUAD) (11.85%, 16 in 135). Meanwhile, the frequency of WDR49-mut in TCGA database was 7.05 % and 3.84% in LUAD and lung squamous cell carcinoma (LUSC), respectively. The Kaplan-Meier curves survival analysis indicated that WDR49-mut was associated with longer progression free survival (PFS) (median PFS 23 months vs 5.2 months, hazard ratio [HR] = 0.17 [95% CI, 0.06–0.47], P < 0.001) and higher objective response rate (ORR) (76% vs 27%, P < 0.001). Furtherly, WDR49-mut was significantly related to higher tumor mutational burden (TMB) (median TMB 495 vs 149, P < 0.001), but it had nothing to do with the expression of PD-L1 (Proportion of PD-L1 positive 72.7% vs 68.5%, P = 1). The CIBERSORT analysis revealed that CD8+ T cell infiltration was significantly higher in WDR49-mut group than WDR49 wildtype group (p < 0.05). Conclusions: Better treatment response and survival benefit in the mutant group suggest that the WDR49 mutation may serve as a novel predictive biomarker in NSCLC patients with ICIs. The significantly higher TMB and CD8+ T cell infiltration in WDR49-mut group may be the potential mechanism.
PAPPA2 mutation as an indicator stratified patients benefit from immune checkpoint inhibitors in NSCLC and SKCM.
Authors: Dong Yiting , Wang Zhijie , Wang Jie , Duan Jianchun , Bai Hua , Zhao Lele , Chen Dong-sheng , Li Si , Yu Yangyang , Zhang Qin , Xiao Mingzhe , Qi Chuang
Published: June 2022

2617

Background: Pappalysin 2 ( PAPPA2) mutation, most occurring in skin cutaneous melanoma (SKCM) and non-small cell lung cancer (NSCLC), is found to be related to anti-tumor immune response. However, the association between PAPPA2 and efficacy of immune checkpoint inhibitors (ICIs) therapy remains unknown. Methods: Forty-one NSCLC patients receiving anti-PD-(L)1 (China cohort, n = 41) and seven public cohorts with whole-exome sequencing (WES) data were included to analyze the performance of PAPPA2 mutation as an indicator stratifying patients benefit from ICIs, consolidating a discovery set (n = 34) and two validation sets (NSCLC validation set, n = 172 ; SKCM validation set, n = 210). The mechanism was analyzed in the Cancer Genome Atlas (TCGA) database (n = 1467). Results: In the discovery set, patients with PAPPA2 mutation exhibited a significantly predominant PFS (HR, 0.11 [95% CI, 0.01-0.83]; P = 0.01), ORR (100.0% vs 21.4%; P < 0.001) and durable clinical benefit (DCB, 83.3% vs 32.1%; P = 0.012) compared to those with wide-type PAPPA2, consistent in NSCLC validation set (PFS, HR, 0.3 [95% CI: 0.16-0.56], P < 0.001; ORR, 70.8% vs. 20.9%, P < 0.001; DCB, 83.3% vs. 36.5%, P < 0.001) and SKCM validation set (OS, HR, 0.49 [95% CI: 0.31-0.78]; P = 0.002; ORR, 34.1% vs. 16.9%, P = 0.039; DCB, 50.0% vs. 30.7%; P = 0.036). Similar results were observed in multivariable models. In contrast, no association between PAPPA2 mutation and OS or PFS was observed in TCGA datasets, suggesting that PAPPA2 mutation may be a predictive but not a prognostic factor in ICI treatment for NSCLC patients. Based on CIBERSORT-inferred tumor infiltrating lymphocytes from TCGA, we found that PAPPA2 mutation was significantly associated with higher activated CD4 memory T cells and lower Treg cells in tumor immune microenvironment, related with higher TMB ( P < 0.001) and neoantigen load ( P < 0.001). In addition, gene set enrichment analysis (GSEA) analysis revealed that PAPPA2 mutation was correlated with upregulated DNA damage repair (DDR) signaling pathway. Conclusions: Our findings indicated that PAPPA2 mutation could serve as a novel indicator to stratify beneficiaries from ICIs therapy in NSCLC and SKCM, warranting further prospective studies.
The expression of aryl hydrocarbon receptor predicts responses to anti-PD-1 antibodies in non-small cell lung cancer.
Authors: Han Si-Chong , Yang Yaning , Wang Gui-Zhen , Fang Wenfeng , Zhang Li , Wang Yan , Zhou Guang-Biao
Published: June 2022

2628

Background: Blockade of programmed cell death receptor 1 (PD-1) by antibodies such as pembrolizumab has revolutionized treatment for patients with non-small cell lung cancer (NSCLC). However, a significant number of patients achieve only marginal benefit. The predictive abilities of the frequently used biomarkers, including programmed cell death 1 ligand (PD-L1) and tumor mutation burden (TMB), are yet limited, highlighting the urgent need for more reliable biomarkers. Aryl hydrocarbon receptor (AhR) is a ligand-dependent transcription factor that controls the transcription of its targets including PD-L1. Whether AhR could be used as a predictive biomarker for response to PD-1 blockade immunotherapy in NSCLC warrants further investigation. Methods: We collected formalin-fixed, paraffin-embedded (FFPE) slides from 104 NSCLC patients before PD-1 blockade immunotherapy treatment, who had sufficient follow-up data for progression-free survival (PFS), and detected the expression of nuclear localized AhR (AhRN) and membrane localized PD-L1 (PD-L1M) with multiplex immunohistochemistry (mIHC). H-score was applied to characterize the specific value with the following formula [1 × (% cells intensity =1) + 2 × (% cells intensity = 2) + 3 × (% cells intensity = 3)]. Survival curve for each group was estimated by the Kaplan–Meier method and log-rank test. The diagnostic performance was assessed with the area under the receiver operating characteristic (ROC) curve (AUC), which was calculated based on the Wilcoxon rank-sum test. All statistical tests were two-sided and P values less than 0.05 were considered statistically significant. Results: Both AhRN and PD-L1M could distinguish responders from non-responders, and patients with higher H-score had longer PFS than those with lower H score. The AUC of AhRN was 0.804 (95 % CI: 0.721-0.881), higher than that of PD-L1M (0.714; 95 % CI: 0.618-0.811) and AhRN+PD-L1M (0.743; 95 % CI: 0.649-0.837), indicating AhRN might show better predictive capacity to the efficacy of PD-1 blockade immunotherapy than PD-L1M. Besides, AhRN exhibited the most significant accuracy in prognosis prediction, since the hazard ratio (HR) of AhRN was 0.1529 (95 % CI: 0.07704-0.3033, P<0.0001), significantly higher than that of PD-L1M [HR:0.283 (95 % CI: 0.1525-0.525, P<0.0001)] and AhRN+PD-L1M [HR: 0.2456 (95 % CI: 0.1309-0.4607, P<0.0001)]. Yet, among the 54 smokers, AhRN+PD-L1M was the best classifier for the efficacy of immunotherapy, of which the AUC was 0.8937 (95 % CI: 0.816-0.971) and HR was infinitely approaching 0 ( P<0.0001). Conclusions: AhR might be a reliable predictive biomarker for PD-1 blockade immunotherapy in NSCLCs.
PD-L1 expression and microsatellite instability in tumors of unknown primary site.
Authors: Neif Joao , Lazarini Maria , Bonatelli Murilo , Berardinelli Gustavo Noriz , Preto Daniel D Almeida , Araujo Hadson Silva , da Silva Vinicius Duval , Pinheiro Celine Marques , Reis Rui Manuel , Carcano Flavio Mavignier
Published: June 2022

2635

Background: Cancer of unknown primary site is a heterogeneous group of tumors for which the origin remains unknown, despite detailed investigation. Its clinical presentation occurs due to symptoms resulting from metastasis, which can be influenced not only by biological processes of the tumor, but also due to regulatory processes in the tumor microenvironment such as PD-L1. Microsatellite instability (MSI) is a predictive biomarker for cancer immunotherapy and its status as well as co-occurrence with PD-L1 expression is poorly evaluated. The aim of this study was to evaluate the expression of PD-L1 and the status of MSI in tumors of unknown primary site and their possible associations with clinical-pathological characteristics and clinical outcomes in patients with this type of tumor. Methods: The PD-L1 expression was evaluated using the immunohistochemistry technique and measured by CPS and TPS scores. MSI status was assessed using a hexa-plex marker panel by polymerase chain reaction followed by fragment analysis. Overall survival was analyzed using the Kaplan Meier method and comparisons of the curves using the log rank test. Results: Of the 121 conclusive cases for MSI status, only two cases (1,6%) were MSI-High. PD-L1 expression, assessed by both TPS and CPS, was positive in approximately 18% of 108 conclusive cases. PD-L1 expression is significantly less frequent in patients with a predominance of hepatic or bone metastasis and more frequent in patients with a predominance of nodal metastasis. The median overall survival was about 4 months, and the predominance of liver metastases was associated with a worse prognosis, while the use of chemotherapy and low ECOG-PS were associated with better survival. PD-L1 expression was associated with better overall survival. Conclusions: PD-L1 is expressed in a subset of patients with cancer of unknown primary site, while MSI is a rare event. It is necessary to better explore the microenvironment of this type of tumor as well as the role of immunotherapy to change such a dismal clinical outcome.
Phase Ia dose-escalation study of the anti-BTLA antibody icatolimab as a monotherapy in patients with advanced solid tumor.
Authors: Schilder Russell J. , Powderly John D. , Park Haeseong , Bilen Mehmet Asim , McKean Meredith , May Rena , Feng Hui , Yao Sheng , Keegan Patricia , Naing Aung
Published: June 2022

2643

Background: The B- and T-lymphocyte attenuator (BTLA) is an inhibitory receptor expressed on B, T and NK cells. Icatolimab (TAB004 or JS004) is a humanized IgG4 monoclonal antibody (mAb) with a hinge mutation (S228P) that binds BTLA and blocks its interaction with its ligand HVEM. In preclinical studies, icatolimab monotherapy suppressed tumor growth in murine tumor models using human BTLA knock-in mice. In this first-in-human dose-escalation study, we report the preliminary safety and efficacy of icatolimab as a single agent in patients with advanced solid tumors. Methods: Eligible patients with advance solid tumors refractory to standard therapies were enrolled in this study. Icatolimab was administered at escalating doses of 0.3, 1, 3 and 10 mg/kg intravenously Q3W and followed by dose expansion in 3 and 10 mg/kg cohorts until disease progression or intolerable toxicity. Dose-limiting toxicity (DLT) was evaluated by a safety monitoring committee. Study objectives included safety, pharmacokinetics, pharmacodynamics, and anti-tumor activity. Results: A total of 25 patients with solid tumor were enrolled in the Part A of this phase I study (NCT04137900). The median age was 62 (range 32-85) years with 16 (64%) male patients. Patients were heavily pretreated with a median of 4 prior lines of therapy. Fifteen (60%) patients received and progressed upon prior anti-PD-1/L1 therapy. By the data cutoff date of December 31, 2021, the median follow-up was 32 weeks. No DLT was observed. 24 (96%) patients experienced treatment emergent adverse event (TEAEs), with 7 (28%) experienced grade 3 TEAEs. No grade 4 or 5 TEAE occurred. The incidence or severity of AE was not associated with the dose. The most common TEAEs were fatigue (32%), abdominal pain (20%), diarrhea (16%), arthralgia (16%), aspartate aminotransferase increased (16%), constipation (16%), and contusion (16%). One (4%) TEAE led to discontinuation of study drug. Four (16%) patients experienced immune related AE. Among 19 evaluable patients by the cutoff date, 1 confirmed PR (melanoma) and 6 SD were observed as assessed by the investigator per RECIST v1.1. The response was still ongoing over 12 months in the melanoma patient who had progressed upon prior nivolumab and BRAF/MEK inhibitors treatments. BTLA receptor was fully occupied in the 3 and 10 mg/kg cohorts. The mean elimination half-life of icatolimab was 7.5 to 19.2 days in four dose cohorts. Biomarker analysis indicated co-expression of HVEM and CD8 was associated with favorable response. Conclusions: Icatolimab monotherapy were well tolerated in all doses evaluated and showed preliminary clinical efficacy as a monotherapy. Icatolimab in combination with toripalimab (anti-PD-1) for the treatment of patients with advanced solid tumors is currently ongoing. Clinical trial information: NCT04137900.
Phase I study of the efficacy and safety of IBI319 in patients with advanced malignant tumors.
Authors: Wu Yi-Long , Zhou Jianfeng , Zhou Qing , Zhang Huilai , Ding Kefeng , Zhou Jianying , Wang Shuyan , Ji Wenting , Zhang Chengli , Wang Yanqi , Ni Ping
Published: June 2022

2646

Background: IBI319 is a recombinant fully human anti-CD137/PD-1 bispecific antibody. In preclinical studies, IBI319 demonstrated a better anti-tumor efficacy and safety. Here we report the initial results from the first-in-human study of IBI319 in patients with advanced malignancies. Methods: Enrolled patients (pts), ECOG PS ≤ 1, had advanced solid tumors or hematological malignancies and failed standard treatment. This phase 1 monotherapy dose-escalation includes accelerated titration (0.03 and 0.1mg/kg) and conventional 3+3 dose escalation (0.3, 1.0, 3.0, 6.0 and 10.0 mg/kg). IBI319 is administered intravenously every 14 days after dose-limiting toxicity (DLT) evaluation. Objectives include evaluation of safety, DLT, pharmacokinetic (PK) and antitumor activity. Adverse events (AEs) were reported per CTCAE v5.0 and DLTs evaluated within a 28-day window. Results: At cutoff date of February 10, 2022, 21 pts were enrolled (median age 55 years; 81.0% male; 19.1% ECOG PS 1; 52.4% advanced solid tumors). The following dose levels have been evaluated; 0.03 mg; 0.1 mg; 0.3 mg; 1 mg; 3 mg and 6 mg. Dose escalation is ongoing. The maximum tolerated dose has not been reached. Treatment-emergent adverse events (TEAEs) was reported in 15 out of 21 (71.4%) pts, among which 1 pts had back pain and nausea of grade 3. The most common TEAEs ( > 10%) were interleukin level increased (6 pts, 28.6%) and C-reactive protein increased (3 pts, 14.3%). Eleven pts (52.4%) experienced treatment-related AEs; none were grade 3 or higher. The most common TRAEs ( > 10%) were interleukin level increased (6 pts, 28.6%) and C-reactive protein increased (3 pts, 14.3%). Importantly, no drug-related elevations in transaminases (ALT, AST) or bilirubin have been seen. No DLT was observed. PK analysis of IBI319 demonstrated consistent exposure with linear PK. For 14 evaluable pts, 1 classical Hodgkin lymphoma patient achieved PR as best response. Conclusions: IBI319 demonstrates good tolerability in patients with advanced solid tumors or hematological malignancies, with a safety profile characterized by a lack of hepatotoxicity frequently observed with CD137-targeting antibodies. Clinical trial information: NCT04708210.
Pan-cancer (ca) analysis of the safety and efficacy of immune checkpoint inhibitors (ICI) in patients (pts) living with HIV (PLWH): Results from the international CATCH-IT consortium.
Authors: El Zarif Talal , Nassar Amin , Adib Elio , Huang Jiaming , McKay Rana R. , Dobbs Ryan , Dizman Nazli , Drolen Claire , Kozaily Elie , Saeed Anwaar , Nebhan Caroline , Lorentsen Michael , Baena Javier , Dalla Pria Alessia , Baden Lindsey , Ramaswami Ramya , Choueiri Toni K. , Lurain Kathryn Anne , Sonpavde Guru P. , Naqash Abdul Rafeh
Published: June 2022

2649

Background: PLWH and ca are inadequately represented in clinical trials evaluating ICI especially in the setting of low CD4 counts (ct) and elevated HIV viral loads (VL). We assembled an international cohort of PLWH and ca treated with ICI to evaluate toxicity profiles and clinical outcomes. Methods: We retrospectively collected data on 204 PLWH and ca receiving ≥ 1 cycle of ICI between 2015-2021 at 14 academic medical centers in the US and Europe. Immune-related adverse events (irAEs) were graded per the Common Terminology Criteria for Adverse Events (CTCAE) V5.0. Baseline CD4 ct, CD8 ct and HIV VL were collected within 3 months (mo) of ICI initiation when available. Fisher’s exact test was performed to compare categorical variables. Median (med) Overall Survival (OS) and Objective Response Rate (ORR) were calculated for 186 pts treated in the metastatic (met) setting. Results: Among 204 PLWH treated with ICI, 174 (85%) were cis-gender males. 61 (31%) were Black and 34 (18%) were Hispanic/Latinx. Pts were treated with pembrolizumab (n=93), nivolumab (n=71), atezolizumab (n= 20), nivolumab and ipilimumab (n=13), durvalumab (n=6), or avelumab (n=1). Med number of prior lines of systemic therapy was 1 (range: 0-5). Among pts with available baseline data, 36/133 (27%) had CD4 ct <200 cells/µL while 12/136 (9%) had VL ≥400 copies/mL. irAEs of any grade occurred in 43 (21%) pts and 13 (7%) were grade ≥3 while 19 (9%) required steroids. Pts with CD4 ct <200 cells/µL experienced fewer irAEs than pts with CD4 ct ≥200 cells/µL (2/36 vs 26/97; p<0.01). The incidence of any grade irAEs was similar between pts with CD4/CD8 ratio <0.4 vs ≥0.4 (8/54 vs 18/72; p=0.16) and between pts with HIV VL ≥400 vs <400 copies/mL (1/12 vs 28/124; p=0.46). Clinical outcomes are shown in the table below. Among 29 pts with met non-small cell lung ca (NSCLC) with available CD4 ct, the ORR of pts with CD4 ct <200 cells/µL was 13% (95% CI:0-53) vs 38% (95% CI:18-62) in pts with CD4 ct ≥ 200 cells/µL (1/8 vs 8/21; p=0.38). Conclusions: In the largest dataset to our knowledge, we demonstrate tolerability and activity of ICI among PLWH regardless of CD4 ct and HIV VL levels. CD4 ct <200 cells/µL may be associated with a lower incidence of irAEs. An analysis of a larger cohort is underway. [Table: see text]
Safety and efficacy of etigilimab in combination with nivolumab in select recurrent/advanced solid tumors.
Authors: McKean Meredith , Dumbrava Ecaterina Elena , Hamid Omid , Merriam Priscilla , Mettu Niharika B. , Call Justin A , Kapoun Ann M. , Lucas Jennifer , Seetharam Mahesh , Vaishampayan Ulka N. , Weroha Saravut John , Krishnan Suba , George Angela Joy
Published: June 2022

2651

Background: Etigilimab (etig), a humanized IgG1 monoclonal antibody, blocks TIGIT interaction with PVR (poliovirus receptor) and inhibits downstream signalling with target cell killing. Etig +/- nivolumab (nivo) showed acceptable safety and preliminary activity in a FIH Phase 1a/b study in solid tumors. ACTIVATE, an open-label Phase 1b/2 basket study is evaluating further efficacy, safety, tolerability and PK/PD of etig+nivo. This is a preliminary efficacy and safety analysis from ACTIVATE. Methods: Subjects with advanced/metastatic solid tumors without curative/standard of care therapies are given IV etig+nivo Q2W until disease progression or intolerable toxicity. Six open cohorts are enrolling in parallel: endometrial cancer (post-front-line platinum), endometrial cancer (2-3 prior lines), PD-L1+ checkpoint-inhibitor-naïve (CPI-n) cervical cancer, rare cancers (germ cell tumor (GCT), sarcoma, uveal melanoma), ovarian cancer (post-front-line platinum) and TMB-h/MSS, (TMB >10mut/mb) tumors. Tumor assessments are done every 8 weeks following baseline scan. Primary endpoint is investigator-assessed ORR by RECIST 1.1. Secondary endpoints include duration of response and safety. Results: Of 27 efficacy-evaluable subjects enrolled in the 6 open cohorts with minimum 1 staging scan or radiological/clinical progression at data cut-off of 02/10/22, 12 had clinical benefit with 1 complete response (CR), 2 partial responses (PRs) and 9 stable diseases (SDs) and 15 had radiological/clinical progressive disease (PD), with an overall response rate (ORR) of 11% and disease control rate (DCR) of 44%. Conclusions: Etig+nivo is safe and well tolerated with no new safety signals. Early efficacy was noted in cervical cancer (1CR, 1PR and 1SD) and uveal melanoma (3 SDs >20 weeks). Encouraging activity was also noted in ovarian cancer and post-CPI treated TMB-H/MSS NSCLC. These early data support continued evaluation of the combination of etig+nivo. Clinical activity was notable as below. Clinical trial information: NCT04761198. [Table: see text]
Immune checkpoint inhibitor-related endocrinopathies: A nationwide population-based study.
Authors: Elantably Dina , Al Armashi Abdul Rahman , Hammad Faris , Alkrekshi Akram
Published: June 2022

2653

Background: Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy. However, unleashing the body’s immune system against cancer is not without consequences and may trigger immune-related adverse events (irAEs), such as endocrinopathies. Real-world data of these endocrinopathies is lacking. This study aims to obtain the prevalence of endocrine irAEs and identify possible underlying demographic risk factors or disparities. Methods: A cross-sectional study was performed using a US-based population database (Explorys) that aggregates records from 26 healthcare systems and includes over 79 million patients. Our sample included all patients on an ICI, and we further identified patients who developed endocrinopathies while on different ICI regimens. The demographic data extracted was categorical, hence presented as counts and percentages. The odds ratio (OR), standard error, and 95% confidence interval were calculated with the use of SPSS software version 28.0 (IBM). Results: There were 20,950 patients on an ICI; 58% males, 83% Caucasians, 10% African-Americans (AA), 38% aged between 18-65, and 63% were over 65 years. The prevalence of the studied endocrinopathies is listed in the table. The most prevalent ICI-induced endocrinopathy was hypothyroidism (7.9-13%). Combination therapy with ipilimumab and nivolumab showed the highest prevalence of ICI-induced endocrinopathies, followed by durvalumab. The odds of developing ICI-induced endocrinopathy were significantly higher with combination therapy than nivolumab monotherapy (OR 1.6; 95% CI 1.4-1.9). There was no statistically significant difference in endocrinopathy prevalence when comparing Caucasians to AA and adults18-65 years to seniors over 65 years. Conclusions: This is the largest epidemiological study of ICI-related endocrinopathies. We find an intriguing divergence from endocrinopathy prevalence reported in the literature and real-world data we are presenting here. Over diagnosis of overt hypothyroidism, as opposed to subclinical hypothyroidism, is concerning as the former necessitates levothyroxine therapy. More alarming is the under diagnosis of hypopituitarism and PAI, in which delay in treatment can be fatal. The diagnosis of these conditions can be challenging. Raising awareness, setting protocols for testing, and involving endocrinologists are crucial. Further studies are needed to clarify our findings. [Table: see text]
Evaluating survival following severe immune-related adverse events requiring hospitalization.
Authors: Wright Francis , Kim Daniel Myung , Silverstein Jordyn , Wang Michelle , de Dios Kimberly , Young Arabella , Quandt Zoe E. , Brondfield Sam
Published: June 2022

2666

Background: As immune checkpoint inhibitors (CPI) are increasingly approved for the treatment of multiple cancer types, hospitalizations related to severe immune-related adverse events (irAE) will increase in tandem. Here, we identify patients hospitalized due to irAEs and describe survival outcomes across irAE, CPI, and cancer type. Methods: We identified patients exposed to CPIs who were hospitalized from 1/2012 to 12/2020 at our tertiary care hospital by computationally extracting data from the electronic health record. We then performed manual chart review to include only confirmed irAE-related hospitalizations. Survival outcomes were analyzed using Kaplan-Meyer survival curves with log-rank tests. Results: Of 3137 patients treated with CPIs, 117 were hospitalized for irAEs (cumulative incidence 4%). Of these, 36% had melanoma, 15% had lung cancer, 9% had renal cell carcinoma (RCC), and the rest were distributed across other cancers. The average number of irAE-related hospitalizations per patient was 1.25 (ranging from 1-3). Among 153 irAEs requiring hospitalization, 39% were gastrointestinal (GI) (including hepatitis), 12% endocrine, 12% pulmonary, 12% neurologic, 12% musculoskeletal, 7% cardiovascular, 6% dermatologic, and the rest affected other organs. Across all patients hospitalized for irAEs, median survival following hospitalization was 980 days. Patients with GI and endocrine irAEs had longer median survival (1474 days and median not reached [NR], respectively), while patients with pulmonary irAEs had shorter median survival (64 days) [p=0.002]. Patients with melanoma and RCC had longer median survival (2796 days and NR, respectively), while patients with lung cancer had shorter median survival (165 days) [p=<0.001]. Survival was not significantly different across CPI type [p=0.20]. Conclusions: Although hospitalization for severe irAE was rare, these findings suggest that among these patients, survival differs by irAE and cancer type. This real world data can contribute to clinical models that predict the risk of hospitalization and the risk of death due to severe irAEs, which may inform patient counseling and treatment decision-making. [Table: see text]
A multicenter, open-label, single-arm, phase 1 dose-escalation study to evaluate the safety, tolerability, and anti-tumor activity of FCN-159 in adults with neurofibromatosis type 1.
Authors: Hu Xiaojie , Zeng Kang , Xu Zhongyuan , Li Wenbin , Li Changxing , Kang Zhuang , Li Shenglan , Hui Ai-Min , Wu Zhuli , Huang Xin , Han Pu , Li Ben , Lin Xiaoxi
Published: June 2022

3011

Background: Neurofibromatosis type 1 (NF1) is an autosomal-dominant genetic disease that increases susceptibility to malignant tumors. Up to 50% of patients with NF1 present with plexiform neurofibroma (PN). Surgery, a common treatment strategy for patients with PN, has limited efficacy. NF1 is caused by mutations in the gene that encodes neurofibromin; the NF1 mutation then leads to tumorigenesis via dysregulation of the Ras/Raf/MEK/ERK pathway. FCN-159 is anti-tumorigenic via highly potent, selective inhibition of MEK1/2. This study aims to assess the safety of FCN-159 in patients with NF1-related PN. Methods: This is a multicenter, open-label, single-arm, phase 1 dose-escalation and phase 2 dose-expansion study (NCT04954001). Patients with NF1-related PN that was not completely resectable or not suitable for surgery were enrolled in the study; they received FCN-159 monotherapy continuously in 28-day cycles. Here, we report safety and clinical efficacy data from adults enrolled in phase 1. Results: As of the data cutoff of December 1, 2021, 19 adults from 3 hospitals in China have been enrolled in the phase 1 dose-escalation study, 3 in 4 mg, 4 in 6 mg, 8 in 8 mg, and 4 in 12 mg. The most common neurofibroma-related complications were disfigurement and pain, occurring in 10 patients (52.6%) and 4 patients (21.1%) at baseline, respectively. Four patients experienced dose-limiting toxicity; G3 folliculitis was reported in 1 patient (16.7%) receiving the 8-mg dose and 3 (100%) patients receiving the 12-mg dose. The maximum tolerated dose was determined to be 8 mg. Study-drug-related treatment-emergent adverse events (TEAEs) were observed in all 19 patients (100%); the majority were grade 1 or 2 in severity. Nine (47.4%) patients reported grade 3 study drug-related TEAEs; 4 patients experienced paronychia and 5 experienced folliculitis, which were the most common causes of dose reduction (42.1%) and drug interruption (21.2%). One patient experienced a serious adverse event of rhegmatogenous retinal detachment, but this was considered unrelated to the study drug as it was preexisting at baseline. Of the 16 patients with at least 1 post-baseline tumor assessment, all (100%) had reduced tumor size and 6 (37.5%) had a reduction in tumor size of > 20%. Three out of 6 patients with a second tumor assessment result had further tumor shrinkage; tumor volumes in the remaining 3 patients were similar to those at first assessment. The largest reduction in tumor size was 84.2%. Conclusions: Overall, FCN-159 at 8 mg is well tolerated, with easy to manage adverse events, and showed promising anti-neurofibroma activity in phase 1; this warrants further investigation in a phase 2 study on efficacy and safety in this indication. Clinical trial information: NCT04954001.
Systemic levels of the soluble co-inhibitory immune checkpoints, CTLA-4, LAG-3, PD-1/PD-L1, and TIM-3 are markedly increased in basal cell carcinoma.
Authors: Rapoport Bernardo Leon , Malinga Nonkululeko , Siwele Shalete , Steel Helen C. , Kwofie Luyanda LI , Meyer Pieter , Smit Teresa , Anderson Ronald , Kgokolo Mahlatse
Published: June 2022

3043

Background: Although co-inhibitory immune checkpoint proteins are primarily involved in promoting inhibitory cell-cell interactions in adaptive immunity, especially tumor immunity, the soluble cell-free variants of these molecules are also detectable in the circulation of cancer patients where they retain immunosuppressive activity. Nevertheless, little is known about the systemic levels of these soluble co-inhibitory immune checkpoints in patients with various subtypes of basal cell carcinoma (BCC), which is the most invasive and treatment-resistant type of this most commonly occurring malignancy. Methods: In the current study, we have measured the systemic concentrations of five prominent co-inhibitory immune checkpoints, namely CTLA-4, LAG-3, PD-1/PD-L1 and TIM-3, as well as those of C-reactive protein (CRP) and vitamin D (VD), in a cohort of patients (n = 40) with BCC, relative to those of a group of control participants (n = 20), using the combination of multiplex bead array, laser nephelometry and ELISA technologies, respectively. Results: The median systemic concentrations of CRP and VD were comparable between the two groups; however, those of all five immune checkpoints were significantly elevated ( P= 0.0184 - P£0.00001), with those of CTLA-4 and PD-1 being highly correlated (r = 0.87; P< 0.00001). Conclusions: This seemingly novel finding not only identifies the existence of significant systemic immunosuppression in BCC, but also underscores the therapeutic promise of immune checkpoint targeted therapy, as well as the potential of these proteins to serve as prognostic/predictive biomarkers in BCC.
Dysregulation of immune checkpoint proteins in patients with newly diagnosed early breast cancer.
Authors: Rapoport Bernardo Leon , Steel Helen C. , Benn Carol , Nayler Simon , Smit Teresa , Heyman Liezl , Theron Annette J. , Hlatswayo Nomsa , Kwofie Luyanda LI , Meyer Pieter , Anderson Ronald
Published: June 2022

3044

Background: Checkpoint proteins regulate the immune system. Breast cancer (BC) cells can up-regulate or down-regulate these proteins to evade anti-tumor immune responses. Soluble forms of immune checkpoint molecules (ICMs) can be measured in human plasma. The study aimed to measure the systemic levels of a series of co-stimulatory and co-inhibitory ICMs at diagnosis, post-neo-adjuvant chemotherapy (NAC) and post-surgery in newly- diagnosed BC patients (pts) relative to those of a healthy control group. Methods: Soluble ICMs were measured using multiplex bead array technology in plasma from 72 BC pts and 45 healthy controls. Data was prospectively obtained and levels compared between pre-treatment, post-NAC, and post-surgery using non-parametric tests (Mann-Whitney & Kruskal-Wallis). Results: Pre-treatment levels of the soluble stimulatory molecules viz. GITR (p<0.0001), GITRL (p< 0.020), CD27 (p< 0.024), CD40 (p< 0.021), ICOS (p< 0.009), as well as the inhibitory molecules PD-L1 (p< 0.0001), CTLA-4 (p< 0.005), TIM-3 (p< 0.0004), HVEM (p< 0.0004) were significantly lower in early BC pts compared to controls. Post-treatment, there were significant increases in most ICM levels (Table), with the exception of CTLA-4, which decreased significantly following treatment. On the other hand, pre-treatment plasma concentrations of CCL5 (RANTES) (84.22 vs. 48.72 pg/mL, p<0.0001), M-CSF (84.41 vs 13.34 pg/mL, p<0.0001), FGF-21 (24.36 vs. 8.64 pg/mL, p<0.001) and GDF-15 (806.82 vs. 430.03 pg/mL, p<0.0001) were significantly increased in the breast cancer pts compared to healthy controls. A pathological complete response (pCR) was documented in 65% of pts (mostly TNBC). There were no correlations between pre-treatment ICM levels, CCL5, M-CSF, FGF-21 and GDF-15 and pCR. Conclusions: We identified low levels of stimulatory and inhibitory ICMs in newly-diagnosed, non-metastatic BC pts compared to healthy controls. Following treatment, with the exception of CTLA-4, most of these pre-treatment abnormalities of systemic ICM levels corrected. NAC is associated with upregulation of sPD-L1 and most other ICMs. These results indicate that early BC is associated with down-regulation of soluble stimulatory and inhibitory ICMs. Newly-diagnosed early BC pts appear to have generalized immune-suppression independent of subtype and stage. To our knowledge, this is the first study to describe the effect of treatment on systemic ICMs in early BC pts. [Table: see text]