bluuebunny/crossref_metadata_2025 huggingface dataset:
Thoracic SMARCA4-deficient undifferentiated tumor: A clinicopathologic study.
Authors: Shold Janna , Hamza Ameer
Published: June 2023

e14642

Background: Thoracic SMARCA4-deficient undifferentiated tumor is a high-grade malignant neoplasm that frequently shows undifferentiated morphology and deficiency of SMARCA4. There is limited data in literature for this entity. The purpose of this report is to describe clinicopathologic features of this rare tumor in a series of 5 patients, diagnosed and treated at our institution. Methods: After approval from institutional review board, pathology department archive was searched for the patients with diagnosis of Thoracic SMARCA4-deficient undifferentiated tumor from January 2020 to December 2022. Data such as patient demographics, pathologic features including immunohistochemical stains, treatment and clinical outcome were collected. Results: Among 5 patients, 3 were male and 2 were female. Median age was 62 years (range 49 to 77 years). In three patients the primary site of the tumor was lung. One patient had tumor of the gastroesophageal junction while one patient had epicenter of the tumor in the paraspinous muscle. Diagnosis was made on biopsy specimen in all cases. All tumor showed undifferentiated histologic appearance. Rare cells with keratin positivity were observed in 2 specimens while 3 were completely negative for keratin stains. Focal TTF1 positivity was observed in one specimen while 4 were negative. Among neuroendocrine markers performed on variable number of cases, synaptophysin was positive in 4/4 cases while chromogranin was negative in 2/2 cases and INSM1 was negative in 1/1 case. PD-L1 (Dako 22C3) was performed on two specimens and showed less than 1% tumor cells to be positive. Next generation sequencing was performed on one specimen and showed pathogenic variants in TP53, CDKN2A, and APC genes and likely pathogenic variants in ATR, SMARCA4, and BCOR genes. Two patients received carbotaxol and radiation, one patient received FOLFOX, nivolumab and radiation, 1 patient pursued hospice care and 1 patient lost follow up. Two patients died 2 and 7 months after diagnosis. One patient is alive with metastatic disease 4 months after initial diagnosis. Conclusions: SMARCA4-deficient undifferentiated tumor is an aggressive malignancy that shows undifferentiated histology with synaptophysin positivity. From a diagnosis standpoint, Pathologists need to keep this entity in mind while working up tumors showing poorly differentiated to undifferentiated histology that are negative for most immunohistochemical markers. From clinical standpoint there is need to develop targeted therapy for this aggressive tumor.
Evaluation of immunotherapy response score (IRS) for predicting pembrolizumab (pembro) clinical benefit in patients (pts) with advanced solid tumors.
Authors: Thomas Sachdev P. , Achacoso Ninah , Jiang Chen , Chung Elaine , Solorzano-Pinto Aleyda V. , Tse Pamela , Bulen Benjamin J. , Khazanov Nickolay A. , Lamb Laura Elaine , Hovelston Daniel H. , Kwiatkowski Kat , Johnson D. Bryan , Rhodes Daniel R. , Tomlins Scott A. , Suga Jennifer Marie , Habel Laurel A.
Published: June 2023

e14646

Background: IRS is a multivariable biomarker algorithm combining tissue-based tumor mutation burden (TMB) with quantitative gene expression biomarkers, previously validated to predict anti-PD-1 and anti-PD-L1 monotherapy (mono) benefit in an observational clinical trial (PMID: 36750617). Herein, we evaluated IRS in pts with advanced solid tumors across the Kaiser Permanente Northern California (KPNC) health system following a pre-specified statistical analysis plan. Methods: KPNC pts with valid IRS results (from 2018 – 2022; specimen collection years 2011-2021) and electronic health record (EHR) documented > 1st line systemic pembro mono treatment were included; pts with gliomas or previous immunotherapy were excluded. All oncologic treatments were obtained from the EHR and standardized to determine time to next treatment (TTNT) as a real-world progression free survival endpoint. A within-pt evaluation was performed, comparing pembro TTNT to the pt’s immediate prior therapy line (prior) TTNT. The primary objective was to determine if IRS status (-H vs. Low [-L]) predicts pembro clinical benefit in Cox proportional hazards models through testing for interaction between IRS status and pembro/prior therapy TTNT. Results: With a data cutoff of 06/15/2022, 211 KPNC pts (142 2nd line and 69 > 2nd line pembro) were eligible and included (from 24 solid tumor types). The median (m) pembro follow-up was 16.0 months. IRS-H pts (n = 77, 36%) had significantly longer pembro vs. prior TTNT (mTTNT 20.3 mo vs. 4.5 mo, log-rank p-value < 0.0001), whereas IRS-L pts (n = 134, 64%) did not (mTTNT 3.3 mo vs. 5.2 mo, log-rank p-value 0.75); the interaction between IRS status and pembro/prior treatment was significant (interaction test p-value < 0.0001). Conclusions: IRS predicted pan-solid tumor pembro mono benefit compared to prior therapy and may be a potential marker for pembro mono treatment decisions. Clinical trial information: NCT03061305 .
Quantitative analysis of MMR deficiency in dMMR/MSI high CRC and levels of instability: Implications for ICI therapy of dMMR tumors.
Authors: Staninova Stojovska Marija , Matevska Geshkovska Nadica , Jovanovic Rubens , Kubelka Sabit Katerina , Angelovska Biljana , Mitrevski Nenad , Panovski Milco , Josifovski Toni , Dimovski Aleksandar J
Published: June 2023

e14650

Background: Mismatch repair deficiency (dMMR) is observed in ~15% of newly diagnosed colorectal cancer (CRC) tumors. It is routinely scored as a qualitative trait (positive or negative) and, if present, is considered a positive predictive marker for immune checkpoint inhibitors (ICI) therapy not only in patients with metastatic CRC (mCRC), but also in patients with other dMMR solid tumors. However, a significant proportion of these patients experience failure of ICI treatment and no predictive biomarkers exist that can identify such patients. Methods: A total of 42 patients with dMMR tumors were selected for analysis, of which 26 had a hereditary Lynch Syndrome (LS) with known pathogenic variants in the MMR genes (MLH1, MSH2, MSH6, PMS2) and 16 had sporadic dMMR CRC due to epigenetic silencing of the MLH1 gene. All tumors were also analyzed for the presence of the RAS/RAF pathway mutations. MMR deficiency was initially evaluated by two standard methods: immunohistochemistry (IHC) and by microsatellite instability (MSI)-PCR on DNA isolated from FFPE tissues with > 50% tumor content. Subsequently, whole exome sequencing (WES) with a mean depth of >150 reads was performed on the same DNA samples using the NovaSeq 6000 platform. NGS data were analyzed using the MSI sensor package which evaluates >2000 sites with mono- to pentanucleotide repeats. Each site was scored as NGS-MSI unstable if it contained at least 20% unstable reads. The percent of unstable loci was referred to as NGS-MSI level. All tumors with >3.5% of unstable loci were classified as NGS-MSI positive. Results: A considerable variability in the NGS-MSI levels ranging from 1.5 – 76% was observed in patients that were initially classified as dMMR/PCR-MSI high. CRC tumors of LS patients with deleterious MMR gene mutations and the majority of patients with sporadic CRC due to MLH1 gene promotor methylation had >50% unstable loci. In contrast, more than 1/3 of patients with isolated loss of MSH6 and PMS2 detected by IHC had substantially lower NGS-MSI levels of 1.5 to 12%. These patients had a negative PCR-MSI result and their molecular defects were primarily missense mutations in MSH6 and PMS2 genes. It is interesting to note that a low NGS-MSI score (<10%) was also detected in patients with sporadic CRC that had MLH1 gene promotor methylation but also the BRAF V600E mutation. Conclusions: Our results indicate that dMMR/MSI-H tumors exhibit a high variability in the percentage of unstable loci that correlates with particular molecular backgrounds. A larger study on different types of tumors is warranted, especially in the context of the efficacy of ICI therapy in patients with MMR tumors classified by qualitative MMR/MSI assays.
A pilot trial of personalized neoantigen pulsed autologous dendritic cell vaccine as adjuvant treatment in hepatocellular carcinoma.
Authors: Wu Qiuji , Li Qiu , Yang Li , Xu Heng
Published: June 2023

e14658

Background: The primary means of treating hepatocellular carcinoma (HCC) is radical surgery. However, HCC has a high propensity to recur post-operatively, and no standard adjuvant therapies have been approved. Tumor neoantigens, which are epitopes derived from tumor-specific mutations, may be utilized in personalized vaccines to activate T cell responses. This trial aims to assess the safety and efficacy of personalized neoantigen pulsed autologous dendritic cell vaccine (Neo-DCVac-02) in patients with HCC. Methods: Eligible patients had histologically confirmed high-risk HCC after radical surgery. Upon obtaining the baseline biopsy specimens and PBMCs of appropriate quality for DNA and RNA sequencing, neoantigen prediction, screening, and synthesis were performed. Subsequently, autologous dendritic cells (DCs) were generated and pulsed with neoantigen peptides to produce Neo-DCVac-02.On day 0, patients were treated with cyclophosphamide at a dose of 250 mg/m2. The prepared Neo-DCVac-02 vaccine was administered subcutaneously on day 1, followed by GM-CSF administered daily for 5 days. The primary objectives of this study were to evaluate the feasibility and safety/tolerability. Secondary objectives included assessment of immune responses (via vaccine response: IFNγ ELISpot), recurrence-free survival (RFS), and overall survival (OS). Results: A total of 32 patients provided informed consent to initiate the process of personalized neoantigen discovery, of which 26 (81%) met the requirements for successful product selection for clinical manufacturing. And feasibility was shown with 13 patients receiving Neo-DCVac-02. Thirteen patients did not receive neoantigen vaccines (7 for progressive disease,6 for withdrawal of informed consent because of COVID-19). Treatment was well-tolerated with no grade 2+ treatment-related adverse events (TRAEs). The common grade 1TRAEs were neutropenia (8.3%), injection site reactions (75%), rash (16.7%), fatigue (8.3%), and headache (8.3%). The median follow-up to date is 19.30 (14.4-31.9) months, with median RFS and OS not yet reached and a 1-year RFS of 83%. Five of 13 evaluable patients showed elevated antigen-specific T-cell activity by IFNγ ELISpot for more than 50% of neoantigen peptides in Neo-DCVac-02, and persistent cellular responses were noted out to 1 year. Increases in activation/co-stimulatory of T cells seen after treatment with Neo-DCVac-02 revealed by Flow-cytometric analyses, suggest immune priming. Conclusions: These data demonstrate that Neo-DCVac-02 is safe, well tolerated, and able to generate durable antigen-specific lymphocyte immune responses. Early signs of clinical efficacy were observed in HCC patients. Clinical trial information: NCT04147078 .
An exploratory trial of a novel R-ISV-RO technique in the treatment of advanced solid tumors.
Authors: Li Rutian , Min Limei , Wang Xiaolu , Chen Anni , Chang Xiaofeng , Cen Lanqi , Chen Jun , Sun Wu , Yan Jing , Zhou Xia , Shen Jie , Liu Baorui
Published: June 2023

e14666

Background: The immunotherapy of bone and soft tissue sarcomas remains a challenge. Our pre-clinical trial confirmed that the combination of Toll-like receptor 7 (TLR7) agonist imiquimod (R837) and OX-40 agonist had prominent synergistic effects. Immunoradiotherapy, especially Stereotactic Body Radiotherapy (SBRT) could further activate specific immune response. We hypothesized that intratumoral injection of “RO” (R837+αOX40) combined with SBRT will realize tumor control and reduce adverse reactions. Meanwhile, the synergetic application of PD-1 mAb systematically will improve the effectiveness of immunotherapy. Methods: This is a single-arm, single-center, open-label, exploratory trial that explore intratumoral injection of an emulsion of “RO” in combination with SBRT as “in situ vaccination” for advanced solid tumor (Ethics number: 2021-133-02). The inclusion criteria included: 1) advanced solid tumors which progress after standard therapies, 2) presence of one or more injectable lesions. SBRT to injected lesions was at a dose of 5-8Gy per fraction at a total dose of 20-32Gy. Imiquimod (0.75mg/ml) and αOX40 (2.5mg/ml) were prepared as emulsion and intratumoral injected into the target lesion for 4 times. Patients were also systematically administrated with PD-1 mAb (serplulimab). The primary endpoint was objective response rate (ORR) of target lesions. The secondary endpoint mainly included disease control rate (DCR) of target lesions, progression free survival (PFS), overall survival (OS), and clinical benefit rate (CBR), etc. Results: From May 2021 to October 2022, 30 patients were eligible for this trial (60% were sarcomas). 46.7% and 33.3% had received radiotherapy or PD-1/PD-L1 mAb respectively before. The ORR, DCR and CBR of target lesions were 29.2%, 91.7% and 41.7%, while these of systemic efficacy were 21.7%, 82.6% and 17.4%, respectively. In sarcomas, the ORR, DCR and CBR of target lesions were 25.0%, 93.8% and 50.0%, while these of systemic efficacy were 20.0%, 93.3% and 26.7%, respectively. Systemic median PFS were 3.67 months. The median event-free survival (EFS) of target lesions and median OS were not reached. Among the evaluable target lesions, 6-month EFS was 85.7% in sarcomas (6/7) and 76.9% in all patients (10/13). The most common TRAEs were leukopenia (50%), hypoproteinemia (30%) and anemia (20%), demonstrating that treatment is tolerable. Grade≥3 treatment-related adverse events (TRAE) occurred in 3 patients, including myocarditis (6.7%) and thyroiditis (3.3%). Conclusions: In situ vaccination with “RO” emulsion, along with SBRT was tolerable and induced anti-tumor immunity, which would also trigger systemic response when synergized with PD-1 mAb. This in situ vaccination has been proved to be a promising option for advanced solid tumors especially for sarcomas. Clinical trial information: ChiCTR2100053870 .
Adverse events (AEs) of immune checkpoint therapy (ICT) combined with vascular endothelial growth factor inhibitors (VEGFi) vs. ICT alone: A pooled meta-analysis of 1735 patients.
Authors: Kovalenko Iuliia , Ng Wern Lynn , Geng Yimin , Benkhadra Raed , Msaouel Pavlos , Alhalabi Omar
Published: June 2023

e14667

Background: ICT combined with VEGFi are established as approved therapies for multiple malignancies. However, added toxicities remain unclear. We hypothesized that the combination of ICT + VEGFi has higher treatment-related AEs (TRAEs) and immune-related AEs (irAEs) compared with ICT alone. Methods: We performed a meta‐analysis to identify studies evaluating toxicity profile of ICT + VEGFi as compared to ICT. Systemic search was performed across all cancer types and major databases until August 10, 2022. Search structures, subject headings, and keywords were tailored to databases by medical research librarian. Screening of studies was done by two investigators. Inclusion criteria consisted of prospective phase II or III clinical studies which included at least one arm of patients treated with ICT + VEGFi and one arm treated with ICT alone. Restricted maximum likelihood fixed effects model was used to pool AEs data; I2 was used for heterogeneity. Results: From a total of 9366 studies found, seven met inclusion criteria. A total of 808 patients were treated with ICT while 927 were treated with ICT + VEGFi. Only one study reported irAEs. Therefore, we restricted our analysis to TRAEs. The total number of TRAEs (including grade 5) was significantly higher in ICT + VEGFi group with more frequent treatment withdrawals attributed to TRAEs. The list of TRAEs and specific effect sizes are summarized. The highest TRAE effect size increases with ICT + VEGFi were noted for rash (RR 6.50), hypertension (RR 6.07), hypothyroidism (RR 5.02), and diarrhea (RR 4.94). Conclusions: Combination therapy with ICT + VEGFi confers increased risk of specific TRAEs in comparison to ICT. Clinicians should be particularly mindful of the increased risk for rash, hypertension, hypothyroidism, diarrhea, nausea, anorexia, and proteinuria with ICT + VEGFi therapies. There are insufficient data on irAEs and future trials should provide more granular details on the AE cause. [Table: see text]
Relationship between ICOS and ICOS ligand RNA expression patterns with tumor type, tumor mutational burden, and clinically relevant immune checkpoints.
Authors: Nikanjam Mina , Kato Shumei , Nishizaki Daisuke , Barkauskas Donald A. , Pabla Sarabjot , Nesline Mary K. , Conroy Jeffrey M. , Naing Aung , Kurzrock Razelle
Published: June 2023

e14669

Background: ICOS (inducible T-cell co-stimulator) has a unique ligand (ICOSL). Together they contribute to both antitumor responses/immune stimulation and potentiating immunosuppression. The interaction of ICOS and ICOSL can stimulate CD4 and CD8 ICOS-positive T-cell populations, but also can increase immunosuppressive regulator T-cells. ICOS agonists and antagonists are both under development as novel therapies. We aimed to quantify ICOS and ICOSL expression relationships with tumor type and other clinically relevant checkpoint inhibitors along with evaluating relationships between ICOS and ICOSL expression patterns. Methods: Data from 514 patients with advanced solid tumors at the University of California San Diego were used in the analysis. RNA expression levels of ICOS, ICOS ligand, PD-1, PD-L1, LAG-3, and CTLA-4 from tumor specimens were analyzed at OmniSeq. Tumor mutational burden (TMB) was also evaluated. Univariate analyses (Fischer’s exact tests) and multivariate analysis (logistic regression) were conducted in SAS v 9.4 to determine relationships between high (>=75 percentile RNA rank) and low (0-24 percentile RNA rank) ICOS and ICOSL expression with age, gender, cancer type, high LAG-3, high TMB, high CTLA4, high PD-1, and high PD-L1. The relationship between ICOS and ICOSL high or low expression were also assessed. Results: Seventy patients had high ICOS (14%) and 192 had high ICOSL (37%) while low ICOS was seen in 226 (44%) and low ICOSL was seen in 76 (15%). High ICOS RNA levels were independently associated with patients not having colorectal cancer (p=0.0009), tumors with high PD-1 expression (p=0.025), tumors with high PD-L1 expression (p<0.0001), and tumors with high CTLA-4 expression (p<0.0001). Low ICOS RNA levels were independently associated with patients whose tumors did not have high PD-1 (p=0.0006), tumors that did not have high PD-L1 (p=0.01), tumors that did not have high CTLA-4 expression (p<0.0001), and those with low ICOSL expression (p=0.0007). High ICOSL was independently associated with a diagnosis of colorectal cancer (p=0.0015), tumors that did not have high PD-L1 expression (p=0.003), and tumors with high CTLA4 (p=0.0001). Low ICOSL was independently associated with patients who did not have colorectal cancer (p=0.0001) and tumors with low ICOS expression (p=0.0032). Conclusions: ICOS and ICOSL RNA expression patterns can provide insight into the complicated ICOS/ICOSL immune checkpoint signaling pathway and help support rational immunotherapy combinations as part of a precision medicine approach. Both stimulators and inhibitors of the ICOS/ICOSL axis are being developed, and their proper application may require interrogation of the individual patient’s tumor/environment.
Factors associated with myocarditis in patients with cancer treated with immune checkpoint inhibitors.
Authors: Izadi Zara , Zhang Yan , Lou Youbei , Dreyfus Brian , Plautz Greg , Wolf Robert , Cooper Leslie
Published: June 2023

e14674

Background: Myocarditis is an uncommon but serious adverse event (AE) of immune checkpoint inhibitor (ICI) therapy. We aimed to identify factors associated with ICI-related myocarditis in cancer patients using pooled data from multiple clinical trials. Methods: Data on 25,965 adults receiving at least one dose of an ICI (nivolumab [NIVO] or ipilimumab [IPI])-containing regimen were extracted from corporate safety and clinical trial databases. Patients missing documentation of AEs, indication, or trial ID were excluded. Myocarditis events were identified using MedDRA preferred terms. A nested case-control study design with controls who had no myocarditis selected at random from the risk sets and matched 1:5 on ICI regimen, duration of exposure to ICI regimen, and trial ID was used. Descriptive statistics were used to derive time to onset of myocarditis and to investigate patterns of myositis and rhabdomyolysis relative to myocarditis. A multivariable conditional logistic regression model was used to identify factors associated with myocarditis. Covariates included age, sex, race/ethnicity, medical history (cardiovascular disease, diabetes, sleep apnea), smoking, cancer type, medication use (within the prior 6 months), and co-occurrences of other AEs (pneumonitis, colitis, and hepatitis). Results: Myocarditis was documented in 122/24,106 (0.5%) patients meeting study eligibility criteria. A total of 732 patients (122 cases and 610 matched controls) from 46 trials were included in the analyses. Mean (SD) age was 63 (12) years; 65% of patients were male, 76% Caucasian, and 52% had a history of cardiovascular disease. NIVO + IPI was the most commonly used regimen (36%), followed by NIVO + relatlimab (25%) and NIVO + chemotherapy (14%). Median (Q1-Q3) time to onset of myocarditis was 38 (26-77) days from first dose of ICI. Myositis was reported in 18/122 (15%) cases and in 2/610 (0.3%) controls (p<0.001). Among the 18 cases, a majority (83%) developed myositis within 3 days before the onset of myocarditis. Rhabdomyolysis was reported in 4/122 (3%) cases, all within a month before myocarditis, and in none of the controls (p=0.001). In adjusted analyses, older age (odds ratio 1.38 per 10-year increase, 95% CI 1.12-1.70) and hepatitis (5.69, 2.24-14.44) were significantly associated with the development of myocarditis. Conclusions: In this large cohort of ICI-treated cancer patients, myocarditis had an early onset and was associated with older age and co-occurrences of hepatitis. Due to a low incidence among controls, rhabdomyolysis and myositis could not be included as covariates in adjusted analyses; however bivariate results showed strong associations between myocarditis and rhabdomyolysis or myositis. These findings suggest that co-occurrences of myositis, rhabdomyolysis, or hepatitis are associated with myocarditis and may originate from a more generalized ICI myopathy.
Preliminary efficacy and safety of camrelizumab plus metronomic oral vinorelbine as first-line therapy for people aged 70 and above with advanced non-small cell lung cancer (NSCLC) from a phase II trial.
Authors: Li Lin , Zhang Ping , Gao Jiayi , Tang Min , Nie Xin , Ma Di , Zhao Zhe , Yuan Yue , Ding Li , Li Chao
Published: June 2023

e14677

Background: Traditional platinum-based combination chemotherapy used as the standard first‐line treatment for advanced NSCLC poses potential safety risk for patients (pts) aged 70 years and above. Moreover, data on immune checkpoint inhibitors treating older pts with lung cancer in the current pivotal trials is limited. Metronomic chemotherapy (MCT) is the frequent administration of chemotherapy drugs at lower doses each time. Compared with traditional chemotherapy, MCT shows better safety profile and antitumor angiogenesis and immunomodulatory effects. Camrelizumab, an anti-PD-1 inhibitor, demonstrated encouraging efficacy in NSCLC (CameL study and CameL-sq study). Here, we designed a phase II trial to evaluate the efficacy and safety of camrelizumab plus metronomic oral vinorelbine (mOV) as first-line therapy for Chinese older pts with advanced NSCLC. Methods: Key inclusion factors were pts aged 70 years and above, histologically or cytologically confirmed unresectable stage III and IV NSCLC without positive EGFR mutation, ALK fusions or ROS1 fusions, ECOG performance status 0-2, no previous systematic treatment. Pts received camrelizumab (200mg, D1, q3w) combined with mOV (30mg, tiw1, day 1-3-5 per week) for 6 cycles, followed by camrelizumab monotherapy maintenance until disease progression or intolerable side effects. The primary endpoint was progression free survival (PFS). The secondary endpoints included overall survival (OS), objective response rate (ORR), disease control rate (DCR), duration of response (DoR) and safety. Results: From March 2021 to November 2022, 12 pts were evaluable for inclusion in the study. The median age was 77 (range: 70-85) with 8 (67%) males. Median follow-up was 7.2 months (range 2.8 months-22.1 months). The median PFS was 9.3 months (95%CI: 3.9 months-14.7 months). The one-year OS rate was 66.3%. The ORR and DCR were 50% (95%CI: 25.4%-74.6%) and 83.3% (95%CI: 50.9%-90.1%), respectively. Pts with positive or negative PD-L1 responded similarly to the treatment (respectively at 5/8 and 1/2 on ORR). The median OS and DoR have not been reached. Adverse events (AEs) with any grade were observed in 10 (83.3%) pts, of which grade III-IV AEs were observed in 2 (16.7%) pts with neutropenia and interstitial pneumonia, respectively. Immune-related adverse events (irAEs) occurred in 3 (25%) pts, of which grade III-IV irAEs occurred in one (8.3%) patient with interstitial pneumonia. No grade 5 adverse event happened. Conclusions: The regimen of camrelizumab plus mOV for the first-line therapy for older NSCLC pts showed initial promising efficacy and safety profile, which suggests it is worth further exploration. Clinical trial information: ChiCTR2100049487 .
Incidence of venous thromboembolism with immune checkpoint inhibitors in a community setting: A single-center retrospective study.
Authors: Kumar Madhan Srinivasan , Majmundar Vidit , Arun Kumar Sumukh , Ramasamy Chidambaram , Seetharaman Kala
Published: June 2023

e14681

Background: Immune activation and inflammation caused by immune checkpoint inhibitors (ICIs) are critical pathobiological drivers for venous thromboembolism (VTE). There is a paucity of data about VTE risk in cancer patients receiving ICI. We aimed to describe the incidence of VTE in cancer patients receiving ICI in a community setting. Methods: We conducted a single center, retrospective cohort study at Saint Vincent Hospital. The study cohort was created using our center's pharmacy database of patients who received any of the five ICIs (ipilimumab, nivolumab, pembrolizumab, atezolizumab, or durvalumab) between Jan 2017 and Dec 2022. VTE events including deep venous thrombosis, splanchnic vein thrombosis, and pulmonary embolism, were identified by chart review. We used a self-controlled risk-interval design, with "control period" and "at-risk period" being 6 months before and after the initiation of ICI treatment respectively. VTE events were also analyzed for subgroups: Single-agent ICI therapy (IA), Dual ICI therapy (IB), and ICI + chemotherapy (IC). Descriptive statistics and cox regression were used for statistical analysis. Results: Study population included 170 patients, with 75, 14, and 81 patients in subgroups IA, IB, and IC respectively. The mean age of the patients was 69.51 ± 10.05 years with a majority being males (62.4%). The most common cancer observed was non-small cell lung cancer (43.5%) followed by small cell lung cancer (6.9%), and malignant melanoma (5.7%). Pembrolizumab (55.3%) was the most common ICI used and nivolumab + ipilimumab (7.64%) was the most common dual ICI used. We noted a 1.25-fold higher incidence of VTE post-ICI use (Incidence rate ratio [IRR]: 11.76 per 100 person-year) compared to pre-ICI use (IRR: 9.41 per 100 person-year) at 6 months. On subgroup analysis, Group IB had the highest risk for VTE at 6 months (IRR: 28.57 per 100 person-year), followed by group IC and IA (IRR: 14.12 and 8.0 per 100 person-year respectively). IRR decreased to 6.62 per 100 person-year at 12-month interval indicating increased VTE risk in the first 6 months of ICI exposure. Type of ICI, adjuvant chemotherapy or type of cancer was not able to predict VTE risk on multivariate analysis. Conclusions: ICI treatment was associated with an increased incidence of VTE in our study cohort with the highest risk among patients on dual ICI followed by ICI + chemotherapy and ICI monotherapy. Future prospective studies are needed to identify risk factors and biomarkers to improve risk stratification and risk-adapted thromboprophylaxis.[Table: see text]
Efficacy of checkpoint inhibitors in hospitalized patients with cancer.
Authors: Medik Yusra B. , Singh Vinit , Alsabaawy Marina , Gerbino Gabriella , Khalid Farhan , Kata Priyaranjan , Divanna Mariela , Yosry Nashwa , Meghal Trishala , Nookala Vinod
Published: June 2023

e14687

Background: Pembrolizumab is approved by FDA in 2014 to treat metastatic melanoma. Use of immune check point inhibitors (ICI) has been expanding in multiple cancer types including non-small cell lung cancer since then. In this mini case series, we will evaluate the benefits and risks of immunotherapy in hospitalized patients. Use of immunotherapy agents in inpatient unit has been associated with poor clinical outcome and higher cost. Byrne et. al have recently shown that more than 45% of hospitalized patients receiving PD1 or PD-L1 antibodies have either died or discharged to hospice care. A large retrospective chart review in Dana Farber Cancer Institute reveals 86% mortality rate in hospitalized immunotherapy recipients within the study period. Understanding the safety and advantages of using immune checkpoint inhibitors in inpatient unit has a pivotal role in decreasing the healthcare associated costs and setting the appropriate goals of care with patients and families. Methods: This is a retrospective observational cohort study conducted by review of electronic health records in last 5 years (from January 1st 2017- January 1st 2022) in Rutgers Health Community Medical Center and Monmouth Medical Center. Adult patients admitted to inpatient unit who received Pembrolizumab, Atezolizumab, or Nivolumab were included. Results: A total of 61 patients has received ICI therapy while in hospital with 57% males and 42% female. All patients had solid tumors, with most common malignancy being lung cancer (55%) followed by colon cancer (14%). Most common ICI given was pembrolizumab (62%) followed by atezolizumab (18%) and Nivolumab (16%). 26% of patients that were treated died in the hospital, 35% were transferred to another care facility and 29% were discharged home. No immune-related adverse events were reported. Age groups, cancer types were comparable with regard to discharge status. Conclusions: Poor mortality and survival outcome from this case series should prompt clinicians to consider benefit and risks of ICI therapy when prescribed to patients who were hospitalized for non-oncological acute conditions.
Real-time customized precision combination therapies based on potential actionability and coalterations to provide therapeutic opportunities for hyperprogressive disease after immune checkpoint inhibitor therapy.
Authors: Wang Lili , Wang Haitao , Li Hong Zheng
Published: June 2023

e14688

Background: Patients with hyperprogressive disease (HPD) after immune checkpoint inhibitor therapies have few treatment options and short survival times. Genomic-based precision medicine within the frame of molecular tumor board might theoretically enable effective treatment identification for HPD. Detailed data on MTB guided treatments and outcome with a focus on HPD have not been reported yet. Methods: This is a single-institution retrospective, open-label, histology-agnostic analysis of the consecutively identified HPD patients that have received a real-time precision combination treatment approach which would rapidly integrate clinical grade targeted next-generation sequencing, NGS interpretation and with or without patient-derived xenografting to identify and prioritize effective customized targeted combination treatments within the frame of molecular tumor board at the Tianjin Medical University Second Hospital, a single large academic medical center, refractory cancer-foucused, between January 2018 and January 2022. Treatment was selected using on-label, off-label or investigational agents either in monotherapy or in combination. Clinicopathologic data, next-generation sequencing results, MTB recommendations, therapy received, outcomes, response assessment based on radiologic imaging and follow-up data were assessed through database searching. Results: A total of 41 HPD suspected patients were referred to the MTB, and 38 conformed HPD with one of the criteria of Russo or Kato. 27 patients were treated with MTB recommended targeted mono or combinational therapy, 4 in accordance with guidelines (on label) in clinical practice, and 23 off label within two ongoing real-time precision medicine programme for patients with exhausted standard care. Of 25 evaluable patients, 20 (80%) achieved either partial response (n = 13, 52%) or stable disease (n = 7, 28%) and with a median overall survival of 12.2 months (95% CI, 8.4 months to not reached). Furthermore, 14 (56%) of those patients showed improvement in progression-free survival of at least 30% while on MTB-recommended treatment compared with the progression-free survival of the previous treatment line. Conclusions: It represents a proof of-concept case series as it demonstrates the feasibility of real time precision approach in the clinical setting and guide individual patient treatment in the rare and high aggressive disease. Patients with MTB-recommended treatments seemed to benefit with respect to PFS ratio and OS.
Do corticosteroids affect immunotherapy efficacy in malignancy? A systematic review.
Authors: Byron Yoni , Yegorova-Lee Sonya , Tio Martin
Published: June 2023

e14692

Background: Early studies indicate that corticosteroids may limit survival benefits from immunotherapy, although this finding is potentially confounded by the poor prognosis of patients who require corticosteroids due to cancer-related symptoms. We conducted this systematic review to evaluate the effect corticosteroids have on immunotherapy, when adjusted for potentially confounding effects of corticosteroids given for palliative indications. Methods: 3 databases (PubMed, Embase, and Medline) were searched on 1st of February 2023. Studies that measured response or survival in patients receiving immunotherapy, while receiving corticosteroids for non-cancer indications, compared to either no corticosteroids or corticosteroids for cancer-related indications were included. Studies exclusively evaluating the effect of corticosteroids administered for immune-related adverse events were excluded to avoid immortal time bias. Pooled odds and hazard ratios with 95% confidence intervals (CI) were calculated using a random effects model. Study heterogeneity was assessed using the I2 statistic, and publication bias was evaluated by funnel plot and Egger's regression model. Results: 8,426 studies were identified, of which 8 studies met our inclusion criteria for meta-analysis. Administration of steroids has no statistically significant effect on survival and response to immunotherapy when administered for non-cancer related indications, with a pooled odds ratio for overall response rate 0.92 (95% CI 0.58-1.44); pooled hazard ratio (HR) for progression free survival 0.87 (95% CI 0.68-1.12); and pooled HR for overall survival 0.79 (95% CI 0.59-1.05). Conclusions: This systematic review indicates that administration of corticosteroids does not affect response to immunotherapy nor survival outcomes, when removing confounding palliative corticosteroid indications. Limiting or minimising corticosteroid treatment in this patient population due to concern of potential lowered efficacy of immunotherapy can therefore be reconsidered. These results are limited by the retrospective nature of the studies, small sample sizes, and the lack of information about corticosteroid dosing or length of treatment.
Immune-mediated adverse event management at a tertiary care cancer center.
Authors: Shatila Malek , Eshaghi Farzin , Thomas Austin , Kuang Andrew , Abudayyeh Ala , Sheshadri Ajay , Palaskas Nicolas , Thomas Anusha , Zhang Hao Chi , Wang Yinghong
Published: June 2023

e14697

Background: Our understanding of immune-related adverse events (irAEs) has evolved rapidly with management guidelines constantly being updated. We aim to explore temporal changes in irAE management at a tertiary cancer care center to identify areas for potential improvement. Methods: This was a single-center, retrospective study including patients who developed a GI, pulmonary, renal, or cardiac irAE between 07/01/2019-10/01/2019 compared to a contemporary cohort from 2021. The follow-up window was for up to a year after diagnosis. Data collected included patient demographics and irAE management and outcomes. Results: Endoscopic evaluation and GI follow-up after discharge for patients with GI irAEs fell over the years. Despite this, there was a decline in symptom duration and steroid taper attempts. The pulmonary service showed improvements in consultation, hospital admission and re-admission, and ICU admission. However, follow up post-hospital discharge were consistently low ( < 50%). Rate of cardiology consultation was consistently high across the years with an equally fast time to consultation, and myocarditis cohort in 2021 had a higher clinical response rate than the 2019 cohort. There were no major differences across the years for renal irAEs. We found that outpatient treatment and earlier GI consult improved outcomes in GI irAEs. For pulmonary irAEs, hospitalization, symptom recurrence, multiple steroid tapering courses, and hospital readmission were associated with less pneumonitis remission. Conclusions: This is one of the few qualitative studies exploring current practice in managing irAEs. We identified areas to improve the management on across all specialties, and found specific factors associated with better outcomes in GI and pulmonary irAEs. Together, these findings can help improve the quality of irAE management algorithms at our institution. [Table: see text]
Plasma proteomics approach to distinguishing PD-1 inhibitor-associated myocarditis from acute myocardial infarction in patients receiving PD-1 inhibitors treatment: A clinical and preclinical study.
Authors: Luo Yuxi , Yi Yali , Lu Zhiqin , Liu Anwen , Zeng Zhimin
Published: June 2023

e14698

Background: Immune checkpoint inhibitor (ICI)-related myocarditis is a rare but severe side effect that requires attention to distinguish it from other cardiovascular emergencies. Therefore, new biomarkers are needed for the early diagnosis of ICI-related myocarditis, especially to distinguish it from other cardiovascular emergencies. Our study aims to explore plasma biomarkers with high specificity and sensitivity using proteomic analysis for the early diagnosis of ICI-related myocarditis and to distinguish it from acute myocardial infarction (AMI). Methods: Patients with ICI-related myocarditis and AMI were selected and matched for potential confounding effects such as age, gender, smoking history, and chronic heart diseases. A label-free liquid chromatography-mass spectrometry (LC-MS) proteomics approach was used to analyze plasma samples and screen sensitive and specific myocarditis protein biomarkers. Further validation will be performed at the level of patients and animal models of ICI-related myocarditis and AMI. Results: We performed plasma proteomics on 15 plasma samples from 5 pairs of samples with PD-1 inhibitor-associated myocarditis at baseline (control group) and diagnosis (myocarditis group) and 5 cases of acute myocardial infarction (MI group) confirmed by coronary angiography in the Second Affiliated Hospital of Nanchang University. In total, we identified a total of 1521 plasma proteins and 1325 quantifiable plasma proteins across all 15 plasma samples. Further analysis of the differential proteins showed that 34 proteins with significantly differentially expressed in myocarditis group samples compared with other groups. Among them, several proteins were significantly up-regulated (MYOM3, TNNC1, MYL1, MYOM2, CA3, MYLPF, ECI1, LGALS1, PSMA7, PSMB3, PSMA4, PSMB6, CKM, ABCB6, UGP2, ALDOA, TPM2) or down-regulated (MAN1A1, SPTB, YTHDC2, CLEC11A, GSN, APOA4) in myocarditis samples. Compared with the other groups, the ICI-related myocarditis group showed molecular changes in myocardial contraction, proteasome, immunoregulation, NF-κB signaling pathway, arginine and proline metabolism, and cysteine and methionine metabolism. We then performed ELISA on additional ICI-related myocarditis and AMI patients and corresponding animal models. The Troponin C, Myom 3, UGP2, and Galectin-1 proteins related to immune or inflammation were significantly increased. Conclusions: Our study has revealed that proteins related to the immune system or inflammation may be sensitive and specific plasma biomarkers for identifying ICI-related myocarditis. However, further large sample cohorts are needed to confirm these findings.
Replacement of anti-PD-1 drugs with prolgolimab during treatment, safety and efficacy.
Authors: Andabekov Timur , Napolskaia Elena , Rodina Maria , Khlobystina Alina , Gulo Elizaveta
Published: June 2023

e14701

Background: The anti-PD-1 treatment has been shown good response in patients with cancer. There is little information in open sources on the possibility of changing anti-PD-1 drugs during treatment for non-medical indications. Prolgolimab (formerly BCD-100) is an IgG1 anti–PD-1 mAb that contains the Fc-silencing mutation LALA, which provides an immunopotential advantage by eliminating the interaction between the Fc region of the antibody and FcyR expressed on various immune cells, thus blocking possible effector functions of the antibody. We report the replacement of anti-PD-1 drugs during treatment on safety and anti-PD-1 response in patients with melanoma and lung cancer. Methods: 5 patients with advanced melanoma and 2 non small cell lung cancer (NSCLC) with RECIST-evaluable disease, with prior anti-PD-1 treatment by nivolumab and pembrolizumab. 5 Patients were with prior anti-PD-1 treatment by nivolumab (median duration of treatment was 4 months) and 2 patients pembrolizumab (median duration of treatment was 7 months). Patients were treated (replaced) with prolgolimab (anti-PD-1) 1 mg/kg every 2 week. The primary objective was safety of replacement anti-PD-1 therapy and objective response rate (ORR) by RECIST 1.1. Replacement of anti-PD-1 drugs during treatment were associated for non-medical indications. Patients were with ECOG 0-1. Results: Median age was 57 years, 5 were male, 1 patients with NSCLC had a KRAS mutation and patients with melanoma had a BRAF mutation. Median follow-up was 10 months. Adverse events continued after prescription of prolgolimab. New adverse events have not experienced. Anti-PD-1 therapy was not discontinued. ORR was 85%, of which 3 were CR. Median PFS was not reached. 1 patient with NSCLC prior anti-PD-1 treatment by nivolumab (2 cycles 480 mg) had PD, but PR was prolgolimab. Conclusions: Anti-PD-1 treatment followed by prolgolimab (anti-PD-1) in our patients undergoing therapy is safe and does not worsen anti-tumor responses. We assume that in certain situations it is possible to make (for example, individual intolerance) substitutions of drugs in the same group anti-PD-1 Replacement anti-PD-1 may reduce financial toxicity.
Ustekinumab for the treatment of immune related cutaneous adverse events (ircAEs).
Authors: Maier Tara , Gu Stephanie , Shah Neil J. , Faleck David M. , Lacouture Mario E.
Published: June 2023

e14702

Background: IrcAEs are one of the most common immune related adverse events (irAEs) associated with immune checkpoint inhibitors (ICI). Ustekinumab, a monoclonal antibody that targets IL12/IL23, is FDA approved for the treatment of autoimmune diseases including psoriasis and inflammatory bowel disease. The IL12/23 pathway may mediate a subset of ircAEs, and ustekinumab may be effective for the treatment of these events. Methods: Patients at Memorial Sloan Kettering Cancer Center who received ustekinumab for treatment of ircAEs were identified from 8/18/2017 to 2/17/2022. Common Terminology Criteria for Adverse Events (CTCAE) v 5.0 was used to grade ircAEs. Patient response to ustekinumab was subcategorized into complete resolution (CR, improvement of symptoms to baseline or grade 0), partial resolution (PR, improvement in CTCAE grade but not CR), or no response/worsening (NR, no clinical improvement or worsening of ircAEs). Results: A total of 11 patients were included in the study. The median age was 72 years (IQR 69.5-77) and 45% of patients were female. The most common ICIs were pembrolizumab (64%, n=7), nivolumab (18%, n=2), atezolizumab (9%, n=1), and avelumab (9%, n=1). Melanoma (27%, n=3) and bladder (27%, n=3) cancer were the two most common neoplasms. All patients had psoriasiform ircAEs (n=10), except one who had a pyoderma gangrenosum (PG) ircAE; most were either grade 2 (46%) or grade 3 (36%) at the time of ustekinumab initiation. The majority of patients (73%, n=8), including the one with PG, noted some improvement with ustekinumab, with 55% (n=6) and 18% (n=2) achieving CR and PR, respectively. The median duration of ustekinumab treatment was 169 days (0 – 1774), and among those with PR or CR, the median time to initial response was 27 days (21 – 39). In addition, the proportion of patients on topical and systemic steroids before and after ustekinumab decreased from 91% (n=10) to 56% (n=6) and from 64% (n=7) to 36% (n=3), respectively. Four patients (36.4%) discontinued ICIs because of severe ircAEs, with 1 (25%) successfully recontinuing their ICI following control of ircAE symptoms with ustekinumab. We noted progression of disease among 55% (n=6) of patients at any point after ustekinumab treatment. Among them, median time to next treatment was 345.5 days (70-925), with a median of 347.5 days (70-576) and 601 days (277-925 days) for patients with non-metastatic (33.3%) and metastatic tumors (66.7%), respectively. Conclusions: Ustekinumab has shown encouraging clinical activity especially for psoriasiform ircAEs and can be an effective steroid-sparing treatment for specific ircAEs. Despite the occurrence of cancer progression in some of our cohort, it was difficult to interpret the ICI anti-tumor activity post ustekinumab given the small numbers and multiple tumor types. Further prospective studies are needed to validate our findings given the significant potential of ustekinumab for the management of ircAEs.