bluuebunny/crossref_metadata_2025 huggingface dataset:
A novel method that leverages existing data to conduct comparative analyses of competing assets: Sugemalimab and agents targeting the PD-L1/PD-1 axis as an example.
Authors: Fojo Antonio Tito , Zhou Mengxi , LaRose Meredith , Bates Susan Elaine , Schwartz Lawrence Howard
Published: June 2023

2609

Background: Non-small-cell lung cancer (NSCLC) remains the leading cause of cancer-related mortality worldwide. Numerous immune checkpoint inhibitors (ICIs) targeting the programmed cell death protein-1/programmed death ligand-1 (PD-1/PD-L1) axis have garnered regulatory approvals. A novel method of comparative analysis that discerns differences/similarities amongst such agents could reduce redundancy and hopefully enhance true competition. Methods: We’ve described an approach for assessing efficacy that assumes changes in tumor quantity result from two simultaneous processes – exponential decay of the treatment-sensitive fraction of tumor at rate d, and exponential growth of the resistant fraction at rate g. Using this method, the USFDA analyzed data from 9934 patients with NSCLC enrolled in registration trials treated with chemotherapy, targeted therapies, and immunotherapies concluding g is inversely associated with survival across treatment types and encouraging prospective studies to evaluate whether g derived from early tumor measurements might serve as an earlier clinical trial endpoint (Gong ASCO 2020). Using data provided by EQRx and CStone we analyzed the GEMSTONE-302 trial comparing chemotherapy +/- the PD-L1 inhibitor sugemalimab in first line NSCLC. Results: 88% of the data could be analyzed. Regression without growth was seen in 10-12% of both arms with indistinguishable d values. Evidence of tumor growth was estimable as a g value in 68-71% with statistically slower g values and longer tumor doubling times (TDT) seen with sugemalimab + chemotherapy [0.0012/day (0.0005-0.0022); TDT 578d] than placebo + chemotherapy [0.0025/day (0.0013-0.0035); TDT 277d] p<0.0001. A comparative analysis with FDA data from 1521 patients who received Combo ICI in front line, finds comparable/slightly slower g values for sugemalimab + chemotherapy using all or a fraction of the data. Conclusions: We used a method of analysis that estimates rates of tumor growth ( g) to analyze the efficacy of the PD-L1 antagonist, sugemalimab, in NSCLC. Because time is included in our equations the intervals of assessment are rendered inconsequential, making this method of analysis ideal for virtual comparisons. We confirmed the value of sugemalimab in the first-line setting by demonstrating its data track very closely with data aggregated from randomized trials reported by the USFDA in patients treated with Combo ICI in front line. Because g values can be estimated with fewer data it can be leveraged for early decisions. [Table: see text]
Incorporating long non-coding RNA (lncRNA) into genome-wide biomarker screening for prognostic gene signatures of immunotherapy outcomes.
Authors: Wang Xuefeng , Li Tingyi , Sukrithan Vineeth , Ratan Aakrosh , McCarter Martin , Carpten John D. , Colman Howard , Ikeguchi Alexandra , Puzanov Igor , Arnold Susanne M. , Churchman Michelle L. , Hwu Patrick , Dalton William S. , Weiner George J. , Tarhini Ahmad A.
Published: June 2023

2617

Background: Emerging data have shown that long non-coding RNA (lncRNAs) have the potential to become biomarkers in cancers with potential roles in regulating cell proliferation, apoptosis, migration, invasion and maintenance of stemness during cancer development. In this research, we aimed for a genome-wide biomarker screening approach incorporating lncRNA in order to identify key molecules and pathways involved in ICI response and resistance. Methods: We utilized clinical and transcriptomic data collected under the Total Cancer Care Protocol (NCT03977402) and Avatar project within the Oncology Research Information Exchange Network (ORIEN). We analyzed RNA-seq data from a total of 875 ICI treated pts. A novel resampling-based technique with elastic net regression was utilized for genome-wide biomarker screening, in which Cox regression was used for survival outcomes and logistic regression for a 2-year-based dichotomized outcome. All search was done through 200 resampling steps, each consisting of randomly selecting 80% of pts and 80% of all gene signatures. Moreover, we searched the genes that are most complementary to the established immune cell scores (i.e., Ecotyper and xCell) by incorporating these scores into the regression adjustment. Finally, we applied the same approach to identify prognostic long non-coding RNA (lncRNA) signatures. All analyses were carried out on all ICI pts, as well as on subgroups stratified by cancer type. Results: Of 875 pts treated with ICI, 125 had melanoma, 143 had kidney cancer, 126 had non-small lung cancer, and 110 had head and neck cancer. The genome-wide selection method successfully identified a panel of top prognostic genes and pathways for all cancer types included. In melanoma, the top five prognostic genes were ZDHHC2, CBX4, MET, NTN4, and HLA-DQA1, with 80%, 78%, 77.5%, 77.5%, 76.5% resampling-based selection probability respectively; the top five lncRNAs were AC073655.3, AC116348.3, PITPNA-AS1, AC011447.3, and AL021978.1. When adjusting for the immune scores in the selection model, the top five prognostic protein-coding genes in melanoma were TENM3, POLR2J3, SCCPDH, MET and SIAH1, and the top five lncRNAs were AC007620.2, PITPNA-AS1, HCG11, SLC25A5-AS1, and LINC02258, respectively. Conclusions: Our analysis has successfully identified gene panels of mRNA and lncRNA molecules with potential roles related to ICI mechanisms of action. Ongoing analyses are further investigating the potential mechanisms and pathways linking these molecules and will be presented at the meeting. [Table: see text]
Tracking plasticity along with proliferation and immune evasion using FOXC1, MKI67 and PDL1 for prediction of therapeutic response and risk for hyperprogressive disease with PD1/PDL1 inhibitors in advanced/metastatic cancers: Pan-tumor validation in clinical trial and real-world cohorts.
Authors: Ray Partha S , Ray Tania , Taylor Clive R , Hussa Robert
Published: June 2023

2627

Background: Accurate prediction of therapeutic response (TR) to treatment with immune checkpoint blockade (ICB) as well as any resultant durable clinical benefit in terms of improved progression-free survival (PFS) and overall survival (OS) is not consistently achieved with existing biomarkers like PDL1 or tumor mutational burden (TMB). We hypothesized that a multi-marker predictive biomarker strategy that tracks plasticity using FOXC1 expression, in parallel to tumor proliferation and immune evasion, using expression of MKI67 and PDL1, respectively, may demonstrate superior TR prediction, and also enable accurate prediction of risk for hyperprogressive disease (HPD). Methods: Pre-treatment tumor RNA-Seq data obtained from training/validation clinical trial cohorts and real-world patients diagnosed with advanced/metastatic non-small cell lung cancer (NSCLC, n=82/28) and melanoma (n=154/121) were analyzed for FOXC1, MKI67 and PDL1 expression, and correlated with overall response rate (ORR), PFS, OS and HPD, the latter defined as time-to-treatment-failure <=2 months post-treatment initiation. Optimized biomarker cutoff values based on model area-under-curve were leave-one-out cross validated and cancer-type specific (CTS) prediction algorithms derived. The unmodified strategy was then validated in the independent, CTS validation datasets. Results: ORR prediction accuracy was confirmed in validation datasets with high accuracy: NSCLC AUC=0.96, OR=9.63 (0.98-94.54, 95%CI) p=0.03 and melanoma AUC=0.91, OR=3.85 (1.73-8.58, 95%CI), p=0.0005. Predicted Responders consistently displayed superior PFS and OS compared to predicted Non-Responders: NSCLC PFS HR=0.51 (0.32-0.82, 95%CI) p=0.007, OS HR=0.44 (0.27-0.73, 95%CI) p=0.003; melanoma PFS HR=0.45 (0.30-0.68, 95%CI) p=0.002, OS HR=0.43 (0.26-0.71, 95%CI) p=0.002. Patients at risk for HPD were identified with high accuracy: NSCLC AUC=0.96, OR=9.67 (2.95-31.73) p<0.0001; melanoma AUC=0.98, OR=44.36 (11.73-167.74, 95%CI) p<0.0001. Conclusions: Tracking multiple dimensions of cancer biology including plasticity (using FOXC1), as opposed to tracking immune evasion alone, proved to be a superior and accurate pan-cancer, tissue-agnostic predictor of TR to ICB therapy in advanced/metastatic tumors in terms of ORR, PFS, OS as well as HPD risk prediction. This approach merits further testing in prospective clinical trials.
Effect of personalized immunization with GNOS-PV02 of patients with hepatocellular carcinoma on TCR clonal expansion, tumor infiltration, and vaccine-specific reactivity.
Authors: Perales Renzo , Cooch Neil , Yarchoan Mark , Sardesai Niranjan Y. , Yan Jian
Published: June 2023

2629

Background: Tumor-specific neoantigens can be identified from cancer biopsies and used to develop personalized therapeutic cancer vaccines (PTCV) to prime neoantigen-specific T cell responses. Here, we characterized the antitumor neoantigen-specific reactivity of tumor-infiltrating, high-frequency TCR clones in a patient treated with personalized therapeutic DNA cancer vaccine GNOS-PV02 in the ongoing GT-30 advanced hepatocellular carcinoma single-arm open-label multi-center phase Ib/IIa trial (NCT04251117). Methods: Paired blood and tumor biopsy samples from patient #8 enrolled in the GT-30 study were collected before and after treatment with GNOS-PV02 (1mg) + plasmid-encoded IL-12 (0.3mg) + Pembrolizumab (200mg). GNOS-PV02 and IL-12 were administered at Q3W for the first 4 doses, then, at Q9W. Pembrolizumab was administered Q3W. Neoantigen positivity was evaluated by IFNγ-ELISpot. TCRβ sequencing was performed on all 4 samples and single-cell TCR and transcriptome sequencing was performed from T cells isolated from the post-treatment blood sample. After vaccination, three newly identified TCRs in blood and tumor were inserted into a pMXs-IRES-GFP retroviral plasmid vector and used to generate engineered TCR T cells. Engineered T cells were tested against the neoantigens included in PTCV by flow cytometry. Results: The treatment resulted in a partial response with a decrease in tumor size of 44% by RECIST1.1. Five vaccine-encoded responding neoantigens were identified. Differential abundance frame network analysis revealed that 27 of 42 (64.28%) significantly expanded peripheral TCR clones were also found enriched in the tumors post-treatment. Importantly, we observed an increase in cumulative frequency (from 0.4 to 7.7%), and absolute numbers (from 3 to 14) of significantly expanded vaccine-specific TCR clones in the tumor. Increased TCR clonality confirmed a focused tumor repertoire response. Single-cell sequencing data analysis revealed that the 6 most expanded clones in blood were activated CD8+CD69+ T cells (81.82%). Three full TCR sequences from T cell clones newly present in the tumor post-vaccination were selected, synthesized and cloned. TCR-engineered patient-specific T cells showed a dose-dependent CD8+ and CD4+ T cell activation (CD69+) upon stimulation with a pool of epitopes covering all the neoantigens in the patient’s PTCV. Conclusions: PTCV treatment resulted in neoantigen-specific T cell responses, clonal expansion in the periphery and primary lesion, and tumor infiltration of T cells with an activated phenotype. TCR-engineered high-frequency T cells found in the tumor are reactive to PTCV-encoded neoantigens post-treatment. These results may account for the observed objective decrease in the primary tumor size.
Multisystem immune-related adverse events from dual agent immunotherapy use.
Authors: Li Yuchen , Pond Gregory Russell , McWhirter Elaine
Published: June 2023

2635

Background: Immune-related adverse events (irAEs) are commonly seen in cancer patients who undergo immunotherapy treatment. Increasingly, there has been recognition that multiple different irAEs can occur during or/and after a single course of immunotherapy treatment, known as multisystem irAEs, though much remains unknown. The primary objective of this study was to assess for rate of multisystem irAEs in patients who received dual agent ipilimumab and nivolumab for cancer treatment. Methods: A retrospective cohort review was completed that included all cancer patients seen at Juravinski Cancer Centre who received at least one dose of ipilimumab and nivolumab from January 1, 2018 to May 31, 2022. Patient characteristics, cancer types, and number and types of irAEs were recorded. Multivariate logistic regressions were also completed comparing those who developed multisystem irAEs, single irAE, and no irAE. Results: A total of 123 patients were included in this study. Median age was 59 years old, with 69% male. 72 out of 123 patients (59%) had melanoma, 50/123 (41%) had renal cell carcinoma (RCC), and 1/123 (1%) had breast cancer. At least one irAE was seen in 72% of patients who were treated with ipilimumab and nivolumab, and most irAEs occurred during the combination phase (89% of first irAE, 59% of second irAE, 75% of third irAE, and 50% of fourth irAE). Multisystem irAEs were seen in 40% of the overall cohort. The most common irAE type was dermatitis (22%), followed by colitis (19%), hepatitis (17%), and thyroiditis (15%). 30 out of 89 patients (34%) who experienced irAE(s) required hospital admission for inpatient treatment of irAE(s). Patients who experienced multisystem irAEs had significantly higher rates of response to immunotherapy irAE (p < 0.001) and improved overall survival (OS) than those who experienced single or no irAE. Conclusions: From our single-centre cohort study, there appeared to be a higher than previously quoted number of patients who experienced irAEs after receiving ipilimumab and nivolumab, with majority of them developing multisystem irAEs. Many patients experienced debilitating associated symptoms and hospital admission relating to irAEs. It is important for both the counselling and consent of patients, and for patient education, to discuss the possibility of multiple irAEs prior to dual immunotherapy initiation.
Comparing the impact of steroid sparing immunosuppression vs. steroid monotherapy for immune-related adverse events in non–small cell lung cancer and melanoma.
Authors: Syed Sharjeel , Hines Jacobi , Baccile Rachel , Rouhani Sherin Juliet , Reid Pankti
Published: June 2023

2637

Background: The effect of steroid-sparing immunosuppressive agents (SSIAs) for immune-related adverse events (irAEs) on immune checkpoint inhibitor (ICI) antitumor activity is not well-known. We compared tumor outcomes of patients who received corticosteroid monotherapy versus those who received an addition of SSIA for irAE treatment. Methods: We conducted a retrospective case-control study of patients age ≥18 years with melanoma or non-small cell lung cancer (NSCLC) who were treated with ≥1 ICI at a quaternary care center between 1/1/2016-11/1/2021. Patients must have received systemic corticosteroids or an SSIA for irAE treatment at least 1 week prior to death. Patients were divided into two cohorts: only corticosteroids (CS cohort) or steroids+SSIA (SSIA cohort). We used propensity score nearest-neighbor matching to match on tumor type, stage, and prior lines of therapy. Primary outcomes were progression-free survival (PFS) and overall survival (OS). Secondary outcomes included time from start of irAE treatment to irAE resolution. Hazard ratios (HR) for PFS and OS were calculated using the Cox proportional hazard regression method with time to steroid and SSIA as a time-varying covariate. Results: After matching, 48 patients were included, 24 in each cohort. Median age was 65. 41.7% of patients had NSCLC and 58.3% melanoma, 79.2% had stage 4 disease. 62.5% received ICIs as first line therapy, 33.3% as second-line, and 4.2% as third-line or higher. There was no significant demographic difference between the cohorts. Colitis was the most common irAE (39.6%). After adjusting for age, tumor type, tumor stage, and weeks from ICI start to steroid start, patients in the SSIA cohort had a shorter OS (HR 2.31, p = 0.037). We did not find a statistically significant difference for PFS (unadjusted HR 0.52, p = 0.20; adjusted HR 0.62, p = 0.34). Time from irAE treatment to resolution was longer in the SSIA cohort (8.1 weeks) compared to the CS cohort (4.9 weeks), but this did not reach statistical significance (p = 0.07). Conclusions: We found an association between decreased OS and use of SSIAs for irAE treatment compared to CS monotherapy, but no significant difference in PFS between the two cohorts. Large, prospective, randomized controlled trials are needed to separate the effects of SSIAs from high-dose CS in order to guide optimal treatment of irAEs.
A phase I/IIa study to assess the safety, tolerability, PK, and PD of T3011, a genetically modified oncolytic virus (OVs) administered intravenously (IV) in patients with advanced solid tumors.
Authors: Li Ziming , Zhang Jian , Zhang Shuang , Zheng Li , Zhang Zhiye , Wang Junbin , Hu Ying , Luo Su-xia , Pang Weijia , Fu Wenmin , Qin Yanmei , Lu Shun
Published: June 2023

2640

Background: T3011 is a genetically modified, next-generation oncolytic HSV-1 with 2 exogenous genes encoding the active heterodimer human IL-12 and the Fab fragment of an anti-human PD-1 antibody. T3011 intratumoral injection (IT) was reported to be well tolerated in patients (pts). IV therapy of OVs is rare and provides an attractive option to many pts with advanced cancers that are not candidates for IT therapy. Methods: It is a phase I/IIa multi-center, open label, single ascending dose (SAD) /multiple ascending dose (MAD) study to evaluate T3011 IV therapy. The primary objective is to evaluate the safety and tolerability. Dose cohort and regimen are shown in Table. PK and PD profiles are tested in samples of blood, saliva, urine, and tumor tissue. Results: As of 16 Dec 2022, 15 pts with stage IV disease were enrolled, 9 pts had received at least 3 lines of prior therapy. The median follow-up time is 1.58 months. Treatment-emergent adverse event (TEAE) occurred in 15 (100%) pts and treatment-related adverse event (TRAE) occurred in 10 (66.7%) pts. G3 TEAE in 3 (20%) pts (hypertriglyceridemia, dyspnea, lymphopenia) and G3 TRAE in 1 (6.7%) pt (lymphopenia), no≥ G4 AE reported. Dyspnea, the only reported SAE (1, 6.7%), is drug-unrelated. TRAEs were lymphopenia (5, 33.3%), anemia (1, 6.7%), diarrhea (1, 6.7%), malaise (1, 6.7%), urticaria (1,6.7%), rash (1, 6.7%), constipation (1, 6.7%), flu like symptoms (1, 6.7%), headache (1, 6.7%) and abnormal laboratory test results (incidence were all 6.7%), most of them are mild and manageable. No AEs led to drug withdrawal. No DLT occurred; MTD was not reached. 11/15 pts achieved stable disease (SD) by RECIST v 1.1. DCR was 73.3%. 1 pt with colorectal cancer who experienced irinotecan-based chemotherapy, anti-VEGF and radiotherapy in Cohort 1 had a long-term SD for over 4 months. In SAD part, T3011 DNA in blood at 2 hours post-dose was detected in 0% (0/3), 0% (0/4), 66.7% (2/3) and 100% (2/2) pts in Cohort 1, 2, 3 and 4 respectively. The DNA copies in pts of Cohort 4 are significantly higher than those of Cohort 3 (Mean viral DNA copies/ul 49.6 vs. 5.7). In cohort 2 of MAD part, T3011 DNA in blood at 2 hours post-dose was detected in 0% (0/3), 66.7% (2/3) and 100% (3/3) pts at C1D1, C1D4 and C1D8 respectively. T3011 DNA was not detected in saliva or urine samples. Pre-existing HSV-1 IgG was shown to hardly affect T3011 activity. Conclusions: T3011 IV is safe and well tolerated, and unlikely to spread to close contacts. Preliminary efficacy is encouraging. T3011 DNA in blood is in a dose-dependent manner with additive effect from repeated doses supporting continued recruitment of pts to higher dose cohorts. Clinical trial information: NCT05598268 . [Table: see text]
The incidence of thyroid-related adverse events in solid tumors receiving immune checkpoint blockade with curative intent: A meta-analysis.
Authors: Zhou Susu , Horita Nobuyuki , Shao Theresa , Harrington Matthew , Fujiwara Yu
Published: June 2023

2641

Background: Adjuvant/neoadjuvant treatments with immune checkpoint blockade (ICB) improve survival outcomes in patients with several types of cancer. However, immune-related adverse events (irAEs) which frequently involve the thyroid gland may lead to delays in curative treatments such as surgery and radiotherapy. Thus, it is essential to report the incidence of thyroid-related adverse events (AEs) associated with the addition of ICB to conventional therapy with curative intent through a meta-analysis of randomized controls trials (RCTs). Methods: We performed a systematic search of PubMed, Embase, Web of Science, and Cochrane library for RCTs evaluating ICB-containing treatment of solid tumors with curative intent. We calculated the odds ratio (OR) of all-grade and grade 3-5 thyroid-related AEs including thyroiditis, hyperthyroidism, and hypothyroidism. We performed a meta-analysis using the random-effect model to compare the incidence of thyroid-related AEs in patients who received therapy with and without the addition of ICB. Subgroup analysis based on the type of ICB (anti-PD-1, anti-PD-L1, and anti-CTLA-4) was conducted. Results: 24 RCTs comprising 12,199 patients were analyzed. The addition of ICB was associated with higher incidence of all-grade thyroiditis (OR=3.53, 95%CI:1.88-6.64, p<0.0001), hyperthyroidism (OR=7.18, 95%CI:4.30-12.01, p<0.00001), and hypothyroidism (OR=5.39, 95%CI:3.68-7.90, p<0.00001). In subgroup analysis, PD-1 and PD-L1 inhibitors were particularly associated with higher incidence of hyperthyroidism and hypothyroidism. The incidence of grade 3-5 thyroid-related AEs in patients who received therapy with the addition of ICB was 0.13% (thyroiditis, N=4/3135), 0.20% (hyperthyroidism, N=12/5877), and 0.19% (hypothyroidism, N=12/6369). Conclusions: The addition of ICB to conventional therapy with curative intent was associated with an increased risk of all-grade thyroid-related AEs, but the incidence of grade 3-5 AEs was low. These results suggest ICB may be added safely as an adjunct to curative treatments such as surgery and radiotherapy. Clinicians should monitor patients’ thyroid function and maintain vigilance for symptoms and signs of thyroid disease. OR (95% CI) and number of studies (N) for thyroid-related AEs with subgroup analysis. [Table: see text]
The study of immune-related adverse events in a community-based centre.
Authors: Cautha Sandhya , Jain Kevin R. , Budhathoki Pravash , Okobi Tobechukwu Joseph , Bhatt Tanushree , Moirangthem Valentina , Gupta Sorab , Luong Thanh-Ha T. , Hanif Ahmad
Published: June 2023

2642

Background: The effectiveness of immunotherapy is often hindered by the development of immune-related adverse events (IrAE). Racial minorities were under-represented in the key clinical trials that led to the approval of different immune checkpoint inhibitors (ICI). In this study, we explore the side effect profile of immune checkpoint inhibitors in our patient population that comprises almost entirely of minorities, mostly African Americans (AA) and Hispanics. We hypothesize that due to race-based differences in immune milieu of the body and disease susceptibility, the timing and severity of immunotherapy-related IrAE would be different in AA and Hispanics compared to Caucasians. This can translate into a difference in clinical outcomes as well. There have been some suggestions of a positive association of the development of IrAE with cancer survival, although the data is limited and heterogeneous. The purpose of our study is to study the frequency and severity of IrAEs in racial minority groups, compare them with previous clinical trials population, and add valuable real-world data in this underrepresented group of patients. Methods: A retrospective chart review was performed on adult patients with solid malignancies treated with any ICI between January 1, 2015 and April 30, 2022. Patients were classified according to age (greater/equal to 65y or younger), sex, race (self-identified), primary cancer, and type of immunotherapy received. Outcome data using type and severity of IrAE, time to development of IrAE, and any association with clinical outcomes was collected and analyzed using descriptive statistics as well as univariate analysis. Results: A total of 78 patients were included in the final analysis. The mean age was 68 years; 51% were males; 42.3% were Hispanics, 37% were AA, 19.7% were others, and 1% were Whites. Most common malignancy was lung cancer (65.5%). Most common ICI agent used was Pembrolizumab (n = 52) and 2 patients were treated with combination therapy using Ipilimumab and Nivolumab. 41 (52.5%) patients had IrAE of any grade while 9 (11.5%) patients experienced grade 3 side effects. None of the patients experienced grade 4 side effects. Most common IrAE of any grade was hypothyroidism (n = 14) while most common grade 3 side effect was colitis (n = 6). 31 patients were less than 65y of age. There was no significant difference in IrAE in patients less than 65 years of age vs ≥ 65 years (51.6% vs 53.1%) or grade 3 IrAE (9.6% vs 12.7%). Conclusions: In our study population consisting mostly of AA and Hispanics, the rate of IrAE of any grade as well as grade 3 or 4 IrAE with ICI therapy was comparable to what was seen in clinical trials involving these drugs. This data and its potential effects on survival outcomes need to be analyzed in prospective studies involving a larger number of patients.
Immune related adverse events (irAEs) in patients with solid tumors and advanced chronic kidney disease (CKD) receiving checkpoint inhibitors (CPIs).
Authors: Kaakour Dalia , Vosoughi Elham , Warnecke Brian , Yazdanpanah Omid , Rezazadeh Arash , Valerin Jennifer Brooke , Mar Nataliya
Published: June 2023

2650

Background: Randomized controlled trials evaluating CPIs in the management of solid tumors have typically excluded patients with advanced CKD and end-stage renal disease (ESRD). Limited available data evaluating the safety of CPI use in this patient population demonstrated a similar incidence of irAEs in patients with advanced CKD compared to those with normal or mildly impaired renal function, with majority of irAEs being grade 1 or 2. CPIs are not modified by dialysis due to their molecular size and, as such, do not require renal dosing. Methods: We performed a retrospective analysis of patients over 18 years of age with solid tumors and advanced CKD, who received CPIs at the University of California Irvine from 1/2015 to 6/2021. Advanced CKD was defined as glomerular filtration rate (GFR) less than 60 ml/min. Patients must have received at least one dose of a PD-1/PD-L1 or CTLA-4 inhibitor as a single-agent or in combination with another therapy. Patients were stratified by severity of CKD, including CKD3 (GFR of 30-59 ml/min), CKD4 (GFR of 15-29 ml/min), and CKD 5/ESRD (GFR less than 15 ml/min). Results: A total of 32 patients were included, 24 (75.00%) with CKD3, 6 (18.25%) with CKD4, and 2 (6.25%) with CKD5/ESRD. 10 (31.25%) patients were female and 22 (68.75%) were male. Median age was 73.5 years [range: 26 to 98]. 22 (68.75%) received CPI monotherapy and 10 (31.25%) received a combination of CPI with another agent. After initiation of CPI therapy, 16 (50.00%) patients experienced an irAE, with a total of 23 unique irAEs due to some patients experiencing multiple irAEs. In patients with irAEs, 13 (81.25%) received CPI monotherapy and 3 (18.75%) received CPI combined with another agent. In patients with CKD3, CKD4, and CKD5/ESRD, 14 (87.50%), 2 (12.60%), and 0 (0.00%) experienced irAEs, respectively. Types of irAEs observed are listed, with the most common being colitis in 6 (26.1%) patients, endocrinopathies in 4 (17.39%) patients, and dermatologic in 4 (17.39%) patients. 18 (78.26%) of unique irAEs were grade 1 or 2, while 5 (21.74%) were grade 3 or higher. 10 (43.48%) of irAEs were managed with steroids as per physician discretion, 8 (80.00%) with CKD3 and 2 (20.00%) with CKD4. Conclusions: The safety of CPIs in patients with solid tumors and advanced CKD has not been rigorously evaluated. Recognizing the small sample size and retrospective nature of this dataset, the incidence and type of irAEs in patients with advanced CKD appears similar to that of patients with normal renal function or mild renal impairment. More prospective data in this population is needed, particularly in patients with CKD5/ESRD. Types of irAEs in patients with advanced CKD. [Table: see text]
Frequency of delayed immune-related adverse events (irAEs) in hospitalized patients treated with immune checkpoint inhibitors (ICIs).
Authors: Durbin Sienna , Zubiri Leyre , Perlman Katherine , Molina Gabriel , Jacoby Ted , Shah Nishi , Reynolds Kerry Lynn
Published: June 2023

2652

Background: Across cancer types and indications, the use of ICIs is increasing. Guidelines indicate that most irAEs occur in the months immediately following receipt of ICI. Little is known about the frequency of delayed irAEs following ICI administration. Methods: Patients who received ICIs and were hospitalized following ICI initiation between January 2011 and October 2022 were identified using pharmacy and hospital admission databases. Patient demographics, and oncologic and irAE history were extracted from the medical record. All admissions were reviewed by two physicians to evaluate for irAEs, which were defined as suspected or confirmed using published disease-specific criteria. We examined the number of irAEs hospitalizations at < 6 months, 6-12 months, 1-2 years, 2-5 years, and >5 years from the first dose of the most recent line of ICI to date of admission. Results: Among the 930 patients hospitalized with irAEs, average age was 66.0 years (range 18.3 - 96.2) and 61.2% were male. Most common tumor types were melanoma (42.0%), lung (24.1%), and gastrointestinal (12.7%). Median time from start of last line of ICI to hospitalization was 98 days (IQR 37-244.3). One hundred sixty-six patients (19.4%) had been treated with >1 prior line of ICI and 102 (11.0%) were diagnosed with multiple irAEs during the same admission. Of all patients admitted, 147 (15.7%) presented 6 months – 1 year after start of ICI line, 79 (8.4%) presented after 1-2 years, 35 (3.7%) presented after 2-5 years, and 2 (0.2%) presented after >5 years. Rates of irAEs by time from start of ICI line are demonstrated. Conclusions: Although irAEs occur in a time-dependent fashion, delayed, serious irAEs in hospitalized patients are common (28% at 6+ months), with a subset presenting two years or more after start of ICI. Providers must remain vigilant for potential irAEs regardless of elapsed time from ICI, especially as patients live longer and ICIs become widely used in different settings. Future work is needed to define potential triggers of and patients at risk for delayed irAEs. [Table: see text]
Tumor fraction to improve patient selection for oncology early phase clinical trials: Analysis of two precision medicine studies.
Authors: Cousin Sophie , Belcaid Laila , Trin Kilian , Bayle Arnaud , Alame Melissa , Rouleau Etienne , Soubeyran Isabelle , Lacroix Ludovic , Blouin Laura , Vasseur Damien , Mathoulin-Pélissier Simone , Bellera Carine A. , Italiano Antoine
Published: June 2023

3005

Background: Typical entry criteria in early phase studies include expected life expectancy greater than 3 months. However, this evaluation is quite subjective and more objective and reproducible tools are needed to improve patients (pts) selection. The quantification of ctDNA shed by measuring tumor fraction (TF) has been associated with prognosis in solid tumors pts. However, prognostic implications of TF quantification have been evaluated primarily in retrospective studies and in a limited number of cancer types. We report here the first prospective evaluation of the prognostic impact of TF in 2 independent precision medicine studies enrolling pts referred to consider their eligibility to early phase trials. Methods: All consecutive adult pts with an advanced solid tumor included between December 2020 and December 2021 in 2 precision medicine studies: BIP (NCT02534649, sponsor: Institut Bergonié, Bordeaux, France) and STING (NCT04932525, sponsor: Institut Gustave Roussy, Villejuif, France). All pts underwent comprehensive genomic profiling with the 324-gene FoundationOne. TF was analyzed as a binary variable, indicating whether a specimen had TF ≥10% or TF <10%. Multivariate analysis included previously validated prognostic scores: the Royal Marsden Hospital (albumin, LDH, number of metastatic sites) and the GRIm (LDH, neutrophil/lymphocyte ratio (NLR), albumin) scores as well as their individual components. Results: 1912 pts: N=965 in BIP and N=947 in STING were included. Their characteristics are described. High TF was associated with significantly worse overall survival (OS) in both BIP and STING studies. On multivariate analysis, TF was associated with worse OS (HR:2.49 [CI95%: 2.11 - 2.95, p<0.001] and HR:2.52 [CI95%: 2.06 - 3.08, p<0.001] in BIP and STING studies respectively) independently of the RMH and GRIM scores as well as their individual components. Conclusions: This is the first prospective analysis confirming that TF is a strong prognostic factor in pts with advanced solid tumors and represent an helpful tool in the process of patient selection for phase I trial entry. [Table: see text]
Debio 0123-101: A phase 1 trial of Debio 0123 in combination with carboplatin in advanced solid tumors—Safety, pharmacokinetic, and preliminary antitumor activity data.
Authors: Gelderblom Hans , Jalving Mathilde , Desar Ingrid , Saavedra Omar , Gietema Jourik A. , van Ravensteijn Stefan , Ajmone Marsan Nina , Bellon Anne , Micallef Sandrine , Luong Noemie , Piggott Luke , Frederiksen Franzen Rikke , Rodrigo Imedio Esteban
Published: June 2023

3012

Background: Cell cycle faults are typical in cancer, with tumor cells depending on G2 checkpoints to avoid excess DNA damage. WEE1, a DNA damage-activated kinase, governs G2 by phosphorylating cyclin-dependent kinase 1 (CDK1) to arrest the cell cycle and permit DNA repair. Via CDK1 inhibition, WEE1 also blocks replication initiation, limiting oncogene-induced replication stress. WEE1 inhibition, with accumulating DNA damage, can induce mitotic catastrophe and apoptosis. Debio 0123, an orally available, ATP-competitive WEE1 inhibitor, is being studied as monotherapy and in combination with carboplatin (CP) in patients (pts) with solid tumors. Here, we report safety, pharmacokinetic (PK), pharmacodynamic, and antitumor activity data for the combination. Methods: Debio 0123-101 (NCT03968653) is a two-arm dose-escalation study in pts with advanced solid tumors that recurred or progressed after receiving platinum-containing therapy, where no standard therapy of proven benefit is available. In Arm A, Debio 0123 was given as monotherapy in cycle (C) 1 (as a single dose on day [D] -3 and once daily over D1–3) and in combination with CP from C2 until end of treatment (EOT). In Arm B, Debio 0123 was given in combination with CP on D1–3 and D8–10, from C1 to EOT. CP was given on D1 of each 21-day cycle in both arms. Skin biopsies were taken at baseline and C1D3 to assess target engagement (TE). Results: Arm A data (cut-off 31.12.2022) is shown. Overall, 38 pts were treated (78.9% female, mean age 58.5 years), with two pts ongoing. Using a continual reassessment method-guided dose escalation, tested Debio 0123 doses ranged from 30–520 mg. The maximum tolerated dose was declared at 520 mg. At this dose level, 2/6 pts experienced a dose-limiting toxicity. The treatment was deemed well tolerated, with a manageable safety profile in line with that expected for CP monotherapy. Most Debio 0123-related toxicities were grade 1/2. Preliminary PK data indicate that Debio 0123 plasma levels rise proportionally with dose. TE was seen from the 150 mg dose, becoming more pronounced with increasing dose levels. Confirmed partial responses (PR) occurred in 5/30 evaluable pts; 4/12 pts with platinum-resistant ovarian cancer achieved a PR (one ongoing). Conclusions: Debio 0123, combined with CP, has a manageable safety profile and is well tolerated up to 520 mg; this combination led to observable antitumor activity in pts with platinum-resistant cancer. Further study of Debio 0123 as a therapeutic agent is warranted. Clinical trial information: NCT03968653 . [Table: see text]
Phase 1 trial evaluating TTI-101, a first-in-class, orally bioavailable, small molecule, inhibitor of STAT3, in patients with advanced solid tumors.
Authors: Tsimberidou Apostolia Maria , Vining David J. , Arora Sukeshi Patel , de Achaval Sofia , Larson Jeffrey , Cartwright Carrie , Avritscher Rony , Alibhai Imran , Kaseb Ahmed Omar
Published: June 2023

3018

Background: Signal transducer and activator of transcription 3 (STAT3) is a transcription factor at the critical intersection of signaling pathways controlling gene networks integral to the survival and immune sequestration of cancer cells. Given the integral role of STAT3 in tumorigenesis and immune suppression, STAT3 signaling inhibition may have dual antitumor activity. TTI-101 is a first-in-class, orally bioavailable, selective small molecule that binds to STAT3 and prevents STAT3-mediated transcriptional activation. A first-in-human, Phase 1, dose escalation and expansion study of TTI-101 monotherapy was conducted in patients with advanced/refractory solid tumors (NCT03195699). Methods: Patients with advanced metastatic cancer who had failed standard therapy were treated with TTI-101 twice daily in 28-day cycles at dose levels (DL) 1-4: 3.2 (DL1), 6.4 (DL2), 12.8 (DL3), and 25.6 (DL4) mg/kg/d (“3+3” design). Three different formulations of TTI-101 were used stepwise, beginning with formulation 1 (F1). A second-generation formulation (F2) was introduced at DL3 during dose escalation and patients were stratified into two cohorts: hepatocellular carcinoma (HCC) and other solid tumors. A third-generation formulation (F3) was evaluated once the recommended phase 2 dose (RP2D) was determined. Treatment continued until disease progression, unacceptable toxicity, or study withdrawal. Results: Key patient characteristics included a median age of 63 years (range, 33-78), 52% male, and a median number of 3 (range, 1-9) prior systemic therapies. No dose limiting toxicities (DLTs), or fatal treatment-related adverse events (TRAEs) were observed. Diarrhea was the only TRAE observed in ≥30% of the safety population (n=64) with events being mostly Grade 1/2. F3 was better tolerated than F1 and F2 with no events ≥Grade 3. One patient experienced transient Grade 4 hyperglycemia which resolved with insulin and metformin. Five patients had serious TRAEs (all Grade 3), which resolved. TTI-101 showed linear pharmacokinetics from DL1-3 plateauing at DL3. The RP2D was determined to be 12.8mg/kg/d (DL3) for both the HCC and other solid tumor cohorts. Of the 39 patients evaluable for response, 5 (13%) patients had confirmed partial responses (cPR) and 16 (41%) stable disease (SD). Of the 15 patients with HCC, 3 (20%) had a cPR with a median duration of 10.5 months. The other two cPRs were in ovarian cancer (n=1) and gastric cancer (n=1). Conclusions: TTI-101 was well-tolerated and no DLTs were noted. cPRs were observed across tumor types. The antitumor activity of TTI-101 monotherapy in the relapsed/refractory setting is promising, particularly in HCC. Two Phase 2 oncology studies of TTI-101 in STAT3-driven cancers (HCC and metastatic breast cancer) are underway. Clinical trial information: NCT03195699 .
SGN-B6A, an integrin beta-6 (ITGB6)-targeted antibody-drug conjugate (ADC), in patients with advanced solid tumors: Updated results from a phase 1 study (SGNB6A-001).
Authors: Hollebecque Antoine , Lopez Juanita Suzanne , Piha-Paul Sarina A. , Dowlati Afshin , Patnaik Amita , Galvao Vladimir , Bockorny Bruno , Sehgal Kartik , Kingsley Ed , Sanborn Rachel E. , Perez Cesar Augusto , Peters Solange , Yan Mingjin , Nazarenko Natalya N. , Calvo Emiliano
Published: June 2023

3024

Background: The receptor ITGB6 plays a role in tumor pathogenesis and invasiveness, and its overexpression is correlated with poor outcomes. Non-small cell lung cancer (NSCLC), head and neck (HNSCC), and esophageal cancer (EC) are among tumors with high ITGB6 expression (Lyon 2021). SGN-B6A is an ITGB6-directed vedotin ADC with a monomethyl auristatin E (MMAE) payload. SGN-B6A elicits antitumor activity via MMAE-mediated cytotoxicity, bystander effect, and immunogenic cell death. Here, we present updated results of an ongoing phase 1 study with a focus on NSCLC, HNSCC, and EC (Hollebecque SITC 2022). Methods: SGNB6A-001 (NCT04389632) is an open-label, multicenter, dose-escalation/expansion study evaluating the safety, pharmacokinetics, and antitumor activity of SGN-B6A (per RECIST v1.1) in patients (pts) with advanced solid tumors. Dose escalation (Part A) explored continuous weekly and intermittent dosing regimens. Dose was calculated using total body weight (TBW) or adjusted ideal body weight. Dose expansion (Part B) is enrolling pts with NSCLC, HNSCC, and EC. Results: As of 14 December 2022, 148 pts received SGN-B6A, 88 pts in Part A and 60 pts in Part B; enrollment for Part A is complete. In all cohorts (N=148), treatment-emergent adverse events (TEAEs) were observed in 88.5% of pts: 50.7% were Grade ≥ 3 (21.6% related), and 37.2% were serious (8.1% related); 6.1% of pts discontinued treatment due to TEAEs. 3 pts (2.0%) died due to TEAEs; none of the deaths were considered treatment-related. The most common TEAE was fatigue (35.1%); the most common Grade ≥ 3 TEAE was neutropenia (8.1%); the most common TEAEs leading to treatment discontinuation were peripheral sensory neuropathy and pneumonia (1.4% each). Prior lines of therapy and efficacy data for Part A (NSCLC, EC, and HNSCC) and Part B (HNSCC) subsets are summarized. Conclusions: SGN-B6A demonstrated a manageable safety profile, and showed encouraging preliminary antitumor activity and response durability in dose escalation in a heavily pretreated population. Part B dose expansion cohorts in NSCLC, esophageal squamous cell carcinoma (ESCC), and HNSCC are ongoing. Clinical trial information: NCT04389632 . [Table: see text]
Plasma lipidomic profiling of chemotherapy-induced peripheral neuropathy.
Authors: Yeung Nicole , Lin Hui-Ming , Timmins Hannah , Li Tiffany , Goldstein David , Friedlander Michael , Harrison Michelle L. , Mahon Kate Lynette , Meikle Peter , Park Susanna , Horvath Lisa
Published: June 2023

3031

Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a dose-limiting side effect of cytotoxic cancer treatment. This may result in dose reduction (DR) or chemotherapy discontinuation (CD) and ultimately decrease the efficacy of therapy. There is a lack of studies examining the role of lipids in relation to CIPN, despite the association of obesity with worse CIPN, and hyperlipidaemia with diabetic neuropathy. The aim of this study is to determine if circulating lipids are associated with CIPN severity. Methods: Pre-chemotherapy plasma samples from 137 patients with CIPN from docetaxel or paclitaxel-based treatment underwent lipidomic analysis (788 lipids). CIPN severity was measured using the neurological grading scale Total Neuropathy Score-clinical version (TNSc score; John Hopkins University) and patient-reported outcome measure EORTC QLQ-CIPN20. The association of baseline lipid levels with severe CIPN, as defined by high TNSc and CIPN20 scores, was performed using linear modelling (LIMMA). Baseline lipids associated with shorter time to dose reduction (DR) or chemotherapy discontinuation (CD) due to CIPN was determined by Cox regression, with adjustment for body mass index (BMI), age and diabetes. Lipid profiles were identified using latent class analysis (LCA) of significant lipids from the Cox regression. Results: Higher TNSc or CIPN20 scores were associated with 107 and 43 lipid species respectively (LIMMA p<0.05), of which only 3 species were in common. Triacylglycerols (TG) represented a significant proportion of lipids with elevated levels associated with higher TNSc (32.5%) or CIPN20 (9.1%) scores (Fisher’s exact test p<0.001). 70 lipid species were associated with shorter time to DR/CD (Cox regression p<0.05), which included 15 TG with higher levels associated with shorter time to DR/CD. Unsupervised LCA identified a specific lipid profile associated with worse CIPN [Hazard ratio 2.61 (95% CI 1.40 – 4.84, p=0.002)]. This lipid profile also had higher levels of TG (t-test p<0.05). The high risk CIPN lipid profile was independently associated with shorter time to DR/CD when modelled with clinical factors (diabetes, age, BMI or prior numbness/tingling; Cox regression p<0.006); however, these clinical factors were not associated with time to DR/CD in the multivariable models (p>0.08). Conclusions: Higher levels of baseline plasma TG are associated with increased CIPN severity and shorter time to DR/CD in taxane-treated patients. These findings are consistent with other reports regarding the association of hyperlipidaemia with neuropathy. Further research is required to determine if TG-lowering medication can reduce the risk of CIPN development.
First report of ELUCIDATOR study: A prospective observational multicenter study on resistance mechanisms in patients with early disease progression during osimertinib.
Authors: Mizumori Yasuyuki , Tamiya Akihiro , Osuga Mitsuo , Isa Shun-ichi , Taniguchi Yoshihiko , Nakamura Keiichi , Harada Daijiro , Shinohara Tsutomu , Yanai Hidetoshi , Nakatomi Katsumi , Oki Masahide , Mori Masahide , Kuwako Tomohito , Yamazaki Koji , Tamura Atsuhisa , Ando Masahiko , Koh Yasuhiro
Published: June 2023

3032

Background: Osimertinib (Osi) is the key standard therapy for patients (pts) with chemo-naive advanced non-small cell lung cancer (NSCLC) harboring sensitizing epidermal growth factor receptor ( EGFR) mutations. However, many of cases treated with Osi experience the disease progression (PD). Therefore, understanding first-line osimertinib resistance mechanisms is essential for future therapeutic strategies. Here, we addressed the underlying mechanisms of resistance to Osi using paired plasma DNA samples and particularly focused on early PD (PD within 6 months) cases. Methods: This trial is the multicenter prospective research, and we prospectively collected plasma DNA samples prior Osi treatment and at PD. Next-generation sequencing (NGS) implemented with the molecular barcoding method was performed to analyze gene mutations in 197 cancer-associated genes. Then using these ct-DNA, we analyzed the Osi resistance by ultra-sensitive NGS. In this interim analysis, we specially analyze the early PD (PD within 6 months) cases. Results: One hundred eighty-eight pts were enrolled between May 2019 and January 2021. Among these pts, 125 (66%) pts were female, 96 (51%) were EGFR exon 19 deletion mutation, and 109 (58%) were never smoker. Seventy-eight pts experienced PD and 36 pts experienced early PD at interim analysis. Baseline shedders, patients with plasma positivity for EGFR-activating mutation were more frequently observed in early PD pts than non-PD (86.1% vs 63.4%, p = 0.009). Early PD patients had significantly more co-occurring gene mutations along with EGFR mutations than non-early PD patients (2.89±1.49 vs 1.97±1.37, p = 0.002). Most notably, 3 among 36 early PD pts and 8 among 78 PD pts had significant reduction of plasma EGFR mutant allele frequency at PD than that at baseline. Among those, 1 had germline BRCA1 mutation and 1 had BRINP3 mutation in 3 early PD pts, and 1 had germline BRCA2 mutation, and 1 had germline TP53 mutation in 5 PD pts excluding early PD pts. Co-occurring TP53 mutations were not relevant to early PD in this study cohort. Conclusions: Germline mutations in BRCA1/2, TP53 and BRINP3 may confer early and unprecedented resistance to Osi monotherapy. Plasma-based serial comprehensive gene profiling may help predict and identify patients unlikely to benefit from Osi treatment, though further study is warranted. Clinical trial information: jRCTs031180051 .