Safety Biomarkers Research Articles

Prognostic analysis of PD-1/CTLA-4 bispecific antibody combined with chemotherapy first-line treatment for recurrent or metastatic cervical cancer: A multicenter real-world study.

e17520 Background: PD-1/CTLA-4 bispecific antibody, cadonilimab, has shown excellent efficacy in advanced cervical cancer patients who have previously received platinum containing chemotherapy. However, its effectiveness in first-line treatment remains unclear yet. This study aims to evaluate the efficacy, safety, and prognostic biomarker of cadonilimab combined with chemotherapy for the first line treatment of recurrent or metastatic cervical cancer. Methods: Information on patients with recurrent or metastatic cervical cancer who received chemotherapy combined with cadonilimab as first-line treatment at three cancer centers from July 2022 to September 2023 were collected. Patients have not received systemic chemotherapy previously and are not suitable for curative local treatment, received cadonilimab 10mg/kg Q3W for up to 17 cycles + chemotherapy for up to 6 cycles (paclitaxel 135-175 mg/m2 + cisplatin 50 mg/m2 or carboplatin AUC 5), ± bevacizumab 10-15 mg/kg. Clinical outcomes were analyzed using the Kaplan–Meier method with log-rank test. RNA-seq was used to analyze differential expressed genes (DEGs) between PR+CR group and PD+SD group. Results: There are 52 patients enrolled, median age 56.5 years (39–87 years). The median follow-up time was 12 months (5–23 months). There were 29 cases of lung metastasis, 7 cases of liver metastasis, 11 cases of bone metastasis, 12 cases of pelvic metastasis, and 11 cases of lymph node metastasis. The median number of cycles of cadonilimab and chemotherapy were 8 and 5, respectively. The 1-year overall survival (OS) and progression-free survival (PFS) rates were 91% and 72.5%, respectively. The objective response rate (ORR) was 75%.The expression of PD-L1 and bevacizumab had no effect on prognosis. The most common treatment-related adverse events (TRAEs) were neutropenia (78.2%), anemia (82.7%), thrombocytopenia (51.9%), thyroid dysfunction (50%), nausea and vomiting (88.5%), fatigue (71.2%). Grade 3 or 4 adverse events (AE) were reported in 36.5% patients, mainly hematological toxicity. The most significant differential pathways between PR+CR group and PD+SD group were adhesion, Hippo signaling pathway, NOD like receptor signaling pathway, programmed cell death, and secretory granules. Conclusions: Cadonilimab combined with chemotherapy ± bevacizumab as first-line treatment for recurrent or metastatic cervical cancer was effective and well-tolerant.

Biomarkers in a phase 1b study of investigational microbiome therapeutic SER-155 in adults undergoing allogeneic hematopoietic cell transplantation (allo-HCT).

6554 Background: Acute graft- versus-host disease (aGvHD) is a life-threatening complication following allo-HCT. Microbiome dysfunction and associated GI barrier disruption may contribute to aGvHD via activation of inflammatory immune responses. Circulating biomarkers in the peri-transplant period are correlated with risk of severe aGvHD, including suppression of tumorigenicity 2 (ST2), regenerating islet-derived 3-alpha (Reg3a) and inflammatory cytokines (IL6, IFNϒγ & TNFα). SER-155 is an investigational cultivated oral microbiome therapeutic designed to restructure the GI microbiome, improve GI barrier integrity and reduce GI inflammation and is being assessed in a 2-part Phase 1b study in adults undergoing allo-HCT. We present preliminary safety, GvHD, PK, and exploratory biomarker data from the completed open-label Cohort 1 through Day 100 post-HCT. Methods: Adult recipients of allo-HCT were eligible. HCT conditioning and aGvHD prophylaxis were per investigator discretion. Patients received 2 courses of SER-155 (pre-HCT and post-neutrophil engraftment, each comprised of 4 days of microbiome conditioning with oral vancomycin followed by 10 days oral SER-155. The primary endpoint was safety. Strain engraftment (PK) and biomarkers were assessed in stool and plasma samples. Results: Fifteen adults enrolled; 13 received at least 1 course of study drug (median age 67; 54% male), and 11 underwent allo-HCT. Following each course, the majority of the 16 SER-155 strains were detected in stool. Treatment-emergent adverse events (AEs) were reported in all patients with GI AEs the most common. No serious AEs (SAEs) were deemed related to SER-155. Most SAEs and AEs of special interest (ie, BSIs, invasive or GI infections) occurred between HCT and the 2nd SER-155 course. There were no deaths before Day 100. No BSIs were attributable to SER-155 strains. The rate of grade 2-4 aGvHD based on MAGIC criteria through Day 100 was 45.5%; no severe grade 3-4 aGvHD was observed. Median levels of plasma biomarkers REG3α, ST2 and inflammatory cytokines were not elevated relative to a reference range (Table). Conclusions: In this small open-label cohort, SER-155 was generally well-tolerated through Day 100 without drug-related SAEs and no severe aGvHD. Plasma biomarkers were not elevated at HCT Day 0 or neutrophil recovery. These preliminary observations align with the design and preclinical evaluation of SER-155. Clinical trial information: NCT04995653 . [Table: see text]

SOGUG-Vexillum: Phase II non-randomized clinical trial of nivolumab/ipilimumab maintenance following first-line chemotherapy in unresectable locally advanced or metastatic urothelial cancer.

4576 Background: Nivolumab (nivo) 1mg/kg plus ipilimumab (ipi) 3mg/kg achieved the highest ORR (42.4%) in refractory metastatic urothelial carcinoma (mUC) with a manageable safety profile. The addition of nivo and ipi subsequently to first-line chemotherapy (CT) could consolidate the clinical benefit. Methods: This single arm, open-label, multicenter study evaluates the effectiveness of ipi 3 mg/kg and nivo 1 mg/kg (Q3W) for 4 cycles followed by nivo maintenance therapy (Q4W) in delaying disease progression in patients with unresectable urothelial cancer that did not progress after first-line platinum-based CT (at least 4-6 cycles of CT). Autoimmune disease, immune deficiency, and symptomatic brain metastasis were excluded. The primary endpoint is Progression Free Survival (PFS) in intention-to-treat and PD-L1 populations. Secondary endpoints include: objective response rate (ORR), duration of response (DoR), overall survival (OS), overall survival from 1st dose of CT (cOS), progression-free survival from 1st dose of CT (cPFS), safety and translational biomarker analysis. Sample size was estimated using a Simon II stage design for 4-months PFS rate (H0= 40%; H1= 60; α= 0.05; β= 80%; attrition 10%), requiring 25 patients in the 1st stage and up to 66 in total. Here we report the interim analysis for 1st stage. Results: As of January 2024, the 1st accrual stage was completed with 25 evaluable patients. Baseline characteristics are outlined in the table. With a median follow-up of 6.8 months (95% CI: 6.2-10.5), the 4-m PFS rate was 64% (95% CI: 47.7-85.9) and the median PFS was 4.3 months (95% CI: 3.2-NR). The median cPFS was 9.4 months (95% CI: 8-NR). The 6-m OS rate was 76.4% (95% CI: 60-97.2), while median cOS was 15.4 months (95% CI: 15.4-NR). The median duration of treatment was 2.6 months (95% CI: 2.1, 5.7). Nivo and ipi were permanently discontinued due to toxicity in 3 (12%) and 1 (4.2%) patients, respectively. Nivo doses were delayed in 8 (32%) patients and ipi in 3 (12%) for management of toxicity. Grade ≥3 toxicities were reported in 8 (32%) patients, being the most common: Immune-mediated hepatitis (8%), ALT/AST increased (8%) and diarrhea (8%). Conclusions: Maintenance treatment with nivo and ipi showed preliminary efficacy consolidating clinical benefit to CT with a manageable safety profile. The 4-m PFS rate surpassed the futility threshold in the interim analysis and the accrual in Stage II is underway. Final survival results are awaited. Clinical trial information: NCT05219435 . [Table: see text]

A phase 1, first-in-human study of autologous monocytes engineered to express an anti-HER2 chimeric antigen receptor (CAR) in participants with HER2-overexpressing solid tumors.

TPS2682 Background: Myeloid cells are actively recruited to the solid tumor microenvironment (TME) and have the potential to mediate tumor control via phagocytosis, TME remodeling, and T cell activation. We previously developed human chimeric antigen receptor macrophages (CAR-M) and have shown potent anti-tumor activity in pre-clinical solid tumor models. The anti-HER2 CAR-M cell therapy product, CT-0508, is currently being evaluated in a Phase I trial as a monotherapy and in combination with pembrolizumab. Early clinical data have shown feasibility, safety, and validated the mechanism of action. We have developed a next-generation CAR monocyte (CAR-Mono) platform to increase the dose, improve tumor trafficking and engraftment, and shorten the manufacturing and vein-to-vein time as compared to CAR-M therapy. CT-0525 is an autologous anti-HER2 CAR-Mono cell therapy based on CD14+ monocytes engineered with an Ad5f35 adenoviral vector to express an anti-HER2 CAR. Pre-clinical studies have demonstrated the feasibility, phenotype, pharmacokinetics, durable CAR expression, cellular fate, antigen specificity, and anti-tumor activity of CT-0525. Pre-clinical studies have shown that CT-0525 differentiated into pro-inflammatory CAR-M in vivo and controlled tumor growth. The CT-0525 manufacturing process takes one day and enables the production of up to 10 billion cells from a single apheresis. CT-0525 is being investigated in a first-in-human, open-label, multi-center, Phase I study in patients with HER2 overexpressing solid tumors. Methods: This Phase 1, first-in-human study evaluates the feasibility, safety, tolerability, trafficking, TME activation, and preliminary evidence of efficacy of the investigational CAR-Mono product CT-0525 in 6 participants (pts) with locally advanced unresectable/metastatic solid tumors overexpressing HER2. Pts previously treated with anti-HER2 therapies are eligible. Filgrastim mobilized autologous CD14+ monocytes are collected by apheresis, followed by manufacturing and cryopreservation. The 1st cohort of pts (n=3) will receive 3 x 109 CT-0525 CAR positive monocytes administered IV in one infusion. If tolerated as per the modified toxicity probability interval algorithm (mTPI), the 2nd cohort of pts (n=3) will receive up to 10 x 109 CT-0525 CAR positive monocytes in one infusion. CT-0525 will be administered without conditioning chemotherapy. Primary endpoints include assessment of safety and tolerability, as well as manufacture feasibility. Correlative assessments include pre- and post-treatment biopsies and blood samples for safety, immunogenicity, pharmacokinetics, tumor trafficking, TME modulation, epitope spreading, and other translational biomarkers. Clinical trial information: NCT06254807 .

Unlocking the Potential: Biomarkers of Response to Antibody-Drug Conjugates.

Antibody-drug conjugates (ADCs) have reshaped the cancer treatment landscape across a variety of different tumor types. ADCs' peculiar pharmacologic design combines the cytotoxic properties of chemotherapeutic agents with the selectivity of targeted therapies. At present, the approval of many ADCs used in clinical practice has not always been biomarker-driven. Indeed, predicting ADCs' activity and toxicity through the demonstration of specific biomarkers is still a great unmet need, and the identification of patients who can derive significant benefit from treatment with ADCs may often be uncertain. With the lack of robust predictive biomarkers to anticipate primary, intrinsic resistance to ADCs and no consolidated biomarkers to aid in the early identification of treatment resistance (ie, acquired resistance), the determination of precise biologic mechanisms of ADC activity and safety becomes priority in the quest for better patient-centric outcomes. Of great relevance, whether the target antigen expression is a determinant of ADCs' primary activity is still to be clarified, and available data remain quite controversial. Antigen expression assessment is typically performed on tissue biopsy, hence only providing information on a specific tumor site, therefore unable to capture heterogeneous patterns of tumor antigen expression. Quantifying the expression of the target antigen across all tumor sites would help better understand tumor heterogeneity, whereas molecularly characterizing tumor-intrinsic features over time might provide information on resistance mechanisms. In addition, toxicity can represent a critical concern, since most ADCs have a safety profile that resembles that of chemotherapies, with often unique adverse events requiring special management, possibly because of the differential in pharmacokinetics between the small-molecule agent versus payload of a similar class (eg, deruxtecan conjugate-related interstitial lung disease). As such, the identification of robust predictive biomarkers of safety and activity of ADCs has the potential to improve patient selection and enrich the population of patients most likely to derive a substantial clinical benefit, especially in those disease settings where different ADCs happen to be approved in competing clinical indications, with undefined biomarkers to make precise decision making and unclear data on how to sequence ADCs. At this point, the identification of clinically actionable biomarkers in the space of ADCs remains a top research priority.

Mechanistic safety assessment via multi-omic characterisation of systemic pathway perturbations following in vivo MAT2A inhibition

The tumour suppressor p16/CDKN2A and the metabolic gene, methyl-thio-adenosine phosphorylase (MTAP), are frequently co-deleted in some of the most aggressive and currently untreatable cancers. Cells with MTAP deletion are vulnerable to inhibition of the metabolic enzyme, methionine-adenosyl transferase 2A (MAT2A), and the protein arginine methyl transferase (PRMT5). This synthetic lethality has paved the way for the rapid development of drugs targeting the MAT2A/PRMT5 axis. MAT2A and its liver- and pancreas-specific isoform, MAT1A, generate the universal methyl donor S-adenosylmethionine (SAM) from ATP and methionine. Given the pleiotropic role SAM plays in methylation of diverse substrates, characterising the extent of SAM depletion and downstream perturbations following MAT2A/MAT1A inhibition (MATi) is critical for safety assessment. We have assessed in vivo target engagement and the resultant systemic phenotype using multi-omic tools to characterise response to a MAT2A inhibitor (AZ’9567). We observed significant SAM depletion and extensive methionine accumulation in the plasma, liver, brain and heart of treated rats, providing the first assessment of both global SAM depletion and evidence of hepatic MAT1A target engagement. An integrative analysis of multi-omic data from liver tissue identified broad perturbations in pathways covering one-carbon metabolism, trans-sulfuration and lipid metabolism. We infer that these pathway-wide perturbations represent adaptive responses to SAM depletion and confer a risk of oxidative stress, hepatic steatosis and an associated disturbance in plasma and cellular lipid homeostasis. The alterations also explain the dramatic increase in plasma and tissue methionine, which could be used as a safety and PD biomarker going forward to the clinic.

Abstract PO1-06-02: Solti-1716 TATEN phase II trial: Targeting non-Luminal disease by PAM50 with pembrolizumab and paclitaxel in Hormone Receptor-positive/HER2-negative advanced breast cancer (ABC)

Abstract Background Within HR+/HER2-negative breast cancer, PAM50 non-luminal tumors (HER2-enriched [HER2-E] and Basal-like) have higher expression of proliferation and immune-related genes and tumor infiltrating lymphocytes and might benefit from immunotherapy. Here, we report the efficacy, safety, and correlative analysis data of the TATEN trial, the first study designed to evaluate pembrolizumab and paclitaxel in HR+/HER2-negative, PAM50 non-luminal, ABC. Methods TATEN trial (NCT04251169) is a single-arm, multicenter, phase II study evaluating pembrolizumab in combination with paclitaxel in patients with HR+/HER2-, PAM50 non-luminal ABC. Key inclusion criteria include progression to prior CDK4/6 inhibitors (CDK4/6i), presence of measurable disease, no prior chemotherapy for ABC, ECOG 0-1, and non-luminal metastatic disease by PAM50. Included patients received pembrolizumab at 200 mg every 3 weeks (beginning at cycle 1) in combination with weekly paclitaxel at 80 mg/m2 beginning at cycle 2. The primary endpoint was overall response rate (ORR) according to RECIST V1.1. in patients who received at least one dose of combination treatment and had a first, post-baseline tumor assessment (evaluable population). Secondary endpoints included progression-free survival (PFS), clinical benefit rate (CBR), safety, and predictive biomarkers. The study was based on a Simon two-stage design. Stage I of the trial would be considered successful if at least 6 of 15 patients achieved a partial response and/or complete response. In that case, the trial would recruit up to 46 evaluable patients for a target ORR ≥ 41%. Metastatic biopsies from patients enrolled in pre-screening were also evaluated for tumor infiltrating lymphocytes (TILs) and were further analyzed with an expression panel of 192 genes, including PDL1 and PD1. Results From July 2020 to December 2021, 132 tumors were screened, and 27 PAM50 non-luminal tumors were identified (20%). Non-luminal tumors trended to have higher PDL1 expression (p=0.090) and TILs (p=0.084) compared to luminal tumors, while no difference was observed for PD1 (p=0.850). Of 20 recruited patients in the study (stage I+II), 18 were evaluable for the primary endpoint. Baseline characteristics were as follows: median age 55 years, ECOG 0 55%, de novo MBC 22%, and visceral disease 72.2%. Eleven patients had received paclitaxel treatment in the adjuvant setting. Regarding PAM50 subtype, 2 patients had basal-like and 16 HER2-E tumors. At the time of data cut-off (June 2023), 13 patients (72.2%) had stopped their treatment because of progressive disease and 3 (16.6%) due to toxicity. Two patients (11.1%) were still on treatment. The ORR was 61.1 % (11 of 18, 95% CI 35.7-82.7). CBR was 88.9% (16 of 18, 95% CI 65.3-98.6), and median PFS was 8.3 months (95% CI 7.3 – 14.1). Treatment-related adverse events (TRAEs) of any grade (G) occurred in 19 patients (95%), while 45% of patients experienced G3 TRAEs. No G4 or G5 TRAEs were reported in the evaluable population. Gene expression analysis was successful for all recruited patients (n=20). High expression of the PAM50 luminal A signature (p=0.049), and the luminal genes PGR (p=0.028) and RRAGA (p=0.038) were associated with worse PFS (univariate analyses). The pan-leucocyte receptor CD84 (p=0.028) was associated with better PFS (univariate analysis). Conclusions Pembrolizumab in combination with paclitaxel is safe and exhibits promising efficacy outcomes in patients with CDK4/6i resistant HR+/HER2- ABC with a PAM50 non-luminal subtype. Although meeting the criteria for stage II, the enrollment was stopped prematurely due to the lack of funding and pembrolizumab supply. More correlative analyses will be presented at the conference. This study was funded in part by MSD. Citation Format: Aleix Prat, Benedetta Conte, Fara Brasó-Maristany, Nuria Chic, Montserrat Muñoz, Cristina Hernando, Manuel Alva, Silvia Vazquez, Salvador Blanch, Mafalda Oliveira, Esther Fernández, Oleguer Castillo, Patricia Galván, Ángela Aguirre, Esther Sanfeliu, Lorea Villanueva, Tomás Pascual, Eva Ciruelos. Solti-1716 TATEN phase II trial: Targeting non-Luminal disease by PAM50 with pembrolizumab and paclitaxel in Hormone Receptor-positive/HER2-negative advanced breast cancer (ABC) [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-06-02.

Abstract PO1-28-04: PILHLE-001: neoadjuvant pyrotinib combined with chemotherapy in HR-positive, HER2-low (IHC 2+/FISH-negative) early breast cancer

Abstract Background: Hormone receptor (HR)-positive/HER2-low (IHC 2+/FISH negative or IHC 1+) breast cancers (BCs) represent the largest proportion of breast carcinomas. However, its response to neoadjuvant chemotherapy or endocrine therapy is the lowest, with a residual cancer burden (RCB) 0/I rate around 15%. Previous studies have demonstrated that pyrotinib (P), a pan-HER tyrosine kinase inhibitor, exhibits excellent response in HER2-positive early or advanced BC (E/ABC). In-vitro experiments have shown that pyrotinib can effectively inhibit colony formation in HER2-low (IHC 2+/FISH negative) BC cells. This PILHLE-001 study (NCT05165225) aimed to evaluate the efficacy and safety of neoadjuvant pyrotinib plus chemotherapy in HR-positive/HER2-low (IHC 2+/FISH negative) EBC patients with potential biomarkers. Methods: PILHLE-001, as a single-arm, single-center phase Ⅱ trial, enrolled patients with previously untreated HR-positive (ER or PR > 1%) and HER2-low (IHC 2+/FISH negative) invasive EBC (TNM stage II-III) to receive pyrotinib 320mg QD and four Q3W of epirubicin-cyclophosphamide followed by four Q3W of docetaxel. MammaPrint/BluePrint at baseline (t0) was assessed. Breast magnetic resonance imaging (MRI) was conducted at t0, the end of cycle 2 neoadjuvant therapy (t1), and the end of all neoadjuvant therapy. Immune cell subpopulations assay and gene sequencing of tumor tissues with whole blood control samples were performed at t0 and surgery (t2). Additional core biopsy was administered to reassess Ki67 and tumor infiltrating lymphocytes (TILs) at t1. The primary outcome was RCB 0/I rate. The short-term secondary outcomes included pathological complete response (pCR, ypT0/is ypN0) rate, objective response rate (ORR), breast conservation surgery (BCS) rate, safety, and exploratory biomarkers analysis. Results: From July 2021 to March 2023, 48 patients were enrolled and treated. The median age of the patients was 48 years (range 28-66), 43 (90%) had cT1-2 tumors, 30 (63%) showed no node involvement, 37 (77%) had tumours with TNM stage II, and 47 (98%) had ER expression ≥ 50%. Twenty-eight (61%) of 46 patients had MammaPrint high risk. Out of the 48 patients, 26 (54.2%) achieved RCB 0/I, with a 95% confidence interval of 39.2% to 68.6%. The RCB 0/I rate was particularly higher in tumors with no lymph node involvement (73.3%), TNM stage II (64.9%), or abundant tumor-infiltrating lymphocytes (66.7%). Three (6.3%) patients obtained a pCR. The rate of BCS was 60.4% (29/48). The ORR was 45.8% (22/48) at t1 and 81.3% (39/48) at the end of all neoadjuvant therapy, respectively. No patients had progressive disease. All treatment-related adverse events (AEs) were mostly of grade 1 or 2 severity. Grade ≥ 3 AEs occurred in 21 (44%) patients, with the most prevalent being diarrhea [10 (21%)]. All AEs were reversible with symptomatic treatment and no treatment-related deaths occurred. Patients with MammaPrint risk-low BC had a lower RCB 0/I rate than those with risk-high BC (60.7% vs. 44.4%), although the difference was not statistically significant. Baseline specific immune cell subpopulations (lower PD-1, higher CD3, etc.) or the presence of non-altered PIK3CA were significantly associated with a higher likelihood of achieving RCB 0/I. Similarly, objective response, greater declines in specific MRI quantitative parameters (Ktrans and Kep), greater declines in Ki67, or more increased TILs at t1 were also significantly associated with a higher rate of RCB 0/I. Conclusions: The PILHLE-001 trial first revealed that neoadjuvant pyrotinib plus chemotherapy has encouraging efficacy and acceptable toxicity in patients with HR-positive/HER2-low (IHC 2+/FISH negative) EBC, and this regimen warrants further investigation in phase III randomized controlled trials. Citation Format: Chang Gong, Yuan Xia, Yingying Zhu, Yaping Yang, Wenqian Yang, Louis W.C. Chow, Li Ling, Yunjie Zeng, Jiajie Zhong, Ziliang Cheng, Jun Shen, Qun Lin, Yinduo Zeng, Qiang Liu, Erwei Song. PILHLE-001: neoadjuvant pyrotinib combined with chemotherapy in HR-positive, HER2-low (IHC 2+/FISH-negative) early breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-28-04.

Utilizing Pharmacogenomic Data for a Safer Use of Statins among the Emirati Population.

Statins are the most prescribed lipid-lowering drugs worldwide. The associated adverse events, especially muscle symptoms, have been frequently reported despite their perceived safety. Three pharmacogenes, the solute carrier organic anion transporter family member 1B1 (SLCO1B1), ATP-binding cassette subfamily G member 2 (ABCG2), and cytochrome P450 2C9 (CYP2C9) are suggested as safety biomarkers for statins. The Clinical Pharmacogenomic Implementation Consortium (CPIC) issued clinical guidelines for statin use based on these three genes. The present study aimed to examine variants in these pharmacogenes to predict the safety of statin use among the Emirati population. Analyzing 242 whole exome sequencing data at the three genes enabled the determination of the frequencies of the single nucleotide polymorphisms (SNPs), annotating the haplotypes and the predicted functions of their proteins. In our cohort, 29.8% and 5.4% had SLCO1B1 decreased and poor function, respectively. The high frequency warns of the possibility of significant side effects of some statins and the importance of pharmacogenomic testing. We found a low frequency (6%) of the ABCG2:rs2231142 variant, which indicates the low probability of Emirati patients being recommended against higher rosuvastatin doses compared with other populations with higher frequencies of this variant. In contrast, we found high frequencies of the functionally impaired CYP2C9 alleles, which makes fluvastatin a less favorable choice. Among the sparse studies available, the present one demonstrates all SLCO1B1 and CYP2C9 function-impairing alleles among Emiratis. We highlighted how population-specific pharmacogenomic data can predict safer choices of statins, especially in understudied populations.

Efficacy and safety of anlotinib plus anti-PD-1 agents in patients with refractory advanced biliary tract cancers.

Anlotinib has demonstrated promising anti-tumor efficacy in various solid tumors. Additionally, there is evidence suggesting that immune therapy can enhance the systemic responses of anlotinib. This study aimed to assess the effectiveness and safety of combining anlotinib with PD-1 inhibitors compared to fluoropyrimidine-based chemotherapy as a second-line treatment option for advanced biliary tract cancers (BTCs). A total of 242 patients with BTCs were screened at the First Affiliated Hospital of Zhengzhou University from October 2015 to October 2022. Among them, 78 patients who received either anlotinib plus PD-1 inhibitors (AP) or fluoropyrimidine-based chemotherapy (FB) as second-line treatment were included in the study. The primary endpoint was progression-free survival (PFS), and the secondary endpoints included objective response rate (ORR), disease control rate (DCR), overall survival (OS), safety, and predictive tumor biomarkers. Among the 78 patients with BTCs, 39 patients received AP, while 39 patients were administered FB. The ORR in the AP group was 20.5%, compared to 5.1% in the FB group. The DCR was 87.2% in the AP group and 66.7% in the FB group. The AP group demonstrated significantly better ORR and DCR compared to the FB group (p=0.042, p=0.032). The median PFS and OS in the AP group were 7.9months (95% CI: 4.35-11.45) and 13.9months (95% CI: 5.39-22.41), respectively. In the FB group, the median PFS and OS were 4.1months (95% CI: 3.17-5.03) and 13.2months (95% CI: 8.72-17.68), respectively. The AP group exhibited significantly better median PFS than the FB group (p=0.027). In the subgroup analysis, patients without liver metastasis had a much longer PFS in the AP group compared to the FB group (14.3 vs. 5.5months, p=0.016). Similarly, patients with CEA≤5μg/L also demonstrated a longer PFS in the AP group compared to the FB group (8.7 vs. 3.9months, p=0.008). The combination of anlotinib and PD-1 inhibitors demonstrated a promising clinical effect compared to fluoropyrimidine-based chemotherapy in the second-line treatment of refractory advanced BTCs. Liver metastases and CEA levels may serve as predictive factors for identifying patients who may benefit from AP therapy.

Biomarkers of Efficacy and Safety of the Academic BCMA-CART ARI0002h for the Treatment of Refractory Multiple Myeloma.

B-cell maturation antigen (BCMA)-chimeric antigen receptor T-cells (CART) improve results obtained with conventional therapy in the treatment of relapsed/refractory multiple myeloma. However, the high demand and expensive costs associated with CART therapy might prove unsustainable for health systems. Academic CARTs could potentially overcome these issues. Moreover, response biomarkers and resistance mechanisms need to be identified and addressed to improve efficacy and patient selection. Here, we present clinical and ancillary results of the 60 patients treated with the academic BCMA-CART, ARI0002h, in the CARTBCMA-HCB-01 trial. We collected apheresis, final product, peripheral blood and bone marrow samples before and after infusion. We assessed BCMA, T-cell subsets, CART kinetics and antibodies, B-cell aplasia, cytokines, and measurable residual disease by next-generation flow cytometry, and correlated these to clinical outcomes. At cut-off date March 17, 2023, with a median follow-up of 23.1 months (95% CI, 9.2-37.1), overall response rate in the first 3 months was 95% [95% confidence interval (CI), 89.5-100]; cytokine release syndrome (CRS) was observed in 90% of patients (5% grades ≥3) and grade 1 immune effector cell-associated neurotoxicity syndrome was reported in 2 patients (3%). Median progression-free survival was 15.8 months (95% CI, 11.5-22.4). Surface BCMA was not predictive of response or survival, but soluble BCMA correlated with worse clinical outcomes and CRS severity. Activation marker HLA-DR in the apheresis was associated with longer progression-free survival and increased exhaustion markers correlated with poorer outcomes. ARI0002h kinetics and loss of B-cell aplasia were not predictive of relapse. Despite deep and sustained responses achieved with ARI0002h, we identified several biomarkers that correlate with poor outcomes.

Genetic biomarkers of methotrexate response and safety in Crohn's disease: Data from the Spanish ENEIDA registry.

Methotrexate (MTX) is used to induce and maintain remission in patients with steroid-dependent Crohn's disease (CD). Despite its proven efficacy, its use is limited due to associated adverse events. Polymorphisms involving folate pathway genes might influence MTX efficacy and toxicity. We aimed to assess the impact of certain polymorphisms on the therapeutic outcomes of MTX in CD. Patients with CD who exclusively followed MTX monotherapy and fulfilled inclusion criteria were identified from the GETECCU ENEIDA registry. Variants of ATIC, DHFR, MTHFR, SLC19A1, ABCB1 and ABCC3 genes were analysed and their association with efficacy and toxicity was assessed. A total of 129 patients were included in the analysis. MTX was used at a median weekly dose of 25 mg (interquartile range, 15-25 mg) and a median time of 14 months (interquartile range, 4-52 months). Thirty-seven percent of the patients achieved disease remission with MTX monotherapy, while 34% were nonresponders (MTX failure). MTX-related toxicity occurred in 40 patients (30%), leading to MTX discontinuation in 19%. DHFR rs408626 (odds ratio [OR] 3.12, 95% confidence interval [CI] 1.22-7.69; P = .017) and MTHFR rs1801133 (OR 2.86, 95% CI 1.23-6.68; P = .015) variants, and smoking (OR 2.61, 95% CI 1.12-6.05; P = .026) were associated with a higher risk of MTX failure. Additionally, the MTHFR rs1801131 variant was associated with a higher risk of MTX-related adverse effects (OR 2.78, 95% CI 1.26-6.13, P = .011). Our study shows that variants of MTHFR and DHFR genes may be associated with MTX efficacy and adverse events in patients with CD.

Low-dose interleukin 2 antidepressant potentiation in unipolar and bipolar depression: Safety, efficacy, and immunological biomarkers

Immune-inflammatory mechanisms are promising targets for antidepressant pharmacology. Immune cell abnormalities have been reported in mood disorders showing a partial T cell defect. Following this line of reasoning we defined an antidepressant potentiation treatment with add-on low-dose interleukin 2 (IL-2). IL-2 is a T-cell growth factor which has proven anti-inflammatory efficacy in autoimmune conditions, increasing thymic production of naïve CD4 + T cells, and possibly correcting the partial T cell defect observed in mood disorders. We performed a single-center, randomised, double-blind, placebo-controlled phase II trial evaluating the safety, clinical efficacy and biological responses of low-dose IL-2 in depressed patients with major depressive (MDD) or bipolar disorder (BD). 36 consecutively recruited inpatients at the Mood Disorder Unit were randomised in a 2:1 ratio to receive either aldesleukin (12 MDD and 12 BD) or placebo (6 MDD and 6 BD). Active treatment significantly potentiated antidepressant response to ongoing SSRI/SNRI treatment in both diagnostic groups, and expanded the population of T regulatory, T helper 2, and percentage of Naive CD4+/CD8 + immune cells. Changes in cell frequences were rapidly induced in the first five days of treatment, and predicted the later improvement of depression severity. No serious adverse effect was observed. This is the first randomised control trial (RCT) evidence supporting the hypothesis that treatment to strengthen the T cell system could be a successful way to correct the immuno-inflammatory abnormalities associated with mood disorders, and potentiate antidepressant response.

Clinical and biomarker analyses of hepatic arterial infusion chemotherapy plus lenvatinib and PD-1 inhibitor for patients with advanced intrahepatic cholangiocarcinoma.

Intrahepatic cholangiocarcinoma (iCCA) is a highly aggressive cancer with a dismal prognosis and few effective therapeutic approaches. This study aimed to investigate the efficacy, safety, and predictive biomarkers of hepatic arterial infusion chemotherapy (FOLFOX-HAIC) in combination with lenvatinib and PD-1 inhibitor for patients with advanced iCCA. Locally advanced or metastatic iCCA patients receiving the triple combination therapy of lenvatinib, PD-1 inhibitor, and FOLFOX-HAIC were included in this retrospective study. Primary endpoint was the progression-free survival, evaluated using the RECIST criterion. The secondary endpoints included overall survival, objective response rate, and safety. Whole exome and RNA sequencing of tumor biopsy tissues were performed for biomarker exploration. Between May, 2019 and December 2022, a total of 46 patients were included in this study. The primary endpoint showed a median progression-free survival of 9.40 months (95% CI: 5.28-13.52), with a 6-month progression-free survival rate of 76.1%. The median overall survival was 16.77 months (95% CI, 14.20-19.33), with an objective response rate of 47.8% and disease control rate of 91.3% per RECIST. In addition, 4.3% and 8.7% of patients achieved complete response of all lesions and intrahepatic target lesions per mRECIST, respectively. The most common treatment-related adverse events were neutropenia, thrombocytopenia, elevated aspartate aminotransferase and alanine aminotransferase level. Furthermore, integrated analysis of genetic, transcriptomic, and immunohistochemistry data revealed that pre-existing immunity (high expression level of immune-related signatures and intra-tumoral CD8+ T cell density) in baseline tumor tissues was associated with superior clinical benefits. However, the evaluation of tumor mutation burden did not show potential predictive value in this triple combination. FOLFOX-HAIC in combination with lenvatinib and PD-1 inhibitor demonstrated a promising antitumor activity with manageable safety profiles in patients with advanced iCCA. Moreover, our study also revealed new perspectives on potential biomarkers for clinical efficacy.

Magnitude of Urine Albumin and KIM-1 Changes Can be Used to Differentiate Glomerular Injury From Tubular Injury in Rats.

Emerging urinary kidney safety biomarkers have been evaluated in recent years and have been shown to be superior to the serum parameters blood urea nitrogen (BUN) and creatinine (sCr) for monitoring kidney injury in the proximal tubule. However, their potential application in differentiating the location of the initial kidney injury (eg, glomerulus vs tubule) has not been fully explored. Here, we assessed the performance of two algorithms that were constructed using either an empirical or a mathematical model to predict the site of kidney injury using a data set consisting of 22 rat kidney toxicity studies with known urine biomarker and histopathologic outcomes. Two kidney safety biomarkers used in both models, kidney injury molecule 1 (KIM-1) and albumin (ALB), were the best performers to differentiate glomerular injury from tubular injury. The performance of algorithms using these two biomarkers against the gold standard of kidney histopathologic examination showed high sensitivity in differentiating the location of the kidney damage to either the glomerulus or the proximal tubules. These data support the exploration of such an approach for use in clinical settings, leveraging urinary biomarker data to aid in the diagnosis of either glomerular or tubular injury where histopathologic assessments are not conducted.

What Have We Learned from Molecularly Informed Clinical Trials on Thymomas and Thymic Carcinomas-Current Status and Future Directions?

Thymic epithelial tumors (TETs), which include thymomas and thymic carcinomas, are a rare, heterogeneous group of malignancies that originate from the thymus gland. As an important organ of immune cell development, thymic tumors, particularly thymomas, are often associated with paraneoplastic autoimmune disorders. The advances in targeted therapies for both solid and hematologic malignancies have resulted in improved patient outcomes, including better and more durable efficacy and improved toxicity. Targeted therapies have also been investigated in the treatment of TETs, though the results have largely been modest. These have included somatostatin-receptor-targeting therapies, KIT- and EGFR-directed tyrosine kinase inhibitors, epigenetic modulators, anti-angiogenesis agents, and agents targeting the cell proliferation and survival pathways and cell cycle regulators. Numerous investigated treatments have failed or underperformed due to a lack of a strong biomarker of efficacy. Ongoing trials are attempting to expand on previous experiences, including the exploration of effective drugs in early-stage disease. Novel combination therapy strategies are also undergoing evaluation, with the goal of augmenting efficacy and understanding the toxicity while expanding the biomarkers of efficacy and safety. With advances in technology to improve target identification and drug delivery, old targets may become new opportunities, and the subsequently developed drugs may find their place in the treatment of thymic tumors.

Performance of biomarkers NF-L, NSE, Tau and GFAP in blood and cerebrospinal fluid in rat for the detection of nervous system injury.

Target organ toxicity is often a reason for attritions in nonclinical and clinical drug development. Leveraging emerging safety biomarkers in nonclinical studies provides an opportunity to monitor such toxicities early and efficiently, potentially translating to early clinical trials. As a part of the European Union's Innovative Medicines Initiative (IMI), two projects have focused on evaluating safety biomarkers of nervous system (NS) toxicity: Translational Safety Biomarker Pipeline (TransBioLine) and Neurotoxicity De-Risking in Preclinical Drug Discovery (NeuroDeRisk). Performance of fluid-based NS injury biomarker candidates neurofilament light chain (NF-L), glial fibrillary acidic protein (GFAP), neuron specific enolase (NSE) and total Tau in plasma and cerebrospinal fluid (CSF) was evaluated in 15 rat in vivo studies. Model nervous system toxicants as well as other compounds were used to evaluate sensitivity and specificity. Histopathologic assessments of nervous tissues and behavioral observations were conducted to detect and characterize NS injuries. Receiver operator characteristic (ROC) curves were generated to compare the relative performance of the biomarkers in their ability to detect NS injury. NF-L was the best performer in detecting both peripheral nervous system (PNS) and CNS injury in plasma, (AUC of 0.97-0.99; respectively). In CSF, Tau correlated the best with CNS (AUC 0.97), but not PNS injury. NSE and GFAP were suitable for monitoring CNS injury, but with lesser sensitivity. In summary, NF-L is a sensitive and specific biomarker in rats for detecting compound-induced central and peripheral NS injuries. While NF-L measurement alone cannot inform the site of the injury, addition of biomarkers like Tau and NSE and analysis in both blood and CSF can provide additional information about the origin of the NS injury. These results demonstrate the utility of emerging safety biomarkers of drug-induced NS injury in rats and provide additional supporting evidence for biomarker translation across species and potential use in clinical settings to monitor drug-induced NS injury in patients.

Abstract PR06: CD40 agonist mitazalimab in combination with mFOLFIRINOX in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC): Interim efficacy results of the OPTIMIZE-1 phase 1b/2 study

Abstract Mitazalimab is a human CD40 agonistic IgG1antibody. Targeting CD40 kickstarts the cancer immunity cycle by licensing dendritic cells leading to tumor specific T cell priming and activation. Furthermore, in PDAC CD40 agonists on myeloid cells promote degradation of the desmoplastic tumor stroma, improving influx of T cells and sensitizing the tumor to chemotherapeutic agents. OPTIMIZE-1 (NCT04888312) is a Phase 1b/2, open label, multicenter study designed to evaluate safety, tolerability, and efficacy of mitazalimab in combination with mFOLFIRINOX (Oxaliplatin 85 mg/m2, leucovorin 400 mg/m2, irinotecan 150 mg/m2, 5-FU 2.4 g/m2) in patients with previously untreated mPDAC. In the first part of the study (phase 1b), 900 µg/kg mitazalimab was selected as the recommended phase 2 dose (RP2D). In the first 21-day treatment cycle, mitazalimab is administered IV at RP2D on day 1 and 10 and mFOLFIRINOX infusion started on day 8. In subsequent cycles, treatment follows a 14-day cycle where mitazalimab is administered 2 days after mFOLFIRINOX. The primary endpoint of this ongoing study is overall response rate (ORR) per RECIST v1.1. Secondary and exploratory endpoints include duration of response, progression free and overall survival, safety, PK and PD biomarker assessments. As of May 24, 2023, study enrolment was complete, 65 patients were treated with mFOLFIRINOX and mitazalimab 900 µg/kg (RP2D). Interim efficacy analysis comprised of 57 evaluable patients. Median follow up was 6.5 months and median exposure to treatment was 5 months. 28 patients (49%) remain on treatment, 18 (32%) continued treatment beyond 6 months, the longest being 17 months (ongoing). ORR was 43.9% (25 patients with partial response), an additional 19 patients achieved stable disease, resulting in a 77.2% disease control rate. Median time to response was 2.2 months and median duration of response was 8.7 months. The most common grade (Gr) ≥3 TEAEs were neutropenia (21.5%), anemia (12.3%), thrombocytopenia (12.3%) and hypokalemia (12.3%). Mitazalimab related Gr >3 AEs occurring in more than one patient were fatigue in 3 (4.6%) patients, increased ALT in 3 (4.6%) patients, diarrhea in 2 (3.1%) patients, asthenia in 2 (3.1%) patients, increased AST in 2 (3.1%) patients, and hypokalemia in 2 (3.1%) patients. 25 patients (38.5%) experienced infusion reactions (all Gr 1-2, managed with symptomatic treatment, none amounting to cytokine release syndrome) and 7 (10.8%) patients discontinued treatment due to TEAEs (pneumonia, gastric obstruction, neuropathy, bacteremia, ileal obstruction, stroke, skin reaction). In this ongoing phase 1b/2 trial, 900 µg/kg mitazalimab has shown no evidence of additive toxicity when administered in combination with mFOLFIRINOX, allowing extended treatment until progression. Interim efficacy results demonstrate encouraging antitumor activity in mPDAC with good durability of responses, meriting continued development. Citation Format: Jean-Luc Van Laethem, Karen P. Geboes, Philippe A. Cassier, Ivan Borbath, Aurélien Lambert, Emmanuel Mitry, Hans Prenen, Jean-Frédéric Blanc, Lorenzo Pilla, Mercedes Rodriguez Garrote, Roberto A. Pazo Cid, Inmaculada Gallego, Jaime Feliú, Karin Nordbladh, Peter Ellmark, Malin Carlsson, Yago Pico de Coaña, Sumeet V. Ambarkhane, Teresa Macarulla. CD40 agonist mitazalimab in combination with mFOLFIRINOX in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC): Interim efficacy results of the OPTIMIZE-1 phase 1b/2 study [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr PR06.

Durable response after tisagenlecleucel in adults with relapsed/refractory follicular lymphoma: ELARA trial update

AbstractTisagenlecleucel is approved for adults with relapsed/refractory (r/r) follicular lymphoma (FL) in the third- or later-line setting. The primary analysis (median follow-up, 17 months) of the phase 2 ELARA trial reported high response rates and excellent safety profile in patients with extensively pretreated r/r FL. Here, we report longer-term efficacy, safety, pharmacokinetic, and exploratory biomarker analyses after median follow-up of 29 months (interquartile range, 22.2-37.7). As of 29 March 2022, 97 patients with r/r FL (grades 1-3A) received tisagenlecleucel infusion (0.6 × 108-6 × 108 chimeric antigen receptor–positive viable T cells). Bridging chemotherapy was allowed. Baseline clinical factors, tumor microenvironment, blood soluble factors, and circulating blood cells were correlated with clinical response. Cellular kinetics were assessed by quantitative polymerase chain reaction. Median progression-free survival (PFS), duration of response (DOR), and overall survival (OS) were not reached. Estimated 24-month PFS, DOR, and OS rates in all patients were 57.4% (95% confidence interval [CI], 46.2-67), 66.4% (95% CI, 54.3-76), and 87.7% (95% CI, 78.3-93.2), respectively. Complete response rate and overall response rate were 68.1% (95% CI, 57.7-77.3) and 86.2% (95% CI, 77.5-92.4), respectively. No new safety signals or treatment-related deaths were reported. Low levels of tumor-infiltrating LAG3+CD3+ exhausted T cells and higher baseline levels of naïve CD8+ T cells were associated with improved outcomes. Tisagenlecleucel continued to demonstrate highly durable efficacy and a favorable safety profile in this extended follow-up of 29 months in patients with r/r FL enrolled in ELARA. This trial was registered at www.clinicaltrials.gov as #NCT03568461.

Pharmacokinetics and coagulation biomarkers in children and adults with hemophilia A receiving emicizumab prophylaxis every 1, 2, or 4 weeks

BackgroundEmicizumab is a bispecific antibody that bridges activated factor (F)IX and FX, mimicking the function of missing activated FVIII and thus improving hemostasis in people with hemophilia A. The efficacy and safety of emicizumab were demonstrated in 4 phase III clinical trials (HAVEN 1-4). ObjectivesHere, we describe pharmacokinetics (PKs), pharmacodynamics (PDs), and exploratory safety biomarkers in HAVEN 1 to 4. MethodsParticipants received emicizumab at a loading dose of 3 mg/kg weekly for 4 weeks, followed by maintenance doses of 1.5 mg/kg weekly, 3 mg/kg every 2 weeks, or 6 mg/kg every 4 weeks. PKs, PDs, and safety biomarkers were assessed in samples collected at regular intervals during the trials. ResultsEmicizumab plasma trough concentrations increased during the loading dose period, reaching a mean of 52.9 μg/mL (SD, 13.6 μg/mL) at week 5, and were sustained at 42.1 to 52.3 μg/mL thereafter with maintenance dosing. Activated partial thromboplastin time shortened following the first emicizumab dose. Mean FVIII-like activity and thrombin generation peak height increased to 25.2 IU/dL (SD, 6.9 IU/dL) and 115.2 nM (SD, 42.5 nM) at week 5, with levels sustained at 17 to 23 IU/dL and >116 nM thereafter, respectively. Emicizumab did not notably affect FIX or FX plasma antigen levels, prothrombin time, or concentrations of exploratory safety markers of coagulation activation (D-dimer, prothrombin fragment 1 + 2, and fibrinogen). ConclusionIn HAVEN 1 to 4, emicizumab demonstrated sustained PKs and PDs and improved coagulation parameters without affecting safety biomarkers.