Advanced Solid Tumors Research Articles

Detrimental effect of an early exposure to antibiotics on the outcomes of immunotherapy in a multi-tumor cohort of patients.

Immune checkpoint inhibitors (ICI) have changed the therapeutic landscape of many solid tumors. Modulation of the intestinal microbiota by antibiotics (Abx) has been suggested to impact on ICI outcomes. Retrospective analysis of 475 patients with advanced solid tumors treated with ICI from 2015 to 2022. For each patient, the use of Abx was recorded from 1 month before ICI initiation until disease progression or death. The impact of Abx on objective response rates (ORR), disease control rates (DCR), progression-free survival (PFS), and overall survival (OS) was analyzed. Kaplan-Meier and log-rank tests were used to compare survival outcomes. In total 475 patients with advanced solid tumors were evaluated. Median age was 67.5 years and performance status (PS) was 0-1 in 84.6%. 66.5% of patients received Abx during treatment with ICI, mainly beta-lactams (53.8%) and quinolones (35.9%). The early exposure to Abx (from 60 days before to 42 days after the first cycle of ICI) was associated with a lower ORR (27.4% vs 39.4%; P < .01), a lower DCR (37.3% vs 57.4%; P < .001), lower PFS (16.8 m vs 27.8 m; HR 0.66; P < .001]) and lower OS (2.5 m vs 6.6 m; HR 0.68; P = .001]). The negative impact of Abx on OS and PFS was confirmed by a multivariable analysis. This effect was not observed among patients receiving Abx after 6 weeks from ICI initiation. Our results validate the hypothesis of a detrimental effect of an early exposure to Abxon the efficacy of ICI in a multi-tumor cohort of patients.

Probiotic neoantigen delivery vectors for precision cancer immunotherapy.

Microbial systems have been synthetically engineered to deploy therapeutic payloads in vivo1,2. With emerging evidence that bacteria naturally home in on tumours3,4 and modulate antitumour immunity5,6, one promising application is the development of bacterial vectors as precision cancer vaccines2,7. Here we engineered probiotic Escherichia coli Nissle 1917 as an antitumour vaccination platform optimized for enhanced production and cytosolic delivery of neoepitope-containing peptide arrays, with increased susceptibility to blood clearance and phagocytosis. These features enhance both safety and immunogenicity, achieving a system that drives potent and specific T cell-mediated anticancer immunity that effectively controls or eliminates tumour growth and extends survival in advanced murine primary and metastatic solid tumours. We demonstrate that the elicited antitumour immune response involves recruitment and activation of dendritic cells, extensive priming and activation of neoantigen-specific CD4+ and CD8+ T cells, broader activation of both T and natural killer cells, and a reduction of tumour-infiltrating immunosuppressive myeloid and regulatory T and B cell populations. Taken together, this work leverages the advantages of living medicines to deliver arrays of tumour-specific neoantigen-derived epitopes within the optimal context to induce specific, effective and durable systemic antitumour immunity.

Targeting the FGFR Pathway in Patients with Advanced Solid Tumors.

In the phase II FUZE trial targeting the FGFR pathway, Debio 1347 showed limited antitumor activity and manageable toxicity in patients with advanced solid tumors. Results from transcriptome-based analysis enhanced our understanding of the genomic landscape of FGFR fusion-driven tumors, informing clinical trial design and generating hypotheses for resistance mechanisms. See related article by Grivas et al., p. 4572.

Comprehensive biomarker and modeling approach to support dose finding for BI 836880, a VEGF/Ang-2 inhibitor

BackgroundBI 836880 is a humanized bispecific nanobody® that binds to and blocks vascular endothelial growth factor (VEGF) and angiopoietin-2 (Ang-2). A comprehensive biomarker and modeling approach is presented here that supported dose finding for BI 836880.MethodsTwo Phase I dose-escalation studies (1336.1 [NCT02674152], 1336.6 [NCT02689505]) assessed BI 836880 in adults with confirmed locally advanced or metastatic solid tumors, refractory to standard therapy or for which standard therapy was not reliably effective. Two dosing schedules were investigated, 3 weeks (q3w) or once weekly (qw), starting at a dose of 40 mg. In a comprehensive biomarker approach, soluble pharmacodynamic markers (free and total plasma VEGF-A and Ang-2), as well as circulating angiogenic factors (soluble VEGF3, soluble Tie2 and placenta growth factor, amongst others) were analyzed to assess target engagement in peripheral blood for q3w doses. A Population based pharmacokinetics/pharmacodynamics (PopPK/PD) model was built using the limited Phase I dataset to support dose finding by simulations. In order to demonstrate drug activity in the tumor, dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) was applied.ResultsDCE-MRI scans supported target engagement in the tumor. Free VEGF-A was depleted at all doses, whereas free Ang-2 decreased dose-dependently, reaching depletion in most patients from 360 mg q3w onwards. While total VEGF-A levels increased in a dose-dependent manner, reaching saturation at 360 mg q3w, total Ang-2 levels increased, but did not plateau. Angiogenic biomarkers showed changes from doses ≥ 360 mg q3w. PopPK/PD modeling showed that doses ≥ 360 mg q3w led to > 90% inhibition of free Ang-2 at steady-state in most patients. By increasing the dose to ≥ 500 mg q3w, > 90% of patients are expected to achieve this level.ConclusionsThe comprehensive analyses of multiple target engagement markers support BI 836880 720 mg q3w as a biologically relevant monotherapy dose schedule.Trial registration: NCT02674152 and NCT02689505.

A first-in-human phase 1 study of BXQ-350, a first-in-class sphingolipid metabolism regulator, in patients with advanced/recurrent solid tumors or high-grade gliomas.

BXQ-350, a nanovesicle formulation of Saposin C, is an allosteric sphingolipid metabolism regulator that increases pro-apoptotic ceramide and decreases oncogenic sphingosine-1-phosphate (S1P) levels. We conducted a first-in-human, phase 1 study of BXQ-350. Adults (≥18 years old) with advanced/recurrent, treatment-refractory solid tumors or high-grade gliomas received BXQ-350 intravenously in five dose cohorts (0.7-2.4 mg/kg) in a 3+3 dose-escalation and expansion design. Primary endpoints during dose escalation were dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD); primary objective in expansion parts was assessment of anti-tumor activity (RECIST v1.1/RANO criteria). Eighty-six patients were enrolled. DLTs were not observed during dose escalation (n=18), and a MTD was not identified. An additional 68 patients received the 2.4 mg/kg dose. Nine patients (10%) discontinued due to adverse events (AEs). The most common treatment-related AEs were nausea (24%) and fatigue (23%). Eight patients had a progression-free survival (PFS) ≥6 months. Two of these achieved a partial response, and six had stable disease, among whom three had a reduction in ≥1 target lesion. Of those with PFS ≥6 months, seven remained on study for >12 months, five for >24 months, and after seven years, two remained on study without disease progression. BXQ-350 was well tolerated as monotherapy at doses up to 2.4 mg/kg. It provided some lasting clinical benefit in patients with recurrent solid malignancies across several tumor types, consistent with a decreased systemic S1P/ceramide metabolic rheostat. BXQ-350 warrants further clinical investigation alone and combined with standard-of-care for advanced solid tumors.

Toripalimab in combination with HBM4003, an anti-CTLA-4 heavy chain-only antibody, in advanced melanoma and other solid tumors: an open-label phase I trial

BackgroundHBM4003 is a novel anti-CTLA-4 heavy chain-only antibody, designed to enhance Treg ablation and antibody-dependent cell-mediated cytotoxicity while ensuring a manageable safety profile. This phase I trial investigated the safety,...

An Ultra-Fast Green UHPLC-MS/MS Method for Assessing the In Vitro Metabolic Stability of Dovitinib: In Silico Study for Absorption, Distribution, Metabolism, Excretion, Metabolic Lability, and DEREK Alerts.

Background and Objectives: Dovitinib (DVB) is a pan-tyrosine kinase inhibitor (TKI) that can be administered orally. In September 2023, the FDA granted Oncoheroes approval to proceed with an Investigational New Drug (IND) application for dovitinib. This application is intended for the treatment of relapsed or advanced juvenile solid tumors, namely, osteosarcoma. Materials and Methods: The target of the present study was to develop a rapid, green, accurate, and sensitive UHPLC-MS/MS method for measuring DVB levels in human liver microsomes (HLMs). The validations of the HLMs were performed via the established UHPLC-MS/MS approach, as stated in the US FDA reported guidelines for the standards of bioanalytical method validation protocol. The StarDrop in silico software package (version 6.6), which involves the DEREK and WhichP450 in silico modules, was used to check the DVB structure for hazardous alerts and metabolic instability. The DVB and encorafenib (EFB), internal standard, and chromatographic peaks were successfully separated using a reversed phase column (an Eclipse Plus Agilent C8 column) and an isocratic mobile phase. The production of DVB parent ions was accomplished by utilizing the positive ionization mode of an ESI source. The identification and measurement of DVB daughter ions were conducted using the MRM mode. Results: The inter-day accuracy and precision exhibited a spectrum of values in the range of -0.56% to 9.33%, while the intra-day accuracy and precision showcased a range of scores between 0.28% and 7.28%. The DVB calibration curve showed a linear relationship that ranged from 1 to 3000 ng/mL. The usefulness of the currently validated UHPLC-MS/MS method was approved by the lower limit of quantification (LLOQ) of 1 ng/mL. The AGREE findings demonstrate that the UHPLC-MS/MS method had a noteworthy degree of ecological greenness. The in vitro half-life (t1/2) and intrinsic clearance (Clint) of DVB were calculated to be 15.48 min and 52.39 mL/min/kg, respectively, which aligned with the findings from the WhichP450 software (version 6.6). Conclusions: Via the usage of in silico software, it has been observed that making small changes to the structure of the aryl piperazine ring and quinolinone moieties, or replacing these groups in the drug design process, shows potential for enhancing the metabolic safety and stability of newly developed derivatives compared to DVB.

Tissue-Agnostic Targeting of Neurotrophic Tyrosine Receptor Kinase Fusions: Current Approvals and Future Directions.

NTRK fusions are oncogenic drivers for multiple tumor types. Therefore, the development of selective tropomyosin receptor kinase (TRK) inhibitors, including larotrectinib and entrectinib, has been transformative in the context of clinical management, given the high rates of responses to these drugs, including intracranial responses in patients with brain metastases. Given their promising activity in pan-cancer cohorts, larotrectinib and entrectinib received U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) approval for tissue-agnostic indications in patients with advanced solid tumors harboring NTRK fusions. The safety profiles for both drugs are quite manageable, although neurotoxicity driven by the on-target inhibition of normal NTRK can be a concern. Also, on- and off-target resistance mechanisms can arise during therapy with TRK inhibitors, but they can be addressed with the use of combination therapy and next-generation TRK inhibitors. More recently, the FDA approved the use of repotrectinib, a second-generation TRK inhibitor, in patients with NTRK fusions, based on data suggesting clinical efficacy and safety, which could offer another tool for the treatment of NTRK-altered cancers. In this review, we summarize the current evidence related to the use of TRK inhibitors in the tissue-agnostic setting. We also elaborate on the safety profiles and resistance mechanisms from a practical perspective.

Development and validation of a new tool to estimate early mortality in patients with advanced cancer treated with immunotherapy

BackgroundImmune checkpoint inhibitors (ICIs) are standard treatments for advanced solid cancers. Resistance to ICIs, both primary and secondary, poses challenges, with early mortality (EM) within 30–90 days indicating a lack of benefit. Prognostic factors for EM, including the lung immune prognostic index (LIPI), remain underexplored.MethodsWe performed a retrospective, observational study including patients affected by advanced solid tumors, treated with ICI as single agent or combined with other agents. Logistic regression models identified factors associated with EM and 90-day progression risks. A nomogram for predicting 90-day mortality was built and validated within an external cohort.ResultsIn total, 637 patients received ICIs (single agent or in combination with other drugs) for advanced solid tumors. Most patients were male (61.9%), with NSCLC as the prevalent tumor (61.8%). Within the cohort, 21.3% died within 90 days, 8.4% died within 30 days, and 34.5% experienced early progression. Factors independently associated with 90-day mortality included ECOG PS 2 and a high/intermediate LIPI score. For 30-day mortality, lung metastasis and a high/intermediate LIPI score were independent risk factors. Regarding early progression, high/intermediate LIPI score was independently associated. A predictive nomogram for 90-day mortality combining LIPI and ECOG PS achieved an AUC of 0.76 (95% CI 0.71–0.81). The discrimination ability of the nomogram was confirmed in the external validation cohort (n = 255) (AUC 0.72, 95% CI 0.64–0.80).ConclusionLIPI and ECOG PS independently were able to estimate 90-day mortality, with LIPI also demonstrating prognostic validity for 30-day mortality and early progression.

Tolerability Assessment of Tyrosine Kinase Inhibitors in Patients With Solid Tumor Malignancies and Hypoalbuminemia.

Hypoalbuminemia is common in patients with advanced solid tumor malignancies. However, despite the increased use of highly protein-bound tyrosine kinase inhibitors (TKIs) in cancer treatments, the tolerability of these agents in patients with hypoalbuminemia is not fully known. Our aim is to assess whether patients on oral TKIs with hypoalbuminemia are at higher risk for experiencing medication-related adverse events, therefore requiring careful considerations. This is a single-center, retrospective study including patients ≥18 years of age with a solid tumor malignancy who had taken at least one dose of oral TKIs with a protein binding of ≥90% between June 1, 2016, and June 1, 2021. The primary outcome was to compare time to TKI discontinuation due to adverse events between patients with and without hypoalbuminemia. Key secondary outcomes include TKI discontinuation and dose reduction rates, time to TKI dose reduction, and severity of adverse events. Out of 282 included patients, 134 (48%) patients had hypoalbuminemia and 148 (52%) had normal albumin levels. Compared with patients without hypoalbuminemia, patients with hypoalbuminemia had shorter median time on treatment at 2.8 months (95% CI = 2.3-4.5 months) versus 4.3 months (95% CI = 2.8-6.4 months; P = 0.003). In patients who had TKI discontinuation, dose reduction was associated with longer time on treatment in patients in the normal albumin group compared with patients in the hypoalbuminemia group or patients without dose reduction (P < 0.0001). Patients in the hypoalbuminemia group experienced significantly more grade 3/4 adverse events compared with those in the normal albumin group (73% vs 27%, P < 0.0001). Hypoalbuminemia is a risk factor for both shorter time on treatment and more severe adverse events in patients with solid tumor malignancies taking highly protein-bound oral TKIs. This study highlights the need for closer monitoring of this patient population by health care providers.

Molecular and functional landscape of malignant serous effusions for precision oncology

Personalized treatment for patients with advanced solid tumors critically depends on the deep characterization of tumor cells from patient biopsies. Here, we comprehensively characterize a pan-cancer cohort of 150 malignant serous effusion (MSE) samples at the cellular, molecular, and functional level. We find that MSE-derived cancer cells retain the genomic and transcriptomic profiles of their corresponding primary tumors, validating their use as a patient-relevant model system for solid tumor biology. Integrative analyses reveal that baseline gene expression patterns relate to global ex vivo drug sensitivity, while high-throughput drug-induced transcriptional changes in MSE samples are indicative of drug mode of action and acquired treatment resistance. A case study exemplifies the added value of multi-modal MSE profiling for patients who lack genetically stratified treatment options. In summary, our study provides a functional multi-omics view on a pan-cancer solid tumor cohort and underlines the feasibility and utility of MSE-based precision oncology.

Preclinical investigations and a first-in-human phase 1a trial of JS007, a novel anti-CTLA-4 antibody, in patients with advanced solid tumors

Abstract Background Blocking cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) shows substantial antitumor efficacy. Here, we report the preclinical data and outcomes of a first-in-human phase 1a trial of JS007, a novel anti-CTLA-4 antibody, in advanced solid tumors. Methods In preclinical studies, both in vitro characteristics and in vivo characteristics of JS007 were investigated. The clinical trial included a dose escalation phase and a dose expansion phase. Eligible patients with previously treated advanced solid tumors were enrolled. In the dose escalation phase, JS007 was administered intravenously every 3 weeks at doses of 0.03, 0.3, 1, 3, and 10 mg/kg. Then, 3 and 10 mg/kg were chosen for the dose expansion phase. The primary endpoints included the maximum tolerated dose (MTD) of JS007 based on dose-limiting toxicities (DLTs) and safety. Results JS007 could effectively bind to CTLA-4 and induce an immune response in vitro. Potent in vivo antitumor activity of JS007 was observed. Increased T cell infiltration and T regulatory (Treg) cell depletion in tumor microenvironment of cancer cell xenografts were detected after treated with JS007. Pharmacological analysis in experimental animals showed a dose-proportional increase in exposure. In the clinical trial, a total of 28 patients were treated with JS007 across 5 dose levels. No DLTs occurred. The MTD did not reach at the highest dose tested (10 mg/kg). Twenty-three (82.1%) patients experienced at least one treatment-related adverse event (TRAE). The incidence of Grade ≥ 3 TRAEs was 28.6% (8/28) with alanine aminotransferase increase (7.1%, 2/28) being the most frequently reported TRAE. No severe immune-related adverse event (irAE) occurred. Pharmacological profiles of JS007 in patients were similar to those in animal models. Serum concentration of JS007 showed a dose-dependent escalation, and the half-life of JS007 was 9.4 ~ 12.2 days. Treatment-induced anti-drug antibody was detected in 2 patients. The disease control rate was 50% (14/28), and the median overall survival was 14.7 months. Conclusions JS007 preliminarily demonstrates good tolerance and encouraging antitumor activity in patients with previously treated advanced solid tumors. Trial registration ClinicalTrials.gov identifier: NCT05049265 (Sep 20, 2021).

71 (PB059): The efficacy and safety of a selective PARP1 inhibitor ACE-86225106 in patients with advanced solid tumors: preliminary results from a first-inhuman phase 1/2 study

71 (PB059): The efficacy and safety of a selective PARP1 inhibitor ACE-86225106 in patients with advanced solid tumors: preliminary results from a first-inhuman phase 1/2 study

P4.11D.03 Trial in Progress: Phase 1/2 Study of OBX-115 Engineered Tumor-Infiltrating Lymphocyte (TIL) Cell Therapy in Patients with Advanced Solid Tumors

P4.11D.03 Trial in Progress: Phase 1/2 Study of OBX-115 Engineered Tumor-Infiltrating Lymphocyte (TIL) Cell Therapy in Patients with Advanced Solid Tumors

444 (PB432): First-in-human phase 1 study of RGT-264, a potent hematopoietic progenitor kinase 1 (HPK1) inhibitor in patients (pts) with advanced solid tumors

444 (PB432): First-in-human phase 1 study of RGT-264, a potent hematopoietic progenitor kinase 1 (HPK1) inhibitor in patients (pts) with advanced solid tumors

1 Oral: First Clinical Results from A Phase 1 Trial of PRT3789, a First-in-Class Intravenous SMARCA2 Degrader, in Patients with Advanced Solid Tumors with a SMARCA4 Mutation

1 Oral: First Clinical Results from A Phase 1 Trial of PRT3789, a First-in-Class Intravenous SMARCA2 Degrader, in Patients with Advanced Solid Tumors with a SMARCA4 Mutation

MO25-3 Safety and pharmacokinetics of tusamitamab ravtansine dosing Q3W in Japanese patients with advanced solid tumors

MO25-3 Safety and pharmacokinetics of tusamitamab ravtansine dosing Q3W in Japanese patients with advanced solid tumors

503LBA LBA Orals: Results from CA240-0007, a phase 1/2 multiple expansion cohort study of BMS-986504 in patients (pts) with advanced solid tumors with homozygous MTAP deletion (MTAP-del)

503LBA LBA Orals: Results from CA240-0007, a phase 1/2 multiple expansion cohort study of BMS-986504 in patients (pts) with advanced solid tumors with homozygous MTAP deletion (MTAP-del)

121 (PB109): TT125-802, a highly selective bromodomain inhibitor of CBP/p300, in patients with advanced solid tumors: an update on the phase I study

121 (PB109): TT125-802, a highly selective bromodomain inhibitor of CBP/p300, in patients with advanced solid tumors: an update on the phase I study

MA16.07 A First in Human (FIH), Phase 1 Open Label, Dose Escalation and Expansion Study of CTM103, a LNP MRNA Encoding an IL2Rß? Selective Il-2v, As Monotherapy and in Combination with Pembrolizumab, in Patients with Advanced Solid Tumors

MA16.07 A First in Human (FIH), Phase 1 Open Label, Dose Escalation and Expansion Study of CTM103, a LNP MRNA Encoding an IL2Rß? Selective Il-2v, As Monotherapy and in Combination with Pembrolizumab, in Patients with Advanced Solid Tumors