Safety and clinical activity of JNJ-78306358, a human leukocyte antigen-G (HLA-G) x CD3 bispecific antibody, for the treatment of advanced stage solid tumors.

BACKGROUND: JNJ-78306358 is a bispecific antibody that redirects T cells to kill human leukocyte antigen-G (HLA-G)-expressing tumor cells. This dose escalation study evaluated the safety, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of JNJ-78306358 in patients with advanced solid tumors. METHODS: Adult patients with metastatic/unresectable solid tumors with high prevalence of HLA-G expression were enrolled. Dose escalation was initiated with once-weekly subcutaneous administration with step-up dosing to mitigate cytokine release syndrome (CRS). RESULTS: Overall, 39 heavily pretreated patients (colorectal cancer: n = 23, ovarian cancer: n = 10, and renal cell carcinoma: n = 6) were dosed in 7 cohorts. Most patients (94.9%) experienced ≥ 1 treatment-emergent adverse events (TEAEs); 87.2% had ≥ 1 related TEAEs. About half of the patients (48.7%) experienced CRS, which were grade 1/2. Nine patients (23.1%) received tocilizumab for CRS. No grade 3 CRS was observed. Dose-limiting toxicities (DLTs) of increased transaminases, pneumonitis and recurrent CRS requiring a dose reduction were reported in 4 patients, coinciding with CRS. No treatment-related deaths reported. No objective responses were noted, but 2 patients had stable disease > 40 weeks. JNJ-78306358 stimulated peripheral T cell activation and cytokine release. Anti-drug antibodies were observed in 45% of evaluable patients with impact on exposure. Approximately half of archival tumor samples (48%) had expression of HLA-G by immunohistochemistry. CONCLUSION: JNJ-78306358 showed pharmacodynamic effects with induction of cytokines and T cell activation. JNJ-78306358 was associated with CRS-related toxicities including increased transaminases and pneumonitis which limited its dose escalation to potentially efficacious levels. Trial registration number ClinicalTrials.gov (No. NCT04991740).

Effect of early vs. delayed extubation on functional outcome among patients with acute ischemic stroke treated with endovascular thrombectomy under general anesthesia: the prospective, randomized controlled EDESTROKE trial study protocol.

BACKGROUND: Recent meta-analyses and randomized studies have shown that among patients with acute ischemic stroke undergoing endovascular thrombectomy, general anesthesia with mechanical ventilation is associated with better functional status compared to local anesthesia and sedation, and they recommend its use. But once the procedure is completed, when is the optimal moment for extubation? Currently, there are no guidelines recommending the optimal moment for extubation. Prolonged mechanical ventilation time could potentially be linked to increased complications such as pneumonia or disturbances in cerebral blood flow due to the vasodilatation produced by most anesthetic drugs. However, premature extubation in a patient who has suffered a stroke could led to complications such as agitation, disorientation, abolished reflexes, sudden fluctuations in blood pressure, alterations in cerebral blood flow, respiratory distress, bronchial aspiration, and the need for reintubation. We therefore designed a randomized study hypothesizing that early compared with delayed extubation is associated with a better functional outcome 3 months after endovascular thrombectomy treatment under general anesthesia for acute ischemic stroke. METHODS: This investigator-initiated, single-center, prospective, parallel, evaluated blinded, superiority, randomized controlled trial will include 178 patients with a proximal occlusion of the anterior circulation treated with successful endovascular thrombectomy (TICI 2b-3) under general anesthesia. Patients will be randomly allocated to receive early (< 6 h) or delayed (6-12 h) extubation after the procedure. The primary outcome measure is functional independence (mRS of 0-2) at 90 days, measured with the modified Rankin Score (mRS), ranging from 0 (no symptoms) to 6 (death). DISCUSSION: This will be the first trial to compare the effect of mechanical ventilation duration (early vs delayed extubation) after satisfactory endovascular thrombectomy for acute ischemic stroke under general anesthesia. TRIAL REGISTRATION: The study protocol was approved April 11, 2023, by the by the Santiago-Lugo Research Ethics Committee (CEI-SL), number 2023/127, and was registered into the clinicaltrials.gov clinical trials registry with No. NCT05847309. Informed consent is required. Participant recruitment begins on April 18, 2023. The results will be submitted for publication in a peer-reviewed journal and presented at one or more scientific conferences.

Safety, pharmacokinetics, pharmacodynamics, and antitumor activity of SAR439459, a TGFß inhibitor, as monotherapy and in combination with cemiplimab in patients with advanced solid tumors: Findings from a phase 1/1b study.

SAR439459 (SAR'459), a "second-generation" human anti-transforming growth factor beta (TGFß) monoclonal antibody, enhances the activity of immune checkpoint inhibitors. In this phase I/Ib study, we evaluated the safety, pharmacokinetics (PK), pharmacodynamics, and antitumor activity of SAR'459 ± cemiplimab (intravenous) in patients with advanced solid tumors. Increasing doses of SAR'459 were administered every 2 or 3 weeks (Q2W, Q3W) alone (Part 1A) or with 3 mg/kg cemiplimab Q2W or 350 mg Q3W (Part 1B). In Part 2A (dose expansion), melanoma patients were randomly (1:1) administered 22.5 or 7.5 mg/kg SAR'459. In Part 2B (dose expansion), 22.5 mg/kg SAR'459 and 350 mg cemiplimab Q3W were administered. The primary end points were maximum tolerated dose (MTD) or maximum administered dose (MAD; Part 1), preliminary antitumor activity (Part 2B), and optimal monotherapy dose (Part 2A). Twenty-eight and 24 patients were treated in Parts 1A and 1B, respectively; MTD was not reached, MAD was 15 (Q2W) and 22.5 mg/kg (Q3W) alone and in combination, respectively. Fourteen and 95 patients, including 14 hepatocellular carcinoma (HCC) patients, were treated in Parts 2A and 2B, respectively. The population PK model yielded satisfactory goodness-of-fit plots and adequately described the observed data by a two-compartment PK model with linear elimination. Objective responses were not observed in Parts 1 and 2A. In Part 2B, objective response rate was 8.4% and 7.1% across tumor types and the HCC cohort, respectively. The most frequent treatment-emergent adverse effects were hemorrhagic events (43.5%), keratoacanthoma (6.8%), and skin neoplasms (6.2%). Fatal bleeding occurred in 21.4% HCC patients despite the implementation of mitigation measures. SAR'459 monotherapy and combination with cemiplimab appeared relatively safe and tolerable in limited number of patients in dose escalation. However, the study was discontinued due to the unclear efficacy of SAR'459 and bleeding risk, particularly in HCC patients.

Agnostic drug development revisited.

The advent of molecular profiling and the generalization of next generation sequencing in oncology has enabled the identification of patients who could benefit from targeted agents. Since the tumor-agnostic approval of pembrolizumab for patients with MSI-High tumors in 2017, different molecularly-guided therapeutics have been awarded approvals and progressively incorporated in the treatment landscape across multiple tumor types. As the number of tumor-agnostic targets considered druggable expands in the clinic, novel challenges will reshape the drug development field involving all the stakeholders in oncology. In this review, we provide an overview of current tumor-agnostic approvals and discuss promising candidate therapeutics for tumor-agnostic designation and challenges for their broad implementation.

Identification of Precise 3D CT Radiomics for Habitat Computation by Machine Learning in Cancer.

Purpose To identify precise three-dimensional radiomics features in CT images that enable computation of stable and biologically meaningful habitats with machine learning for cancer heterogeneity assessment. Materials and Methods This retrospective study included 2436 liver or lung lesions from 605 CT scans (November 2010-December 2021) in 331 patients with cancer (mean age, 64.5 years ± 10.1 [SD]; 185 male patients). Three-dimensional radiomics were computed from original and perturbed (simulated retest) images with different combinations of feature computation kernel radius and bin size. The lower 95% confidence limit (LCL) of the intraclass correlation coefficient (ICC) was used to measure repeatability and reproducibility. Precise features were identified by combining repeatability and reproducibility results (LCL of ICC ≥ 0.50). Habitats were obtained with Gaussian mixture models in original and perturbed data using precise radiomics features and compared with habitats obtained using all features. The Dice similarity coefficient (DSC) was used to assess habitat stability. Biologic correlates of CT habitats were explored in a case study, with a cohort of 13 patients with CT, multiparametric MRI, and tumor biopsies. Results Three-dimensional radiomics showed poor repeatability (LCL of ICC: median [IQR], 0.442 [0.312-0.516]) and poor reproducibility against kernel radius (LCL of ICC: median [IQR], 0.440 [0.33-0.526]) but excellent reproducibility against bin size (LCL of ICC: median [IQR], 0.929 [0.853-0.988]). Twenty-six radiomics features were precise, differing in lung and liver lesions. Habitats obtained with precise features (DSC: median [IQR], 0.601 [0.494-0.712] and 0.651 [0.52-0.784] for lung and liver lesions, respectively) were more stable than those obtained with all features (DSC: median [IQR], 0.532 [0.424-0.637] and 0.587 [0.465-0.703] for lung and liver lesions, respectively; P < .001). In the case study, CT habitats correlated quantitatively and qualitatively with heterogeneity observed in multiparametric MRI habitats and histology. Conclusion Precise three-dimensional radiomics features were identified on CT images that enabled tumor heterogeneity assessment through stable tumor habitat computation. Keywords: CT, Diffusion-weighted Imaging, Dynamic Contrast-enhanced MRI, MRI, Radiomics, Unsupervised Learning, Oncology, Liver, Lung Supplemental material is available for this article. © RSNA, 2024 See also the commentary by Sagreiya in this issue.