Selinexor in Advanced, Metastatic Dedifferentiated Liposarcoma: A Multinational, Randomized, Double-Blind, Placebo-Controlled Trial

PURPOSE Antitumor activity in preclinical models and a phase I study of patients with dedifferentiated liposarcoma (DD-LPS) was observed with selinexor. We evaluated the clinical benefit of selinexor in patients with previously treated DD-LPS whose sarcoma progressed on approved agents. METHODS SEAL was a phase II-III, multicenter, randomized, double-blind, placebo-controlled study. Patients age 12 years or older with advanced DD-LPS who had received two-five lines of therapy were randomly assigned (2:1) to selinexor (60 mg) or placebo twice weekly in 6-week cycles (crossover permitted). The primary end point was progression-free survival (PFS). Patients who received at least one dose of study treatment were included for safety analysis (ClinicalTrials.gov identifier: ). RESULTS Two hundred eighty-five patients were enrolled (selinexor, n = 188; placebo, n = 97). PFS was significantly longer with selinexor versus placebo: hazard ratio (HR) 0.70 (95% CI, 0.52 to 0.95; one-sided P = .011; medians 2.8 v 2.1 months), as was time to next treatment: HR 0.50 (95% CI, 0.37 to 0.66; one-sided P < .0001; medians 5.8 v 3.2 months). With crossover, no difference was observed in overall survival. The most common treatment-emergent adverse events of any grade versus grade 3 or 4 with selinexor were nausea (151 [80.7%] v 11 [5.9]), decreased appetite (113 [60.4%] v 14 [7.5%]), and fatigue (96 [51.3%] v 12 [6.4%]). Four (2.1%) and three (3.1%) patients died in the selinexor and placebo arms, respectively. Exploratory RNA sequencing analysis identified that the absence of CALB1 expression was associated with longer PFS with selinexor compared with placebo (median 6.9 v 2.2 months; HR, 0.19; P = .001). CONCLUSION Patients with advanced, refractory DD-LPS showed improved PFS and time to next treatment with selinexor compared with placebo. Supportive care and dose reductions mitigated side effects of selinexor. Prospective validation of CALB1 expression as a predictive biomarker for selinexor in DD-LPS is warranted. (C) 2022 by American Society of Clinical Oncolog

Designs of preoperative biomarkers trials in oncology: A systematic review of the literature

International audienceBackground: The identification of predictive and pharmacodynamics (PD) biomarkers of efficacy of anticancer-targeted therapies is not always straightforward. To address this problem, preoperative trials have been set up. The present study aimed at evaluating how these trials are designed. Design: We retrieved all preoperative oncology trials, defined as preoperative trials having a PD end point. Results: Only 56 trials met our selection criteria. Of these, 27 trials (48%) were randomized. Forty-nine trials (88%) evaluated at least a noncytotoxic agent. In 37 trials (66%), a single agent was administered. The most prevalent tumor type was breast cancer (59%). Median duration of accrual was 28 months (range: 9-98). In these trials, there was a mean of two patients included per month (range: 0-7). The date of surgery was fixed before study entry in 35 trials (62%), while surgery was set up after preoperative therapy in the remaining 21 trials (38%). In the former trials, median duration of preoperative therapy was 17 days (range: 1-112), whereas in the latter trials it ranged from 4 to 29 weeks. The primary end point was a PD end point in 26 of the 45 trials (58%) in which it was mentioned. One percent of patients could not undergo surgery as per protocol due to an adverse event. Statistically significant predictive and PD biomarkers were identified in 17 (30%) and 27 trials (48%), respectively. Conclusion: Preoperative biomarkers trials are infrequent but safe and feasible. These trials often permit the identification of predictive and PD biomarkers

Initial results from a first-in-human, phase I study of immunomodulatory aryl hydrocarbon receptor (AhR) inhibitor BAY2416964 in patients with advanced solid tumors.

2502Background: AhR activation is involved in tumor growth, immunomodulation, and resistance to immune checkpoint inhibitors. BAY2416964 is a novel, potent, oral AhR inhibitor (AhRi) that antagonizes AhR ligand-induced immunosuppressive effects, resulting in enhanced proinflammatory activity of antigen-presenting cells and T cells and reduced activity of immunosuppressive myeloid cells. Methods: A first-in-human, Phase I clinical trial of AhRi BAY2416964 (NCT04069026) is evaluating its safety, pharmacokinetics, pharmacodynamics, recommended Phase II dose, and anti-tumor activity per RECIST v1.1 and iRECIST. BAY2416964 was administered orally in patients with advanced solid tumors in a dose-escalation cohort using a modified toxicity probability interval (mTPI) design. The initial expansion cohorts enrolled patients with non-small-cell lung cancer (NSCLC) and head and neck squamous cell carcinoma (HNSCC). Results: As of November 4, 2022, 72 patients had been treated with BAY2416964: 39 patients in dose escalation and 33 patients in the initial dose expansion treated with 500 mg twice daily (25 NSCLC, 8 HNSCC). The most common tumor types enrolled in dose escalation were colorectal cancer ( n= 12), breast cancer ( n= 6), and pancreatic cancer ( n= 4). Median age was 61 years (range 35-80). 51/72 (70.8%) patients had received ≥3 lines of therapy (including 16 [22.2%] who had received ≥6 lines) and 47/72 (65.3%) had received immune checkpoint inhibitors. Drug-related treatment-emergent adverse events (TEAEs) of all grades reported in ≥10% of patients were nausea (13.9%; 1.4% grade 3) and fatigue (11.1%; 1.4% grade 3). Most drug-related TEAEs were grade 1 or 2; 9 (12.5%) patients experienced drug-related grade 3 TEAEs and no patients experienced drug-related grade ≥4 TEAEs. No dose-limiting toxicities were observed. Two patients in dose expansion discontinued treatment due to drug-related TEAEs. Plasma exposure to BAY2416964 increased according to dose and food intake. Analysis of biomarkers demonstrated evidence of target engagement and an increase in immune activation at the doses tested. Of 67 patients evaluable for response by RECIST, 22 (32.8%) had stable disease per RECIST v1.1, including 1 with thymoma in dose escalation achieving an iRECIST partial response. Conclusions: BAY2416964 was well tolerated across all dose levels and regimens tested. Initial evaluation of biomarkers shows BAY2416964 inhibits AhR and modulates immune functions. Encouraging preliminary anti-tumor activity was observed in heavily pretreated patients. The disease-specific dose-expansion part of this study is ongoing. The observed manageable safety profile also supports combination therapies. Clinical trial information: NCT04069026