Andre Blais

PURPOSE The global, phase 3, open-label, randomized TROPION-Breast01 study assessed the trophoblast cell surface antigen 2–directed antibody-drug conjugate datopotamab deruxtecan (Dato-DXd) versus investigator's choice of chemotherapy (ICC) in hormone receptor–positive/human epidermal growth factor receptor 2–negative (HR+/HER2–) breast cancer. METHODS Adult patients with inoperable/metastatic HR+/HER2‒ breast cancer, who had disease progression on endocrine therapy, for whom endocrine therapy was unsuitable, and had received one to two previous lines of chemotherapy in the inoperable/metastatic setting, were randomly assigned 1:1 to Dato-DXd (6 mg/kg once every 3 weeks) or ICC (eribulin/vinorelbine/capecitabine/gemcitabine). Dual primary end points were progression-free survival (PFS) by blinded independent central review (BICR) and overall survival (OS). RESULTS Patients were randomly assigned to Dato-DXd (n = 365) or ICC (n = 367). Dato-DXd significantly reduced the risk of progression or death versus ICC (PFS by BICR hazard ratio [HR], 0.63 [95% CI, 0.52 to 0.76]; P < .0001). Consistent PFS benefit was observed across subgroups. Although OS data were not mature, a trend favoring Dato-DXd was observed (HR, 0.84 [95% CI, 0.62 to 1.14]). The rate of grade ≥3 treatment-related adverse events (TRAEs) with Dato-DXd was lower than ICC (20.8% v 44.7%). The most common TRAEs (any grade; grade ≥3) were nausea (51.1%; 1.4%) and stomatitis (50%; 6.4%) with Dato-DXd and neutropenia (grouped term, 42.5%; 30.8%) with ICC. CONCLUSION Patients receiving Dato-DXd had statistically significant and clinically meaningful improvement in PFS and a favorable and manageable safety profile, compared with ICC. Results support Dato-DXd as a novel treatment option for patients with inoperable/metastatic HR+/HER2‒ breast cancer who have received one to two previous lines of chemotherapy in this setting.

BACKGROUND: Standard treatment for patients with newly diagnosed glioblastoma includes surgery, radiotherapy (RT), and temozolomide (TMZ) chemotherapy (TMZ/RT→TMZ). The proteasome has long been considered a promising therapeutic target because of its role as a central biological hub in tumor cells. Marizomib is a novel pan-proteasome inhibitor that crosses the blood-brain barrier. METHODS: European Organisation for Research and Treatment of Cancer 1709/Canadian Cancer Trials Group CE.8 was a multicenter, randomized, controlled, open-label phase 3 superiority trial. Key eligibility criteria included newly diagnosed glioblastoma, age > 18 years and Karnofsky performance status > 70. Patients were randomized in a 1:1 ratio. The primary objective was to compare overall survival (OS) in patients receiving marizomib in addition to TMZ/RT→TMZ with patients receiving the only standard treatment in the whole population and in the subgroup of patients with MGMT promoter-unmethylated tumors. RESULTS: The trial was opened at 82 institutions in Europe, Canada, and the U.S. A total of 749 patients (99.9% of the planned 750) were randomized. OS was not different between the standard and the marizomib arm (median 17 vs. 16.5 months; HR = 1.04; P = .64). PFS was not statistically different either (median 6.0 vs. 6.3 months; HR = 0.97; P = .67). In patients with MGMT promoter-unmethylated tumors, OS was also not different between standard therapy and marizomib (median 14.5 vs. 15.1 months, HR = 1.13; P = .27). More CTCAE grade 3/4 treatment-emergent adverse events were observed in the marizomib arm than in the standard arm. CONCLUSIONS: Adding marizomib to standard temozolomide-based radiochemotherapy resulted in more toxicity, but did not improve OS or PFS in patients with newly diagnosed glioblastoma.

Abstract BACKGROUND The standard of care for patients with newly diagnosed glioblastoma includes maximum safe resection followed by radiotherapy (RT) with concomitant and maintenance temozolomide (TMZ) chemotherapy (TMZ/RT→TMZ). Among potential new therapeutic strategies, targeting the proteasome has been considered promising because of its implication in numerous biological processes in tumors cells. Marizomib is a novel small molecule proteasome inhibitor that crosses the blood brain barrier and showed signs of activity in recurrent glioblastoma. METHODS EORTC 1709/CCTG CE.8 was a randomized, controlled, multicenter, open label phase 3 superiority trial. Major inclusion criteria were histologically confirmed newly diagnosed glioblastoma, age of 18 years or older and a Karnofsky performance status (KPS) > 70. Patients with tumors known to harbor an isocitrate dehydrogenase mutation were not eligible. RESULTS The trial was opened at 82 institutions in Europe, Canada and the US and 749 patients (of 750 planned) were randomized in a 1:1 ratio. Following a pre-planned interim analysis and a recommendation of the independent data monitoring committee, enrolment was discontinued. No significant difference in the median OS (mOS) was observed (standard arm: 17 months, marizomib arm: 16.5 months; p = 0.64; HR = 1.04). Median PFS was 6.0 vs. 6.3 months (p = 0.67; HR = 0.97). Patients with tumors harboring an unmethylated O6-methylguanine DNA methyltransferase (MGMT) promoter had a mOS of 14.5 months in the standard therapy group and 15.1 months in the marizomib arm (p = 0.27, HR = 1.13). Among patients with an MGMT promoter-methylated tumor, median OS was 29.4 months in the marizomib arm and 25.5 months in the standard arm (p = 0.41, HR = 0.86). More CTCAE grade 3/4 treatment-emergent adverse events were noticed in the marizomib arm than in the standard arm. CONCLUSIONS The addition of marizomib to standard temozolomide-based radiochemotherapy was associated with more toxicity but did not confer a survival benefit in glioblastoma patients, independent of the MGMT promoter methylation status.