Background. Tisotumab vedotin (TV; HuMax-TF-ADC), is a first-in-class antibody-drug conjugate directed against tissue factor (TF), which is expressed across multiple solid tumor types and is associated with poor clinical outcomes. We hypothesize that TV could have antitumor activity in tumors known to express TF. Methods. This is a phase 1/2 open-label, dose-escalation and-expansion study (innovaTV201; NCT02001623) evaluating the safety, tolerability, pharmacokinetics (PK) profile, and antitumor activity of TV in patients with locally advanced and/or metastatic solid tumors known to express TF. In the dose-escalation phase, patients were treated with TV intravenously once every 3 weeks in a traditional 3 + 3 design to determine the maximum-tolerated dose (MTD) and recommended phase 2 dose (RP2D). Plasma was collected to characterize the PK profile of TV. In the dose-expansion phase, patients are treated at the RP2D in seven advanced solid tumor-type cohorts, including bladder, cervix, endometrium, esophagus, lung, ovary, and prostate cancers. Findings. In the dose-escalation phase, 27 patients with advanced solid tumors received TV in eight sequential dose cohorts between 0•3 and 2•2 mg/kg. Dose-limiting toxicities, including grade 3 type 2 diabetes mellitus, mucositis, and neutropenic fever, were observed at TV 2•2 mg/kg. TV at 2•0 mg/kg was identified as the MTD and the RP2D. The PK profile of TV was dose proportional. In the dose-expansion phase, 147 patients with solid tumors were treated with TV at 2•0 mg/kg. The most common (≥20%) treatment-emergent adverse events (AEs) of any grade included epistaxis, fatigue, nausea, alopecia, conjunctivitis, decreased appetite, and constipation. Across tumor

PURPOSE ATHENA (ClinicalTrials.gov identifier: NCT03522246 ) was designed to evaluate rucaparib first-line maintenance treatment in a broad patient population, including those without BRCA1 or BRCA2 (BRCA) mutations or other evidence of homologous recombination deficiency (HRD), or high-risk clinical characteristics such as residual disease. We report the results from the ATHENA–MONO comparison of rucaparib versus placebo. METHODS Patients with stage III-IV high-grade ovarian cancer undergoing surgical cytoreduction (R0/complete resection permitted) and responding to first-line platinum-doublet chemotherapy were randomly assigned 4:1 to oral rucaparib 600 mg twice a day or placebo. Stratification factors were HRD test status, residual disease after chemotherapy, and timing of surgery. The primary end point of investigator-assessed progression-free survival was assessed in a step-down procedure, first in the HRD population (BRCA-mutant or BRCA wild-type/loss of heterozygosity high tumor), and then in the intent-to-treat population. RESULTS As of March 23, 2022 (data cutoff), 427 and 111 patients were randomly assigned to rucaparib or placebo, respectively (HRD population: 185 v 49). Median progression-free survival (95% CI) was 28.7 months (23.0 to not reached) with rucaparib versus 11.3 months (9.1 to 22.1) with placebo in the HRD population (log-rank P = .0004; hazard ratio [HR], 0.47; 95% CI, 0.31 to 0.72); 20.2 months (15.2 to 24.7) versus 9.2 months (8.3 to 12.2) in the intent-to-treat population (log-rank P < .0001; HR, 0.52; 95% CI, 0.40 to 0.68); and 12.1 months (11.1 to 17.7) versus 9.1 months (4.0 to 12.2) in the HRD-negative population (HR, 0.65; 95% CI, 0.45 to 0.95). The most common grade ≥ 3 treatment-emergent adverse events were anemia (rucaparib, 28.7% v placebo, 0%) and neutropenia (14.6% v 0.9%). CONCLUSION Rucaparib monotherapy is effective as first-line maintenance, conferring significant benefit versus placebo in patients with advanced ovarian cancer with and without HRD.

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