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Background Several cancer immunotherapies that target the PD-L1/PD-1 pathway show promising clinical activity in patients with hepatocellular carcinoma (HCC). However, the standard of care in first-line treatment with atezolizumab (anti-PD-L1 therapy) in combination with bevacizumab is associated with a limited objective response rate. Telomerase reverse transcriptase (TERT) activation meets the criteria of oncogenic addiction in HCC and could be actionable therapeutic target and a relevant tumor antigen. Therefore we hypothesized that combining anti-PD-1/PD-L1 therapy with an anti-telomerase vaccine might be an attractive therapy in HCC. UCPVax is a therapeutic cancer vaccine composed of two separate peptides derived from telomerase (human TERT). UCPVax has been evaluated in a multicenter phase I/II study in non–small cell lung cancers and has demonstrated to be safe and immunogenic, and is under evaluation in combination with atezolizumab in a phase II clinical trial in tumors where telomerase reactivation contributes to an oncogene addiction (HPV +  cancers). The aim of the TERTIO study is to determine the clinical interest and immunological efficacy of a treatment combining the CD4 helper T-inducer cancer anti-telomerase vaccine (UCPVax) with atezolizumab and bevacizumab in unresectable HCC in a multicenter randomized phase II study. Methods Patients with locally advanced, metastatic or unresectable HCC who have not previously received systemic anti-cancer treatment are eligible. The primary end point is the objective response rate at 6 months. Patients will be allocated to a treatment arm with a randomization 2:1. In both arms, patients will receive atezolizumab at fixed dose of 1200 mg IV infusion and bevacizumab at fixed dose of 15 mg/kg IV infusion, every 3 weeks, according to the standard of care. In the experimental arm, these treatments will be combined with the UCPVax vaccine at 0.5 mg subcutaneously. Discussion Combining anti-PD-1/PD-L1 therapy with an anti-telomerase vaccine gains serious consideration in HCC, in order to extend the clinical efficacy of anti-PD-1/PD-L1. Indeed, anti-cancer vaccines can induce tumor-specific T cell expansion and activation and therefore restore the cancer-immunity cycle in patients lacking pre-existing anti-tumor responses. Thus, there is a strong rational to combine immune checkpoint blockade therapy and anticancer vaccine (UCPVax) in order to activate antitumor T cell immunity and bypass the immunosuppression in the tumor microenvironment in HCC. This pivotal proof of concept study will evaluate the efficacy and safety of the combination of a CD4 Th1-inducer cancer vaccine derived from telomerase (UCPVax) and atezolizumab plus bevacizumab in unresectable HCC, as well as confirming their synergic mechanism, and settling the basis for a new combination for future clinical trials. Trial registration NCT05528952.

The standard of care for patients with locally advanced squamous cell anal carcinoma (SCAC) is concurrent chemoradiotherapy; however, recurrence rates are almost 40% and severe toxic effects include treatment-related colostomy. Anti-PD-1 agents are effective in those with treatment-naive recurrent or metastatic SCAC. We aimed to evaluate the activity and safety of the PD-1 inhibitor ezabenlimab plus modified docetaxel, cisplatin, and fluorouracil (mDCF) in patients with treatment-naive stage 3 SCAC. This open-label, single-arm, phase 2 trial was conducted at ten French hospitals and university hospitals. Eligible patients (aged ≥18 years with stage 3 SCAC [TxN1 or T4N0], Eastern Cooperative Oncology Group performance status score of 0–1, and adequate haematological and end-organ function) received induction treatment with intravenous mDCF every 2 weeks for four cycles (docetaxel 40 mg/m2 on day 1, cisplatin 40 mg/m2 on day 1, and fluorouracil 1200 mg/m2 on days 1 and 2) and intravenous ezabenlimab 240 mg every 3 weeks for three cycles. After induction at 8 weeks, patients were assessed using Response Evaluation Criteria in Solid Tumours (version 1.1). Those without disease progression received two additional cycles of mDCF and one additional cycle of ezabenlimab. Patients with a major response (defined as a radiological objective response [≥30% tumour reduction]) and pathological complete or near-complete response (<10% viable cells) at biopsy and biological complete response (defined as no residual HPV circulating tumour DNA) received intensity-modulated radiotherapy with involved-node chemoradiotherapy (INRT), then seven cycles of ezabenlimab maintenance therapy (240 mg intravenously every 3 weeks). Patients who did not respond received standard concurrent chemoradiotherapy. The primary endpoint was clinical complete response at 40 weeks (with a lower 90% CI greater than 65%), assessed in the modified intention-to-treat (mITT) population (defined as all evaluable patients who received at least one cycle of treatment). This study is registered with ClinicalTrials.gov, NCT04719988 (active, not recruiting). Between Jan 4, 2022, and Nov 20, 2023, 60 patients were assessed for eligibility, five were ineligible, 55 were enrolled, and 54 were evaluable (mITT population). The median age was 63·9 years (IQR 57·1–72·3). 42 (76%) of 55 patients were female and 13 (24%) were male. After induction, 41 (84%) of 49 evaluable patients reached a pathological complete or near-complete response and 36 (90%) of 40 had a biological complete response. 38 (75%) of 51 patients received INRT and 13 (26%) received standard concurrent chemoradiotherapy. Clinical complete response rates at 40 weeks were 86·8% (90% CI 74·3–94·7) with INRT in 33 patients and 69·2% (42·7–88·7) with concurrent chemoradiotherapy in nine patients (overall 77·8% [66·5–86·7]). Grade 3 or worse treatment-related adverse events were neutropenia (three [6%]), nausea, diarrhoea, anaemia, and asthenia (two [4%] each) during induction; lymphopenia (17 [45%]), neutropenia (seven [18%]), epithelitis (six [16%]), anal inflammation (five [13%]), and thrombocytopenia (three [8%]) during INRT; lymphopenia (13 [100%]), thrombocytopenia, anal inflammation (three [23%]), neutropenia (two [15%]), and diarrhoea (two [15%]) during concurrent chemoradiotherapy; and lipase increase, CMV colitis, and lichen planus (one [3%] each) during maintenance. Serious adverse events occurred in 20 (36%) patients; the most common were diarrhoea, nausea, and neutropenia during induction (two [4%] each). Seven (13%) of 55 patients died during the study, with three attributed to adverse events. There were no treatment-related deaths during the study. Our study met the primary endpoint, showing antitumour activity (clinical complete response rates) and a manageable safety profile for ezabenlimab and mDCF induction when given with INRT in patients with locally advanced SCAC, enabling personalised INRT, and supporting phase 3 trials of this treatment in patients with stage 3 SCAC. Centre Hospitalier Universitaire de Besançon and Boehringer Ingelheim.

Background Modified docetaxel, cisplatin, and 5-fluorouracil (mDCF) regimen has become a new standard for the treatment of metastatic or unresectable locally advanced recurrent squamous cell carcinoma of the anus (SCCA) after demonstrating improved efficacy (12-month PFS of 47%) in the Epitopes-HPV02 trial. Antibodies targeting the checkpoint inhibitor (CKI) programmed cell death protein-1 (PD1) have demonstrated the efficacy as monotherapies in second-line treatment of SCCA. The aim of this study is to evaluate the combination of atezolizumab and mDCF as first-line chemotherapy in a non-comparative multicentre randomized phase II study of advanced SCCA patients. Methods Patients with chemo-naive advanced histologically proven SCCA, metastatic or unresectable locally advanced recurrence, and Eastern Cooperative Oncology Group-performance status (ECOG-PS) < 2 will be eligible. The primary endpoint is a 12-month PFS rate. Using one-arm non-parametric survival with unilateral alpha type I error of 5% and a statistical power of 80%, the upper critical value for the 12-month PFS rate is 47% to reject H0. Assuming 5% lost to follow-up, 99 patients will be randomized on a 2:1 basis, 66 to the experimental arm (arm A, mDCF plus atezolizumab) and 33 to the standard arm (arm B, mDCF). In both arms, 8 cycles of mDCF will be administered. In arm A, patients receive mDCF with a fixed dose of atezolizumab (800 mg every 2 weeks) and are followed up to 1 year. Secondary endpoints are overall survival, PFS, response rate, safety, health-related quality of life, and an extensive biomarker programme and its correlation with the treatment efficacy. Discussion Although the Epitopes-HPV02 trial has changed long-lasting prognosis of patients with SCCA in advanced stage disease, more than 50% of patients will progress at 12 months. The purpose of the SCARCE trial to establish the addition of atezolizumab to mDCF as a new standard in this rare disease. Associated biomarker studies and the control arm could contribute to better understanding of the potential synergic and tumour resistance mechanisms in SCCA. Trial registration NCT03519295 .