Annals of Oncology最新文献

Background: Despite treatment advances in newly diagnosed advanced-stage ovarian cancer (aOC), improved outcomes are needed.

Patients and methods: DUO-O (NCT03737643), a phase III placebo-controlled trial, enrolled patients with newly diagnosed aOC. Following one cycle of carboplatin/paclitaxel ± bevacizumab, patients without a tumor BRCA mutation (non-tBRCAm) were randomly assigned (1 : 1 : 1) at cycle 2 to carboplatin/paclitaxel plus bevacizumab followed by bevacizumab (control); carboplatin/paclitaxel, bevacizumab plus durvalumab followed by bevacizumab plus durvalumab (durvalumab arm); or carboplatin/paclitaxel, bevacizumab plus durvalumab followed by bevacizumab, durvalumab plus olaparib (durvalumab + olaparib arm). Investigator-assessed progression-free survival (PFS; primary endpoint) was tested for the durvalumab + olaparib arm versus control in the non-tBRCAm homologous recombination deficiency (HRD)-positive and non-tBRCAm intention-to-treat (ITT) populations.

Results: One thousand one hundred and thirty patients were randomly allocated to the study. The prespecified interim PFS analysis [data cut-off (DCO): 5 December 2022] qualified as the primary analysis; PFS hazard ratio (HR) for the durvalumab + olaparib arm versus control was 0.49 [95% confidence interval (CI) 0.34-0.69, P < 0.0001; median (m) PFS 37.3 versus 23.0 months] in the non-tBRCAm HRD-positive and 0.63 (95% CI 0.52-0.76, P < 0.0001; mPFS 24.2 versus 19.3 months) in the non-tBRCAm ITT population. For the durvalumab arm versus control, PFS HR was 0.87 (95% CI 0.73-1.04, P = 0.13; mPFS 20.6 versus 19.3 months) in the non-tBRCAm ITT population. At final PFS and interim overall survival (OS) analysis (DCO: 18 September 2023), PFS results were consistent with primary analysis; interim OS HR for the durvalumab + olaparib arm versus control was 0.95 (95% CI 0.76-1.20, P = 0.68; 39.0% maturity) in the non-tBRCAm ITT population. Safety was generally consistent with the profiles of the individual agents.

Conclusions: DUO-O met its primary PFS endpoints for first-line durvalumab plus carboplatin/paclitaxel and bevacizumab followed by durvalumab, bevacizumab plus olaparib maintenance versus carboplatin/paclitaxel and bevacizumab followed by bevacizumab in the non-tBRCAm HRD-positive and non-tBRCAm ITT populations. Further insight into long-term benefit is anticipated with additional follow-up.

Background: Advanced/metastatic soft tissue sarcomas (STSs) remain an unmet clinical need. We previously reported the feasibility and preliminary activity of trabectedin-olaparib combination in patients with advanced STS progressing after anthracycline-based regimens.

Patients and methods: In this investigator-initiated, open-label, phase II randomized trial, adult patients with advanced STS progressing after one or more prior lines of therapy, including at least one anthracycline-based regimen, were randomly assigned 1 : 1 to trabectedin 1.1 mg/m² every 21 days (q21d) intravenous (i.v.) plus olaparib tablets 150 mg twice a day, or trabectedin 1.5 mg/m² q21d i.v. Randomization stratified patients by histology (L-sarcoma, i.e. leiomyosarcoma and liposarcoma versus non-L-sarcoma) and number of prior therapies (one versus two or more). The primary endpoint was progression-free survival (PFS) rate at 6 months (PFS6m) per RECIST1.1. Secondary endpoints included PFS, overall survival (OS), RECIST1.1 overall response rate (ORR), and safety. Exploratory endpoints encompassed biomarker/molecular analyses.

Results: Between 25 May 2020 and 2 November 2022, 130 patients were enrolled at 13 Italian Sarcoma Group centers (81 female; 67 L-sarcoma; 93 one prior line). With a median follow-up of 37.4 months, PFS6m and median PFS were 32% [95% confidence interval (CI) 22% to 46%] and 3.9 months (95% CI 2.7-5.2 months) with trabectedin-olaparib versus 28% (95% CI 19% to 42%) and 2.9 months (95% CI 2.2-3.6 months) with trabectedin [hazard ratio (HR) 0.722, 95% CI 0.501-1.041, P = 0.081]. Among 126 assessable patients, ORR was 12.7% (95% CI 6.1% to 22.7%) versus 7.9% (95% CI 3.0% to 16.7%), respectively (odds ratio 1.60, 95% CI 0.50-5.16, P = 0.43). In the uterine leiomyosarcoma subgroup, 12-month PFS was 42.9% with trabectedin-olaparib versus 0% with trabectedin. PARP1 expression significantly correlated with improved PFS with trabectedin-olaparib (PFS6m and median PFS were 41.5% and 4.3 months versus 27.8% and 2.5 months; HR 0.537, 95% CI 0.337-0.855, P = 0.009). Grade ≥3 hematological toxicities were significantly more frequent with trabectedin-olaparib.

Conclusions: Although trabectedin-olaparib combination reached the prespecified threshold for statistical significance for PFS (P < 0.10), the benefit was marginal in the all-comers STS population. Nonetheless, patients affected by PARP1-expressing STS and uterine leiomyosarcoma derived substantial benefit from the combination, supporting further histology- and biomarker-driven investigation in these settings.

Background: Perioperative immunotherapy, particularly anti-programmed cell death protein 1 therapy, combined with neoadjuvant chemotherapy has emerged as one of the standard-of-care options for resectable non-small-cell lung cancer (NSCLC). We report the final analysis of RATIONALE-315, a randomized, double-blind, phase III trial evaluating the efficacy and safety of perioperative tislelizumab plus neoadjuvant chemotherapy versus neoadjuvant chemotherapy alone in patients with resectable, stage II-IIIA NSCLC.

Patients and methods: Adult patients in China were randomized (1 : 1) to receive either perioperative tislelizumab or placebo in combination with neoadjuvant chemotherapy. The dual primary endpoints were event-free survival (EFS) and major pathological response, assessed by blinded independent central review. The secondary endpoints included pathological complete response, overall survival (OS), disease-free survival, and safety.

Results: In total, 453 patients were randomized (226 to tislelizumab and 227 to placebo). At the final analysis (median study follow-up of 38.5 months), patients in the tislelizumab group experienced statistically significantly improved OS versus those in the placebo group {hazard ratio (HR) 0.65 [95% confidence interval (CI) 0.45-0.93]; P = 0.009}. The median OS was not reached in either group. The 36-month OS rate was 79.3% in the tislelizumab group versus 69.3% in the placebo group. The median EFS was not reached in the tislelizumab group versus 30.6 months in the placebo group [HR 0.58 (95% CI 0.43-0.79)]. Survival benefits were generally consistent across subgroups. The safety profile of tislelizumab plus chemotherapy was tolerable and consistent with known profiles of the individual therapies.

Conclusions: Neoadjuvant tislelizumab plus chemotherapy and adjuvant tislelizumab demonstrated a statistically significant, clinically meaningful OS benefit and sustained, clinically meaningful EFS improvement compared with neoadjuvant chemotherapy, with a tolerable safety profile in patients with resectable stage II-IIIA NSCLC. These results support the use of this regimen in this patient population.

Clinical trial number: NCT04379635.