Ilaria Colombo

Safety of antibody-drug conjugates in gynecologic cancers: current evidence and management approaches

A systematic review of phase I trials in patients with ovarian cancer

Ovarian cancer (OC) is the leading cause of death among gynecological malignancies, with limited treatment options for advanced and platinum-resistant disease. This systematic review analyzes phase I trials to assess recent therapeutic advancements. We performed a systematic review of phase I trials in OC, published between 2012 and 2023, retrieving data on trial characteristics and outcomes. Studies were classified according to the tested treatment strategies into chemotherapy-only (CO), chemotherapy + non-chemotherapy agents (CNC) and chemotherapy-free (CF). 78 trials were included, with more than 50 % of them published in the last four years. Overall, chemotherapy and immunotherapy were the most investigated agents. Fourteen trials (17.9 %) evaluated a CO strategy, 42 (53.8 %) a CNC combination and 22 (28.2 %) a CF therapy. Dose-limiting toxicities and toxic deaths were observed in 71 % and 100 % of CO studies, in 45.2 % and 21 % of CNC trials and in 37.4 % and 13.6 % of CF trials, respectively. CNC regimens outperformed the other treatment types in terms of efficacy outcomes, including overall response rate (11.5 % CO; 32.2 % CNC; 25.5 % CF), clinical benefit rate (40 % CO; 62 % CNC; 52 % CF) and median progression free survival (mPFS 5.9 months CO; 6.45 months CNC; 4.85 months CF). Trials enrolling platinum resistant or agnostic patients displayed worse clinical outcomes. In the last years, there has been an increasing number of phase 1 trials assessing new agents and new combinations in patients with OC. Chemotherapy-free strategies display a more favorable safety profile, while regimens combining CNC agents seem to be more effective compared to CO approaches.

Can we learn from failures? A systematic review of phase III trials in platinum-resistant ovarian cancer

This systematic review analyzed phase III trials in platinum-resistant ovarian cancer to understand their poor outcomes and guide future trials. A systematic review adhering to PRISMA guidelines was conducted. PubMed/Medline, Cochrane Library CENTRAL, and EMBASE were searched for randomized phase III trials (2010-January 2024) involving patients with platinum-resistant ovarian cancer. Fifteen studies (5,468 patients) were included. Platinum resistance was defined by the interval between last platinum administration and recurrence/progression. Heterogeneity existed in defining platinum-refractory patients. Experimental arms included chemotherapy (4 trials), immune checkpoint inhibitors, anti-angiogenic agents, targeted agents, or antibody-drug conjugates (2 trials each), and others (3 trials). Control arms consistently used single-agent chemotherapy (paclitaxel, gemcitabine, pegylated liposomal doxorubicin, or topotecan). Only four trials had biomarker-selected populations. Most trials (except TRINOVA1, AURELIA, and MIRASOL) showed no progression-free survival benefit. Only MIRASOL had statistically significant overall survival improvement. Negative outcomes likely stem from various factors, including inconsistent platinum resistance definitions, inadequate control arm benchmarks, and suboptimal biomarker use. A deeper understanding of tumor biology and its integration into trial design is crucial to enhance drug development in this patient population, aiming for improved efficacy while preserving quality of life.

ESMO management and treatment adapted recommendations in the COVID-19 era: gynaecological malignancies

The rapid spread of severe acute respiratory syndrome coronavirus 2 infection and its related disease (COVID-19) has required an immediate and coordinate healthcare response to face the worldwide emergency and define strategies to maintain the continuum of care for the non-COVID-19 diseases while protecting patients and healthcare providers. The dimension of the COVID-19 pandemic poses an unprecedented risk especially for the more vulnerable populations. To manage patients with cancer adequately, maintaining the highest quality of care, a definition of value-based priorities is necessary to define which interventions can be safely postponed without affecting patients' outcome. The European Society for Medical Oncology (ESMO) has endorsed a tiered approach across three different levels of priority (high, medium, low) incorporating information on the value-based prioritisation and clinical cogency of the interventions that can be applied for different disease sites. Patients with gynaecological cancer are at particular risk of COVID-19 complications because of their age and prevalence of comorbidities. The definition of priority level should be based on tumour stage and histology, cancer-related symptoms or complications, aim (curative vs palliative) and magnitude of benefit of the oncological intervention, patients' general condition and preferences. The decision-making process always needs to consider the disease-specific national and international guidelines and the local healthcare system and social resources, and a changing situation in relation to COVID-19 infection. These recommendations aim to provide guidance for the definition of deferrable and undeferrable interventions during the COVID-19 pandemic for ovarian, endometrial and cervical cancers within the context of the ESMO Clinical Practice Guidelines.

TLD-1, a Novel Liposomal Doxorubicin, in Patients with Solid Tumors: Comparative Pharmacokinetics and Final Results of a Multicenter Phase 1 Study (SAKK 65/16)

Targeted liposomal doxorubicin (TLD-1) is a novel PEGylated liposomal doxorubicin (PLD) with optimized formulation characteristics, developed to improve the benefit-risk profile of PLD. This randomized intrapatient crossover amendment to the phase 1 SAKK 65/16 trial (NCT03387917) compared the pharmacokinetics (PK) of TLD-1 and Caelyx™ and included a pooled analysis of safety and preliminary antitumor activity at the recommended phase 2 dose (RP2D). Patients with advanced breast or platinum-resistant ovarian cancer in the comparative PK part were randomized to receive TLD-1 in cycle 1 and Caelyx™ in cycle 2, or vice versa, followed by TLD-1 thereafter. Both formulations were administered intravenously at 40 mg/m In 10 evaluable patients from the comparative PK part, TLD-1 showed higher encapsulated doxorubicin exposure (AUC Targeted liposomal doxorubicin demonstrated prolonged systemic circulation and low variability in liposomal drug release, likely due to its formulation characteristics. At 40 mg/m NCT03387917, registered 2017-11-21.