ESTRO 2025 - Abstract Book

S3989

Radiobiology - Tumour radiobiology

ESTRO 2025

Purpose/Objective: Repurposing the anti-malarial drug atovaquone represents a novel approach to tackling tumour hypoxia through reprogramming cancer metabolism. Hypoxia is a barrier to many anti-cancer treatments, particularly radiotherapy. This study evaluated safety of atovaquone with concurrent chemoradiation (CRT), whilst assessing hypoxia biomarkers. Material/Methods: This was a UK multi-centre, open label, phase I trial to determine the maximum tolerated dose (MTD) and recommended phase two dose (RP2D) of atovaquone in combination with CRT in NSCLC. Oral atovaquone was self-administered for a two-week run-in period (+/- 7 days) and continued during CRT: thoracic radiotherapy 66Gy in 33 fractions once daily with cisplatin IV 80mg/m 2 days 1 and 22 and vinorelbine IV 15mg/m 2 days 1, 8, 22 and 29. Four escalating dose levels of twice-daily atovaquone were tested: 450mg, 600mg, 675mg and 750mg, with dose assigned using a time-to-event continual reassessment method (TiTE-CRM). Dose limiting toxicities (DLTs) were assessed for three months post CRT. A secondary endpoint was change in tumour hypoxic volume following atovaquone run-in measured using FMISO PET-CT. Further secondary endpoints assessed tumour hypoxia metagene signature expression by RNA-Seq and plasma miR-210 levels, with correlation of all hypoxia biomarkers performed. Results: 21 patients were recruited (February 2021 to December 2022), with all patients eligible for safety analysis. One patient withdrew consent prior to CRT and of remaining patients, 19 (95%) completed the full course of radiation with all patients treated using VMAT. 15 patients received the highest atovaquone dose. 750mg BD was declared the MTD of atovaquone with CRT. Two DLTs were observed, both occurring in the same patient: Grade 3 oesophagitis and Grade 3 nausea. Treatment-related Grade 3 AEs which did not meet DLT definition were reported in seven (33%) patients: nausea in two patients and fatigue, ataxia, tremor, vomiting, cough, pneumonia and chest pain each occurred in one patient. One patient developed treatment-related Grade 4 lymphopenia which did not meet DLT criteria. One patient experienced treatment-related Grade 5 pneumonitis and Pneumocystis jirovecii pneumonia after the DLT assessment period. Twelve patients were evaluable for assessing change in tumour hypoxic volume using FMISO PET-CT during atovaquone run-in. Eight (67%) patients had ≥10% reduction, thus classed responders, with mean change -21.5% (95% CI, -44.3 to 1.4). Correlation of hypoxia biomarker data will be presented. Conclusion: This is the first clinical study combining atovaquone with CRT. This combination was well-tolerated in patients with NSCLC and RP2D established. Rapid tumour hypoxia reduction following atovaquone was observed in most patients.

Keywords: Tumour hypoxia, phase I trial, chemoradiation

2181

Proffered Paper Exploring the effect of radiotherapy (RT), hyperthermia (HT), and immunotherapy (IO) in head and neck squamous cell carcinoma (HNSCC) Ifigenia Vasiliadou 1 , Abul Azad 1 , Phoebe Yuen Ka Chan 1 , Rami Mustapha 1 , Azzaya Sengedorj 2 , Shahram Kordasti 3 , Maya Thanou 4 , Anthony Kong 1 1 Comprehensive Cancer Centre, King's College London, London, United Kingdom. 2 PhD research, Universitätsklinikum Erlangen, Erlangen, Germany. 3 Faculty of Life Sciences & Medicine, King's College London, London, United Kingdom. 4 Institute of Pharmaceutical Science, King's College London, London, United Kingdom