238TiP An update on the CONCORDE study: A phase Ib platform study of DNA damage repair inhibitors (DDRIs) in combination with conventional radiotherapy in NSCLC

Abstract

Background The innovative dose-finding open-label CONCORDE study (NCT04550104) is a randomised, phase Ib, multi-institution, platform trial investigating DDRIs in patients with non-small cell lung cancer (NSCLC) treated with curative-intent radiotherapy (RT). The study is funded by Cancer Research UK and AstraZeneca, and is sponsored by the University of Leeds. Trial design Methods: Key eligibility: inoperable stage IIB-IIIC NSCLC, unsuitable for concurrent chemoradiotherapy, ECOG 0-2. All participants receive 60 Gy/30# and are randomised 3:1 to RT with concurrent DDRI or RT-alone in each study arm. In 2 study arms, participants also receive consolidation durvalumab +/- DDRI for up to 12 months. Study arm allocation is per the TMG-agreed prioritisation schedule, with recruitment at 13 UK centres. CONCORDE employs an adaptive Bayesian model-based approach to drug dose-escalation. The primary objective is to assess safety and to determine the recommended phase II dose of each DDRI. Recruitment update: Since 17/03/21, 4 arms have opened: A (olaparib, PARPi), B (AZD1390, ATMi), C (ceralasertib, ATRi) and E (saruparib, PARP-1i). 102 participants have been registered and 78 have been randomised: n = 25 received RT-alone, n = 16 olaparib+RT, n = 14 AZD1390+RT, n = 9 ceralasertib+RT, n = 11 saruparib+RT and n = 3 await treatment assignment. DDRIs have been successfully escalated to dose level 2 (C + E) or 3 (A) with integration of consolidation durvalumab in 2 arms (C + E). Baseline characteristics: median age 73 (range 49-88), male 56%, ECOG PS0 9% PS1 82%, PS2 7%, squamous carcinoma 59%. The independent Safety Review Committee decided to close CONCORDE-B on 02/07/24 due to oesophageal toxicity (severity, duration, late-onset events). CONCORDE continues to recruit patients to three study arms (A,C,E). The platform demonstrated excellent capacity in identifying excess toxicity in DDRI-RT combinations, leading to Arm-B closure. Analysis of patient-reported outcomes and efficacy are ongoing. A multimodality translational program to identify toxicity biomarkers is in development. Clinical trial identification: NCT04550104. Legal entity responsible for the study University of Leeds. Funding Cancer Research UK, AstraZeneca. Disclosure All authors have declared no conflicts of interest.