Camonsertib, an ATRi, in Combination with Low-Dose Gemcitabine in Solid Tumors with DNA Damage Response (DDR) Aberrations: Preclinical and Phase 1b Results

Abstract Purpose: The utility of combination treatment with gemcitabine and camonsertib, an ataxia telangiectasia and Rad3-related kinase inhibitor (ATRi), in mediating tumor cell death was assessed in preclinical models, prompting clinical investigation. The phase 1b TRESR study (NCT04497116) aimed to evaluate the safety, tolerability and preliminary efficacy of the combination in patients with advanced solid tumors harboring DNA damage repair (DDR) gene alterations. Methods: Cell lines and tumor xenografts were tested across a range of dose levels and schedules. Patients (N = 76) harboring tumors with DDR gene alterations received camonsertib (80–120 mg) and de-escalating gemcitabine (1000–100 mg/m²) in 21- or 28-day cycles on an intermittent dosing regimen. Safety, tolerability, and preliminary efficacy were assessed to identify an optimal dosing regimen. Results: In pre-clinical models, low-dose camonsertib (1/3 maximum tolerated dose [MTD]) and gemcitabine led to tumor regression and was well tolerated with minimal body weight loss observed. In patients, synergistic toxicities were observed, primarily myelosuppression, resulting in gemcitabine de-escalation. The introduction of a one week on / one week off (1/1w) schedule in combination with low-dose gemcitabine allowed for spontaneous neutrophil recovery, fewer dose modifications, and improved tolerability. Tumor responses were primarily observed in patients with gynecological cancers, with tumor control maintained for greater than one year in some patients. Conclusion: Camonsertib and low-dose gemcitabine demonstrated preliminary clinical activity, but due to challenging tolerability further evaluation is warranted to identify the optimal dosing regimen and subset of patients who may benefit most from this combination.