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

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

  • Clin Cancer Res. 2026 Jan 21. doi: 10.1158/1078-0432.CCR-25-2240.
Ezra Y Rosen 1,  Timothy A Yap 2,  Elisa Fontana 3,  Elizabeth K Lee 4,  Devalingam Mahalingam 5,  Martin Højgaard 6,  Niharika B Mettu 7,  Gregory M Cote 8,  Ruth Plummer 9,  Maria Koehler 10,  Danielle Ulanet 11,  Kezhen Fei 12,  Ian M Silverman 13,  Joseph D Schonhoft 14,  Victoria Rimkunas 11,  Emeline S Bacque 12,  Gabriela Gomez 12,  Adrian J Fretland 11,  Anne Roulston 15,  Li Li 12,  Prasamit Baruah 12,  Michal Zimmermann 16,  Julia Yang 11,  Benedito A Carneiro 17,  Stephanie Lheureux 18
Affiliations

Affiliations

  • 1 Memorial Sloan Kettering Cancer Center New York, NY United States.
  • 2 The University of Texas MD Anderson Cancer Center Houston, TX United States.
  • 3 Sarah Cannon Research Institute London, London United Kingdom.
  • 4 Dana-Farber Cancer Institute Boston, Massachusetts United States.
  • 5 Feinberg School of Medicine, Northwestern University.
  • 6 Rigshospitalet Copenhagen Denmark.
  • 7 Duke University Medical Center Durham, NC United States.
  • 8 Massachusetts General Hospital and Harvard Medical School Boston, MA United States.
  • 9 Newcastle University Newcastle upon Tyne, Tyne and Wear United Kingdom.
  • 10 Repare Therapeutics United States.
  • 11 Repare Therapeutics Cambridge, MA United States.
  • 12 Repare Therapeutics, Inc. United States.
  • 13 Repare Therapeutics Cambridge, Massachusetts United States.
  • 14 Tagworks Pharmaceuticals (Netherlands) Boston, MA United States.
  • 15 REPARE THERAPEUTICS INC St-Laurent Canada.
  • 16 Repare Therapeutics Inc. Montreal Canada.
  • 17 Brown University Providence, RI United States.
  • 18 Princess Margaret Cancer Centre Toronto, Ontario Canada.
PMID: 41563386 DOI: 10.1158/1078-0432.CCR-25-2240
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.

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