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A Translational Study of the ATR Inhibitor Berzosertib as Monotherapy in Four Molecularly Defined Cohorts of Advanced
Gregory M Cote1,2, Bose S Kochupurakkal3, Khanh Do2,3
1Mass General Cancer Center, Boston, Massachusetts.
Purpose:
Preclinical studies have identified molecular correlates of sensitivity to ATR inhibition. This translational study was designed to test the ATR inhibitor berzosertib in patients with advanced solid tumors carrying alterations in ATRX, ataxia-telangiectasia-mutated (ATM), genes conferring replication stress (RS), or SDH.
Patients And Methods:
Patients were recruited to four cohorts: T1: ATRX-mutant leiomyosarcoma; T2: ATM-mutant solid tumors; T3: solid tumors with mutations in RS-associated genes; and T4: SDH-deficient gastrointestinal stromal tumors (GIST). Patients were treated with berzosertib 240 mg/m2 intravenously twice per week. Pretreatment and on-treatment biopsies were obtained in cohorts T1 to T3.
Results:
Patients with SDH-mutant GIST had the longest median progression-free survival (PFS; 229 days) with stable disease as the best response. Patients in the other cohorts experienced progressive disease within 4 months. There was no significant difference in PFS comparing outcomes in patients with/without mutations in ATM or RS genes. Decreased pS345-CHK1 levels in on-treatment biopsies indicated target engagement by berzosertib and were accompanied by substantial increases in levels of DNA damage (γ-H2AX) and RS (pKAP1) markers in a subset of patients. However, these biomarker changes did not translate to clinical benefit. In contrast, in cohorts T1 to T3, increased expression of SLFN11 on treatment correlated with clinical benefit (HR = 0.045; 95% confidence interval, 0.005-0.400).
Conclusions:
Across cohorts, only patients with SDH-mutant GIST experienced prolonged disease control. Despite evidence of target engagement, patients enrolled to all other cohorts had short PFS, suggesting rapid adaptation to ATR inhibitor monotherapy. Among these patients, those with tumors expressing SLFN11 during berzosertib exposure derived the most clinical benefit.
Insights
The ATR inhibitor berzosertib showed limited efficacy in advanced solid tumors, except for SDH-mutant GIST. SLFN11 expression correlated with clinical benefit in other cohorts, suggesting a predictive biomarker for ATR inhibition.
Area of Science:
- Oncology
- Molecular Biology
- Translational Research
Background:
- Preclinical studies identified molecular markers for ATR inhibitor sensitivity.
- ATR inhibition targets DNA damage response pathways, crucial for cancer cell survival.
Purpose of the Study:
- To evaluate the efficacy of the ATR inhibitor berzosertib in patients with advanced solid tumors.
- To assess berzosertib in patients with specific genetic alterations: ATRX, ATM, replication stress (RS) genes, or SDH.
Main Methods:
- A translational study involving four patient cohorts based on genetic alterations.
- Treatment with berzosertib (240 mg/m2 IV twice weekly).
- Collection of pre-treatment and on-treatment biopsies for biomarker analysis.
Main Results:
- SDH-mutant GIST patients showed the longest progression-free survival (PFS).
- Biomarker analysis indicated target engagement (decreased pS345-CHK1) but did not consistently correlate with clinical benefit.
- Increased SLFN11 expression during treatment correlated with clinical benefit in cohorts T1-T3.
Conclusions:
- Berzosertib demonstrated efficacy primarily in SDH-mutant GIST.
- Other patient groups showed rapid adaptation to ATR inhibitor monotherapy.
- SLFN11 emerged as a potential predictive biomarker for response to berzosertib.
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