figure
posted on 2025-01-06, 08:22 authored by Gregory M. Cote, Bose S. Kochupurakkal, Khanh Do, Andrea Bullock, Michael L. Cheng, Alona Muzikansky, Daniel E. McLoughlin, James M. Cleary, Xin Gao, Aparna Parikh, Jong Chul Park, Colin D. Weekes, Oladapo Yeku, Lee Zou, Geoffrey I. Shapiro <p>Figure S1: (A) Study schema. Patients were recruited into one of four cohorts based on NGS or IHC. Patients received twice-per week infusions of berzosertib at the recommended phase 2 dose. Paired biopsies were collected for cohorts 1 to 3 for translational studies. Six patients were allowed per cohort; however, patients could be replaced if paired biopsies were unsuccessful. *For cohort T3, gene alterations included: germline BRCA1/2 mutations, other homologous repair (HR) alterations (e.g., somatic BRCA1/2, BARD1, BRIP1, CDK12, CHEK2, FANCA, FANCC, FANCE, FANCF, FANCM, MRE11A, NBN, PALB2, RAD51B, RAD51C and RAD51D), MYC amplification, FBXW7 truncating or missense mutations, CCNE1 amplification, ARID1A mutations. (B) Kaplan-Meier plot showing Progression free survival of patients in each cohort</p>
Funding
Janelle Lavender Tobin Charity
Mass General Cancer Center (MGCC)
History
ARTICLE ABSTRACT
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 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.
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).
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.
