JS02.6.A PRELIMINARY SIGNS OF CLINICAL ACTIVITY OF TUVUSERTIB (M1774), A HIGHLY POTENT ORAL ATR INHIBITOR, IN REFRACTORY IDH MUTATED GLIOMA PATIENTS WITH P53 AND ATRX MUTATIONS; A CASE SERIES FROM A FIH STUDY
Authors: Vieito M , Moreno I , Gomez-Puerto D , Victoria Ruiz I , Indacochea A , Garralda E , Gonzalez S , Calvo E , Juanita L , Szucs Z , Reischmann N , Pineda E 
Published: October 2024

Abstract

BACKGROUND
ATP-dependent helicase (ATRX) loss-of-function mutations are a hallmark driver in IDH-mutated astrocytoma, and they are usually associated with the loss of P53 and the presence of the alternative lengthening of telomeres (ALT) phenotype. Inhibition of ataxia telangiectasia and Rad3-related (ATR), a key protein kinase involved in response to DNA damage, has shown preclinical synthetic lethality in ATRX mutated tumors, more specifically with ALT. Preclinical evidence also suggests that IDH mutant tumors show increased DNA damage and potential sensitization to ATR inhibition.

MATERIAL AND METHODS
Here we report a case series of 5 IDH mutant glioma patients who also harbored ATRX loss andP53 mutations enrolled in the biomarker-selected (ATRXX/DAXXmut) expansion cohort of the NCT04170153 study. We have summarized the clinical and pathological characteristics of the patients as well as the treatment duration, the PFS1/PFS2 ratio and the growth rate prior and after tuvusertib (ATR inhibitor) treatment given at its recommended dose for expansion (RDE): 180 mg QD, 2 weeks on/1 week off.

RESULTS
A total of 5 patients were included with an age range of 32-49 years. 3/5 were male. All of them had high-grade IDH mutant gliomas(G3-Astrocytoma) showing tumor enhancement on the baseline MR in all cases. All patients had received multi-modal treatment with surgery, radiotherapy, and systemic treatment with alkylating chemotherapy. Three patients had received 1 previous line of therapy, and 2 patients had received 3 previous lines of therapy. Treatment duration with tuvusertib was 0.5/ 1/ 2.5/ 18+/ 19+ months. No patient achieved a partial or complete response, but 2/5 patients experienced prolonged disease stabilization (&gt;18 months), currently still on treatment. In those 2 cases, median growth rate (calculated as mm/year of change in the major axis of the target lesion) was 22 and 9 mm/year before treatment with tuvusertib but decreased to 1 mm and 2 mm/yearafter. PFS2/PFS1 in those two patients was 1.56 and 2.25, respectively.

CONCLUSION
While the number of patients is very limited, this is the first report showing preliminary signs of clinical activity of an ATR inhibitor in patients with recurrent IDH-mutant glioma in the clinical setting. The observed decrease in tumor growth rate associated with prolonged disease stabilization in treatment-refractory glioma warrants further investigation of tuvusertib in this indication. [MV1]All patients had molecular G3 IDH mutant astrocytoma, but one case has the diagnosis of G3 IDH mutant oligo-astrocytoma based on morphology [MV2]We can mention here that IDH inhibitors efficacy seems to be limited to low-grade, treatment naive non enhancing disease, where tuvusertib is active in high grade refractory tumors