Abstract B025: Exceptional response to the ataxia telangiectasia and Rad3-related inhibitor (ATRi), camonsertib, in a patient with alternative lengthening of telomeres (ALT)-positive metastatic melanoma

Abstract

Abstract One hallmark of cancer tumorigenesis is the maintenance of telomere length which canonically occurs through the reactivation of telomerase. Alternative lengthening of telomeres (ALT) is a minor telomere maintenance mechanism that uses homologous recombination (HR) to maintain telomere length and is associated with replication stress and defects in genome maintenance. In preclinical models, ALT positivity (ALT+) has been shown to sensitize tumor cells to ataxia telangiectasia and Rad3-related inhibitors (ATRi). Here we describe a confirmed clinical and molecular response to the ATRi, camonsertib, in a patient with ALT+ metastatic melanoma. To our knowledge, this is the first report of clinical experience with ATRi in ALT+ tumors. A 63-year-old male was diagnosed in July 2019 with stage IV (cTX, cNX, pM1c[1]) metastatic melanoma and treated with nivolumab (nivo) + ipilumumab (ipi) with initial partial response (PR) documented after 3 months which was confirmed on subsequent nivo maintenance. Ipi was resumed following suspected pseudoprogression in March 2020, and continued until confirmed progression in June 2020. Genomic profiling of a liver biopsy collected at the time of progression identified somatic alterations in TP53 (p.S127F, p.R65fs), NF1 (p.K1263*), BRCA2 (p.R2482C) and ATRX (p.R418*), a germline CHEK2 mutation (p.T376fs), and high tumor mutational burden. The patient received additional targeted regimens with olaparib (ola): nivo ± ola and later ola ± trametinib; no response was documented, and progression was noted in April 2021. In June 2021, the patient received camonsertib monotherapy at an initial dose of 120 mg QD 3 days on/4 days off in the phase I TRESR trial (NCT04497116). The patient tolerated treatment well and continued at the same dose until dose was reduced via a change in schedule (to 2 weeks on/1 week off) at 9 months due to anemia. The patient had an initial RECIST PR (-36%) at 3 months with circulating tumor DNA (ctDNA) clearance. The target lesions continued to decrease with a best decline of -74% after about 1 year of treatment. The cancer progressed at 19 months (+105% from nadir, -47% from baseline) though due to ongoing clinical benefit treatment was continued for a total duration of 22 months. Interrogation of ctDNA tumor fraction in longitudinal plasma samples is ongoing and will be reported. To understand the long and deep response to camonsertib treatment in this patient, we further characterized the screening biopsy by a custom targeted sequencing panel, SyNthetic lethal Interactions for Precision Diagnostics (SNiPDx), and whole genome sequencing (WGS). Both the BRCA2 and gCHEK2 mutations were monoallelic and genomic signature analysis defined the tumor as HR-proficient, consistent with the lack of benefit from ola. WGS confirmed a biallelic loss of ATRX with a genomic signature consistent with an ALT+ phenotype. The clinical experience of ATRi therapy in patients with ALT+ tumors is limited but further investigation of ATRi such as camonsertib is warranted in this patient population. Citation Format: Timothy A. Yap, Ian M. Silverman, Adrienne Johnson, Chenfeng Meng, Joseph D. Schonhoft, Michal Zimmermann, Danielle Ulanet, Victoria Rimkunas, Maria Koehler. Exceptional response to the ataxia telangiectasia and Rad3-related inhibitor (ATRi), camonsertib, in a patient with alternative lengthening of telomeres (ALT)-positive metastatic melanoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: DNA Damage Repair: From Basic Science to Future Clinical Application; 2024 Jan 9-11; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2024;84(1 Suppl):Abstract nr B025.