Patients with advanced solid tumors carrying ATM gene alterations and BRCA1/2 defects had durable and prolonged responses when treated with the oral ataxia-telangiectasia and Rad3–related protein inhibitor elimusertib (Bayer). These results were from a phase 1b trial (NCT03188965) that involved more than 140 patients and was presented at the American Association for Cancer Research (AACR) 2022 Annual Meeting this week.
Timothy A. Yap presented the study. He is medical director of The Institute for Applied Cancer Science and associate director of Translational Research at the Khalifa Institute for Personalized Cancer Therapy of the University of Texas MD Anderson Cancer Center in Houston.
Ataxia telangiectasia-mutated (ATM) protein is a key player in the pathways to initiate the DNA damage response (DDR). Elimusertib is a selective ataxia telangiectasia and Rad3-related protein (ATR) inhibitor that targets ATM protein loss and/or ATM in solid tumors. There are currently eight studies of elimusertib (formerly BAY 1895344), all in solid tumors, listed on ClinicalTrials.gov.
In this study, patients with advanced solid tumors resistant or refractory to standard treatment were screened for pathogenic DDR defects by next-generation sequencing or for ATM protein loss by immunohistochemistry (IHC) analysis of baseline tumor tissue. Of these patients, 56% had undergone four or more prior therapy lines.
A total of 143 patients were enrolled into the phase 1b dose-expansion portion of the study, based on ATM loss by IHC or DDR in tumor tissue or ctDNA. These included 19 patients with castration-resistant prostate cancer (CRPC), 24 with colorectal cancer (CRC), 45 with gynecologic cancers, 19 with breast cancer, 45 with gynecologic (mainly ovarian and endometrial), and 36 with “advanced cancers” and ATM loss. Most were treated with elimusertib 40 mg twice daily (BID) 3 days on/4 days off (3 on/4 off). A schedule of 3 on/11 off was also explored by dose escalation in pts with ATM loss or inactivating mutation.
Investigators noted that objective response was observed in a variety of cancer types, including one in ovarian, one in breast, three with ATM loss, two in CRPC.
Results from the first trial of elimusertib were published in early 2021, with Yap as the lead author. The researchers surmised that “Oral BAY 1895344 [elimusertib] was tolerable, with antitumor activity in heavily pretreated patients with various advanced solid tumors, particularly those with ATM deleterious mutations and/or loss of ATM protein; pharmacodynamic results supported a mechanism of action of increased DNA damage.”
That study used a 40-mg, twice-daily dose on a 3-days-on, 4-days-off schedule. But treatment-emergent adverse events (TEAEs), such as anemia and thrombocytopenia, were common. In this latest study, an alternate dosing schedule of 3 days on and 11 days off was used for those with ATM loss or mutations. The researchers noted that 80 mg 3 on/11 off was determined as the recommended dose.
In their abstract, the researchers reported that: “Further biomarker analysis is underway to identify potential gene signatures associated with response. Clinical development of elimusertib in combination with checkpoint inhibitors and chemotherapy is ongoing.”
