Elimusertib Elicits Responses in Solid Tumors With ATM Alterations and BRCA Mutations

Timothy A. Yap, MBBS, PhD

The oral ataxia-telangiectasia and Rad3–related protein inhibitor elimusertib produced durable and prolonged responses in patients with advanced solid tumors who have ATM gene alterations and BRCA1/2 defects, according to results of a phase 1b trial (NCT03188965) presented at the 2022 AACR Annual Meeting.¹

When patients were treated with a 3-days-on, 11-days-off schedule, there was a reduction in hematologic adverse effects (AEs) as well as dose interruptions or reductions.

“The most common drug-related treatment-emergent AEs [TEAEs] of grade 3 or higher observed with elimusertib 40 mg [twice a day for a] 3-days-on, 4-days-off weekly schedule were hematologic, ie anemia, consistent with anticipated class-effect toxicity,” Timothy A. Yap, MBBS, PhD, FRCP, 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, said during the presentation.

Previously published results from the dose-escalation portion of the trial found the optimal 40-mg, twice-daily dose for advanced solid tumors and non-Hodgkin lymphoma on a 3-days-on, 4-days-off schedule.² An alternate dosing schedule of 3 days on and 11 days off was found for those with advanced solid tumorsand ATM loss or mutations.

Patients treated in the dose-expansion portion were divided into cohorts; those with ATM protein loss by immunohistochemistry (IHC) were treated in a tumor agnostic fashion whereas those with DNA damage repair (DDR) gene defects by next-generation sequencing were limited to those with gynecologic cancers, castration-resistant prostate cancer (CRPC), HER2-negative breast cancer, and colorectal cancer (CRC).

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, including 19 patients with CRPC, 24 with CRC, 45 with gynecologic cancers, 19 with breast cancer, and 36 with ATM loss. A total of 32 patients with ATM loss or mutations were enrolled in the dose-escalation portion and received 60 to 120 mg of elimusertib twice a day with 3 days on and 11 days off.

Patients in the dose-expansion portion with CRPC had a median age of 67.0 years, and mostly presented with an ECOG performance score of 1 (94.7%), 4 or more lines of prior therapy (73.7%), and BRCA2 (47.4%) or ATM alterations (36.8%). Those with CRC had median age of 56.0 years, and most presented with an ECOG performance score of 1 (66.7%), 3 to 4 lines of prior therapy (50.0%), and BRCA2 (29.2%) or ATM alterations (50.0%). Those with gynecologic cancer had a median age of 57.0 years, and mostly ECOG performance scores of 1 (71.1%), 4 or more lines of prior therapy (64.4%), and BRCA1 mutations (60.0%). Those with breast cancer had a median age of 48.0 years, with most presenting with ECOG performance scores of 1 (63.2%), 4 or more lines of prior therapy (73.7%), and ATM alterations (47.4) or BRCA2 mutations (36.8%). Those with ATM loss were mostly men (58.3), had ECOG of performance scores 1 (75.0%), had 4 or more prior lines of therapy (41.7%), and had a median age of 57.5 years.

Those in the dose-escalation phase with ATM mutations/loss were mostly men (71.9%) with a median age of 60 years and were most likely to presented with an ECOG performance score of 1 (65.6%) and 3 to 4 prior lines of therapy.

The most common grade 3 or higher TEAEs in the dose-expansion phase were grade 3 anemia (65.7%), grade 3 neutropenia (34.3%), and grade 4 neutropenia (13.3%).

In the dose-escalation portion, patients treated with on the alternate dose schedule had lower rates of grade 3 or greater anemia across the 60 mg (50.0%), 80 mg (54.5%), 100 mg (50.0%), and 120 mg (33.3%) groups. Similarly, grade 3 or greater neutropenia across the 60 mg (16.7%), 80 mg (27.3%), 100 mg (66.7%), and 120 mg (44.4%) groups was also reduced.

TEAEs led to fewer dose interruptions in the alternate dose group (55.6% vs 76.2%); similar associations were noted with TEAEs leading to dose reductions (22.2% vs 37.1%).

In the alternate dosing schedule, the maximum tolerated dose was not reached and there were 2 dose-limiting toxicities of febrile neutropenia at 120 mg. At 80 mg twice daily on the alternative schedule, investigators found improved tolerability compared with 40 mg twice daily at 3 days on and 4 days off over a 14-day period.

Response rates in patients treated with 3-days-on, 11-days-off schedule were 33% (n = 2) stable disease (SD) at 60 mg, 55% (n = 6) SD at 80 mg, 17% (n = 1) SD and 17% (n = 1) partial response (PR) at 100 mg, and 22% (n = 2) SD and 11% (n = 1) complete response (CR).

In the 3-days-on, 4-days-off expansion group (n = 138), 1 out of 44 patients with gynecologic cancer, 1 of 19 with breast cancer, and 3 of 34 with ATM loss had a PR. Disease control was observed in 4 of 18 patients with prostate cancer (22.2%), 12 of 23 with CRC (52.2%), 32 with gynecologic cancer (72.7%), 11 with breast (57.9%), and 22 with ATM loss (64.7%), for a rate of 58.7% in the whole cohort. A clinical benefit was observed in 11.1% of patients with prostate cancer, 30.4% with CRC, 38.6% with gynecologic cancers, 36.8% with breast cancer, and 44.1% with ATM loss.

Investigators noted that across all parts of the study, objective response was observed in a variety of cancer types.

Patients with ovarian cancer treated at 40 mg twice daily for 3 days on and 4 days off (n = 36) had a 6-month progression-free survival (PFS) rate of 26%, 1 patient had a PR (2.9%), and the clinical benefit rate was 40.0%. Those with CRC had a 6-month PFS rate of 24%; those with breast cancer had a 6-month PFS rate of 20%, with 1 patient remaining on treatment at the time of analysis.

Patients with ATM loss treated with 40 mg twice daily for 3 days on and 4 days off experienced PR at a rate of 9% and stable disease in 56%. Clinical benefit lasted for more than 6 months in 9 patients (27%), and at the time of analysis there was 1 patient still on treatment. The 6-month PFS was 28%.

References

1. Yap TA, Tan DS, Stathis A, et al. Phase 1b expansion trial of the safety and efficacy of the oral ataxia telangiectasia and Rad3-related inhibitor elimusertib in advanced solid tumors with DNA damage response defects. Presented at: 2022 AACR Annual Meeting; April 8-13, 2022; New Orleans, Louisiana. Abstract CT006. Accessed April 10, 2022.
2. Yap TA, Tan DSP, Terbuch A, et al. First-in-Human trial of the oral ataxia telangiectasia and RAD3-related (ATR) inhibitor BAY 1895344 in patients with advanced solid tumors. Cancer Discov. 2021;11(1):80-91. doi:10.1158/2159-8290.CD-20-0868