Phase 1 Study of BAY 1895344 Shows Promise in Advanced, Heavily Pre-treated Cancers

The ataxia telangiectasia and Rad3-related (ATR) inhibitor BAY 1895344 showed promise in patients with a range of advanced, heavily pre-treated cancers, including breast, bowel, and prostate tumors in a dose-escalation portion of a first-in-human phase 1 clinical trial, according to the Institute of Cancer Research (ICR), the leader of the trial.¹

Importantly, the agent was also found to be well tolerated and stopped the growth of tumors in over half of patients treated.

“Our new trial shows that this promising new treatment is safe and can benefit some patients even with very advanced cancers,” study leader Johann S. de Bono, MRCP, PhD, MSc, professor of Experimental Cancer Medicine at the ICR and consultant medical oncologist at The Royal Marsden, said in a press release.² “The new drug, which is currently known only by the code BAY 1895344, works by blocking a molecule called ATR which is involved in repairing DNA. It seems to be especially effective in patients whose tumors have defects in a gene called ATM which mean their ability to repair DNA is already weakened – suggesting that this could become a new form of targeted treatment.”

The trial, published in Cancer Discovery, intermittently dosed 22 patients with advanced solid tumors with 5 mg to 80 mg of BAY 1895344 twice daily from July 6, 2017 through June 17, 2018. Specifically, 18 patients received BAY 1895344 twice daily for 3 days on and 4 days off weekly and 4 patients received a less dose-intense variation of this schedule, consisting of 3 days on and 4 days off for 2 weeks followed by 1 week off.

At the time of data cut-off, the median duration of treatment was 64.5 days (range, 8-472) and 5 patients were ongoing with BAY 1895344 treatment. The most common reason for discontinuation was disease progression in 15 patients (68.2%); 2 patients (9.1%) discontinued due to adverse events (AEs).

The maximum tolerated dose was found to be 40 mg twice daily with 3 days on and 4 days off. Partial responses were achieved by 4 patients and stable disease by 8 patients. The median duration of response was 315.5 days. Responders had ataxia telangiectasia mutated (ATM) protein loss and/or deleterious ATM mutations and received doses 40 mg or greater twice daily.

AEs observed were manageable and reversible hematological toxicities. The most common all-grade treatment-emergent AEs were anemia (81.8% [all grade 3]), neutropenia (72.7% [grade 3/4, 54.5%]), and thrombocytopenia (45.5% [grade 3/4, 18.2%]). However, fatigue (68.2% [grade 2 requiring dose reduction, 4.5%; grade 3, 9.1%]) and nausea (50.0% [grade 3, 9.1%]) were also reported. Other nonhematological treatment-emergent AEs were of low frequency and were primarily grade 1 or 2.

Overall, BAY 1895344 was well tolerated with antitumor activity observed against cancers with certain DNA damage response (DDR) defects, including ATM loss. An expansion phase of the trial is ongoing in patients with DDR deficiency. Based on preclinical studies of BAY 1895344, clinical trials assessing combination regimens of the ATR inhibitor are also underway (NCT04095273; NCT04267939).

“It is very promising to see patients responding in an early-stage trial like this, and we are looking forward to further clinical trials to test the drug’s efficacy,” said de Bono.

References:

1. Yap TA, Tan DSP, Terbuch A, et al. First-in-Human Trial of the Oral Ataxia Telangiectasia and Rad3-Related Inhibitor BAY 1895344 in Patients with Advanced Solid Tumors. Cancer Discovery. doi: 10.1158/2159-8290.CD-20-0868

2. New drug targeting DNA repair shows promise in range of advanced cancers [news release]. Published September 28, 2020. Accessed September 29, 2020. https://www.icr.ac.uk/news-archive/new-drug-targeting-dna-repair-shows-promise-in-range-of-advanced-cancers