Researchers are optimistic that data from a first-in-human clinical trial of Bayer’s ATR-inhibiting agent, BAY-1895344, may pave the way for a new class of precision oncology treatments for patients with certain DNA damage response (DDR) defects in their tumors.
The study results, published Tuesday in the journal Cancer Discovery, suggest that patients whose tumors have ATM protein loss or deleterious ATM mutations may be particularly sensitive to ATR inhibition.
The Phase I clinical trial of BAY-1895344 includes patients with advanced solid tumors or lymphomas, though the recently published paper detailed the results from 21 patients with solid tumors, including those with breast, colorectal, prostate, ovarian, and endometrial cancers, among others. The majority of patients had received more than four prior lines of chemotherapy.
Half of the enrolled patients had one or more ATM aberrations detected by next-generation sequencing or immunohistochemistry analysis of baseline tumor biopsies. Six patients had both an ATM deleterious mutation and loss of ATM protein expression; two patients had ATM deleterious mutations with normal ATM protein expression; and three patients had loss of ATM protein expression and no ATM mutations. Four patients had normal ATM protein expression and no mutations in the gene. Beyond ATM, three patients’ tumors had BRCA1 mutations and one had a BRCA2 mutation.
As a first-in-human trial, the primary aim of the study was to evaluate the safety and maximum tolerated dose of BAY-1895344, though anti-tumor activity was assessed as a secondary endpoint. The objective response rate was 19 percent among all patients evaluated and 36.4 percent among those with ATM loss and/or ATM mutations.
In terms of safety, the investigators, led by Johann de Bono of the Institute of Cancer Research in London and Timothy Yap of MD Anderson Cancer Center in Texas, noted that the drug was tolerated well when dosed in an intermittent schedule of three days on followed by four days off. ATR is essential for the functioning of normal cells, and the days off treatment, researchers noted, allowed for the recovery of normal tissue.
Most of the adverse events observed, such as anemia, were hematological in nature, leading the authors to conclude that future studies attempting to combine ATR inhibition with chemotherapy should be approached with caution, since systemic chemo agents are also known to cause hematological toxicities.
The authors of the Cancer Discovery paper highlighted that one patient with a deleterious BRCA1 mutation experienced stable disease and a partial response for over a year on the ATR inhibitor. This case was particularly noteworthy because the patient had previously progressed after treatment with chemotherapy, immunotherapy, and the PARP inhibitor olaparib (AstraZeneca/Merck’s Lynparza).
“The clinical benefit observed in this patient following BAY-1895344 monotherapy is of particular interest in view of preclinical data suggesting that acquired PARP inhibitor resistance may be mediated by ATR-induced protection of the replication fork and is a clinical area of unmet need,” wrote the authors. In other words, ATR inhibitors may potentially be coupled with PARP inhibitors.
Indeed, Bayer has an additional ongoing Phase Ib clinical trial exploring the combination of BAY-1895344 with the PARP inhibitor niraparib (GlaxoSmithKline’s Zejula) as a treatment for patients with ovarian cancers and other advanced solid tumors. Evidence of up-regulation of PD-L1 expression after treatment with BAY-1895344 in patients whose tumors were PD-L1 positive also bolstered the case for another advanced solid tumor Phase I clinical trial, in which Bayer is studying the ATR inhibitor in combination with the PD-L1 inhibitor pembrolizumab (Merck’s Keytruda).
According to the authors, the study of BAY-1895344 is, to their knowledge, the first study to provide clinical evidence of an oral ATR inhibitor with durable single-agent antitumor activity in patients with advanced cancers with ATM aberrations.
The investigational drug is now being evaluated in a dose expansion phase of the study, specifically as a treatment for patients with DDR deficiencies resulting from genetic mutations or the loss of ATM protein expression as determined by IHC.
“It is very promising to see patients responding in an early-stage trial like this,” wrote de Bono in a statement about the results, adding that ATR inhibition with BAY-1895433 may become a new form of targeted treatment. “We are looking forward to further clinical trials to test the drug’s efficacy.”
This article was published by Precision Oncology News.