SAN DIEGO – Treatment with AstraZeneca's investigational ATM inhibitor, AZD1390, could be a promising strategy for preventing glioblastoma cells from repairing DNA damage that arises from radiation therapy, according to two early studies presented during the American Association for Cancer Research's annual meeting.
The idea behind the drug is not unlike a PARP inhibitor. When the DNA in patients' tumors are damaged from radiation, many tumor cells have biological machinery to repair the double-stranded breaks so they can proliferate despite the treatment. If a drug can prevent the repair mechanisms cancer cells are exploiting, DNA damage can be sustained and kill cancer cells as intended.
On Tuesday, Nader Sanai, the director of the Ivy Brain Tumor Center, presented results from a Phase 0/I trial of AZD1390 in 17 patients. Then, Jonathan Yang, a radiation oncologist at Memorial Sloan Kettering Cancer Center, presented results from a Phase I/II trial of AZD1390 in 111 glioblastoma patients. In both trials, the drug — which researchers called a radiosensitizer — appeared to have preliminary efficacy and was well tolerated by patients.
"ATM is one player among a cascade of other mechanisms that regulate and protect glioblastoma and other cancer cells from DNA damage from radiotherapy," Sanai said.
The smaller Phase 0/I study that Sanai presented had two arms, one that included patients with newly diagnosed glioblastoma and the other with recurrent glioblastoma. Patients received three doses of AZD1390 before undergoing planned surgery. Then, upon analysis of resected tumors, patients with glioblastomas that were MGMT unmethylated and had a certain level of AZD1390 exposure from initial doses went on to the expansion phase of the trial and received AZD1390 plus radiation.
Roughly 60 percent of glioblastoma patients don't harbor MGMT methylation and are unlikely to benefit from Merck's Temodar (temozolomide), Sanai pointed out. Unfortunately, this drug is often the only standard of care option other than radiation for glioblastoma patients.
The safety profile for AZD1390 based on pRAD50 expression, which researchers gauged to track pharmacokinetics in the Phase 0/I trial, was encouraging, Sanai said. All 14 tumors tested for pRAD50 expression met the threshold for moving onto the expansion stage.
After radiating the tumor samples ex vivo, Sanai and his colleagues found that pRAD50 expression was significantly suppressed in the tumors following AZD1390 treatment compared to control samples that hadn't been exposed to the drug.
In a discussion of the data on AZD1390, Alison Schram, an oncologist at Memorial Sloan Kettering, called this particular "window of opportunity" design of the Phase 0/I trial innovative.
The expansion Phase of Sanai's early trial was ongoing as of the November 2023 data cutoff, with three MGMT unmethylated glioblastoma patients still receiving AZD1390 plus radiation. While the survival data are too early for definitive conclusions, Sanai shared that the median overall survival for the recurrent glioblastoma patients in the trial receiving AZD1390 plus radiation was 15.4 months, and the median progression-free survival was 11.3 months.
"What we can read out at this point is that the combination of AZD1390 is well-tolerated in newly diagnosed and recurrent glioblastoma patients that, in all cases, were well in excess of what we would define as a pharmacologically relevant excess of a concentration of the drug, and we're seeing that in the exact compartment of the tumor that's really beyond the reach of conventional surgery, radiation, and adjuvant therapy," Sanai said, adding that while the preliminary clinical signals are "encouraging," the study must go on for the data to mature.
In the subsequent presentation of the Phase I/II study of AZD1390 plus radiation, Yang shed further light on the clinical signals that Sanai alluded to.
In the Phase I/II study, patients were also enrolled into one of two arms. Arm A included 75 patients with recurrent glioblastoma, and Arm B included 40 patients with newly diagnosed MGMT unmethylated glioblastoma. Patients all received AZD1390 plus radiation, though in different doses depending on the arm.
In terms of safety and tolerability — the trial's primary endpoints — Yang said the ATM inhibitor plus radiation was well-tolerated, with the most common adverse events being fatigue, nausea, and headache.
Yang and colleagues settled on a maximum tolerated dose of 400 mg of AZD1390 once daily for the recurrent glioblastoma patients. Above this dose, the drug led to skeletal and muscle toxicities, he said. Among recurrent glioblastoma patients receiving AZD1390, 9.3 percent discontinued the drug due to adverse events from either the ATM inhibitor or radiation, and 6.7 percent discontinued the drug because of toxicities from AZD1390 alone.
Among the patients who were newly diagnosed, the drug combination was also well-tolerated, he said. The most common side effects were fatigue, radiation skin injury, and headaches. For this newly diagnosed cohort of patients, the investigators determined the maximum tolerated dose to be 300 mg daily. In this cohort, 10 percent of patients discontinued AZD1390 due to adverse events from either the drug or the radiation, and none of the patients discontinued treatment due to toxicities from AZD1390 alone.
Among patients with recurrent glioblastoma, the median event-free survival on AZD1390 plus radiation was 4.7 months and the overall survival was 12.7 months. The survival data in the newly diagnosed arm, he said, are still maturing.
"The most immediate impact of what we saw here today is that we may have a promising regimen," Yang said during a presentation to members of the media Tuesday morning. "But obviously the study is still ongoing, and there's a lot of work that needs to be done to push that forward."
Schram noted that it won't be until randomized Phase III trials that researchers will be able to truly home in on the relative benefit of AZD1390 versus the radiation alone in these patients. What's more, "there's a growing list of DNA damage response proteins that may act as radiosensitizers, and it remains to be seen which of these will be the most effective," she said.
For now, Yang is looking ahead to readouts from Arm C of the Phase I/II trial, which includes the newly diagnosed patients, while also focusing on selecting a Phase II dose for AZD1390. Though he and Sanai acknowledged that their studies are too early to say AstraZeneca's investigational agent definitively works in these patients, Yang, as a radiation oncologist, was optimistic that a new radiation-drug combination has entered clinic trial at all.
"There is a paucity of novel therapeutics being developed with radiation," Yang said at the press conference. "This study really emphasized that we need to do more of this."