AACR: Zentalis’ WEE1 inhibitor shows promise in phase 1, with potential for
PARP inhibitors such as Merck and AstraZeneca’s Lynparza have changed the game for patients with ovarian cancer, but they’re still not a cure, as cancers can outsmart these drugs and develop resistance. Zentalis Pharmaceuticals is developing a WEE1 inhibitor that it hopes to combine with PARP inhibitors and other cancer medicines to boost their efficacy—and its early phase 1 data are promising.
The study was geared to measure safety in patients with different kinds of advanced cancer, but it turned up “unexpected” and “dramatic” responses in very sick patients, Zentalis CEO Anthony Sun, M.D., said. The drug, ZN-c3, shrank tumors in two patients enough for them to be considered responders: One patient had stage 4 ovarian cancer and had tried 18 lines of treatment, while the other patient had stage 4 colorectal cancer and had undergone five prior lines of treatment, according to data presented virtually at the American Association for Cancer Research meeting on Saturday.
The ovarian cancer patient saw targeted tumors shrink by about half (56%) and, four weeks into treatment, saw a “large rapid drop” in blood levels of CA-125, an antigen used to monitor certain cancers. As of the data cutoff, the patient had been on the drug for more than six months (185 days) and is still being treated. As for the colorectal cancer patient, tumors shrank by 42% and the patient remained on treatment for about six months before disease worsened.
“We are extra excited because every time you develop a drug, you wonder, ‘Do we have a drug?’” Sun said. “I think we unequivocally have a drug … You don’t see these kinds of exceptional responses very often.”
Three other patients had their tumors shrink, too—including one with non-small cell lung cancer and two with uterine serous carcinoma, an uncommon form of endometrial cancer—but these responses need to be confirmed with repeat measurements.
The study tested doses of ZN-c3 starting at 25 mg per day and going as high as 450 mg per day. Zentalis has landed on 300 mg per day as the dose for a phase 2 study testing the drug as a single agent. The company has already started the phase 1 expansion of the trial with this dose and will explore combining the drug with other cancer treatments.
The drug’s safety profile could make it particularly well suited for use in combinations. Side effects were mostly mild to moderate, with nausea affecting about half of the 55 patients evaluable for safety, and diarrhea, fatigue and vomiting afflicting less than one-third of them. Of note, blood-related side effects struck less than 10% of patients: 1.8% of patients suffered a low white blood cell count, 7.2% of patients had a low platelet count and 7.2% of patients developed anemia.
Others who have…