AACR: Zentalis' WEE1 inhibitor shows promise in phase 1, with potential for combos down the line

Anthony Sun
Zentalis CEO Anthony Sun, M.D. (Zentalis Pharmaceuticals)

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.

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“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.

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Others who have tried blocking the WEE1 enzyme have run into blood-related side effects, Sun said. “White blood cells, red blood cells and platelets all get driven down. Because of our very limited rate of adverse events on the hematological side, our drug could be a fantastic partner to be used with chemotherapy.”

And it doesn’t stop at chemo—Zentalis could potentially pair ZN-c3 with targeted treatments, including PARP inhibitors, Sun said.

Like PARP enzymes, WEE1 enzymes play a role in the DNA damage response, or DDR, pathway. When DNA damage is detected in a cell, the cell halts the cell cycle, or the processes that occur in a cell as it grows and divides, and then tries to repair that damage.

“Inhibiting WEE1 prevents that cell cycle from stopping,” Sun said. “If you have a cancer car, blocking WEE1 is like cutting the brake line: They can’t slow down and drive off a cliff. When a cell has damaged DNA and goes into cell replication, that’s a huge no-no and the cells die.”

A combination of chemotherapy and a WEE1 inhibitor like ZN-c3 would deliver a one-two punch to cancer cells, with the former damaging the cells’ DNA and the latter preventing the cells from fixing that damage. As for combining WEE1 inhibitors with PARP inhibitors, the approach could “resensitize” patients whose cancers have become resistant to PARP inhibitors to care.

AstraZeneca is also developing a WEE1 inhibitor, adavosertib, but its safety, tolerability and “awkward” dosing regimen could be its “Achilles heel,” SVB Leerink analyst Andrew Berens, M.D., wrote in an investor note Thursday evening, noting that adavosertib led to anemia in 52% of patients, low platelet counts in 48% of patients and low white blood cell counts in 40% of patients in a phase 1 study.

Zentalis' decision to take the 300-mg dose of ZN-c3 forward "implies a clean profile at this dose level, and we are encouraged by the daily dosing regimen, which appears to be a significant commercial liability for AZN's (OP) WEE1,” Berens followed up in a note Friday morning.