AACR21: Zentalis keeps the heat on AstraZeneca with early WEE1 data showing a group of 'exceptional' responders
Long a target for drugmakers, the DNA damage repair pathway has picked up some new steam in recent years with Big Pharma placing its bets. One of the leading candidates there is a WEE1 enzyme inhibitor from AstraZeneca, and now a small biotech player is looking to play catch up.
Zentalis’ WEE1 inhibitor, ZN-c3, posted partial responses across a slate of tumor types with a tolerable safety profile as monotherapy for solid tumor patients who are either treatment-resistant or have no established standard of care, according to interim Phase I data presented as a late breaker Saturday at the virtual AACR annual meeting.
In what the Zentalis team hopes will be a meaningful competitor to AstraZeneca’s own WEE1 inhibitor, ZN-c3 posted three “exceptional responses” among 55 patients by the Feb. 12 data cutoff, including in patients with a long history of prior therapy and across tumor types. Exceptional responders are patients who post a complete or partial response where less than 10% of the patient population is expected to show results.
In one case, a Stage IV ovarian cancer patient with 18 prior lines of therapy — 11 of those in the metastatic setting — posted a 56% reduction in target lesions with a key biomarker showing rapid onset at the four-week mark of therapy. Researchers also saw partial responses in patients with colorectal cancer and non-small cell lung cancer and two non-exceptional partial responses in uterine serous carcinoma.
It’s early days, but Zentalis has enough to go on to move along into the Phase II portion of the monotherapy study with an optimal dose — 300 mg — that the biotech says can minimize side effects while showing PD biomarker activity.
The monotherapy study — which CEO Anthony Sun said showed “remarkable safety and tolerability” — is part of a broad clinical program for ZN-c3, one of a class of WEE1 inhibitors that targets tumor cells’ DNA damage repair pathway. Given its aim to prevent cell repair caused by other agents, WEE1s are a natural target for combination therapy, and Zentalis is currently working on a ZN-c3/chemo combo trial as well as planned studies in combination with PARP inhibitors, which also target the DDR pathway.
But Zentalis is also keeping its eye on AstraZeneca’s WEE1, AZD1775, which has shown OS benefit in pancreatic cancer patients and is being envisioned as a successor drug to PARP inhibitor Lynparza. Back in August 2019, the drug spurred an OS of 22 months with progression-free survival of 9 months in a small-scale study of 32 pancreatic cancer patients.
Zentalis thinks ZN-c3 could eventually best AZD1775 with a better safety profile, which Sun said was the result of the molecule being more selective with better pharmacokinetic qualities. The biotech is also in the process of developing what it calls novel biomarkers to help identify solid tumor patients who could best benefit from ZN-c3’s use.
Editor’s Note: This story has been updated to correct an error. Zentalis recorded three exceptional tumor responses in the Phase I data.