Trial Will Explore WEE-1 Inhibition With Encorafenib and Cetuximab in Colorectal Cancer

A phase 1/2 dose-escalation study will investigated ZN-c3 in combination with encorafenib (Braftovi) and cetuximab (Erbitux) for the treatment of patients with BRAF V600E-mutated colorectal cancer, according to a collaborative press release by Zentails Pharmaceuticals and Pfizer.¹

ZN-c3, a selective WEE-1 inhibitor designed to induce synthetic lethality in cancer cells. The drug prevents tumor growth, causing tumor regression by generating DNA damage in the cancer cells.

“We are extremely excited to announce this investigational study, which we believe will benefit greatly from the expertise and support gained through our collaboration with Pfizer,” said Carrie Brownstein, MD, chief medical officer of Zentalis, in the press release. “Combining ZN-c3 with the BEACON agents in this study represents an opportunity in our ZN-c3 clinical development program, alongside ongoing studies in both the monotherapy and chemotherapy combination settings in multiple tumor types. If successful in clinical trials and approved, the combination of ZN-c3 with targeted / DNA damage response agents could be another potential treatment option to help improve the lives of people living with BRAF-mutated metastatic colorectal cancer.”

According to published studies, up to 21% of patients with colorectal cancer have BRAF mutations and BRAF V600E mutations account for over 95% of BRAF mutations. BRAF-mutated metastatic colorectal cancer is a more aggressive than non-BRAF-mutated metastatic colorectal cancer and is typically linked with worse rates of survival and outcomes.

Currently, encorafenib plus cetuximab is an FDA-approved standard of care known as the BEACON regimen for the treatment of adult patients with metastatic colorectal cancer harboring a BRAF V600E mutation, after prior therapy.

However, while the development of the BEACON regimen established a new standard of care and demonstrated statistically significant and clinically meaningful improvements in overall survival, all patients taking this regimen eventually progress. Once they do, there are limited additional treatment options available for patients.

Ultimately, this area of BRAF-mutated colorectal cancer continues to remain one of significant unmet medical need.

Based on findings from preclinical trials, BRAF inhibition combined with a Wee1 inhibitor and EGFR warrants further investigation. Previously, Wee1 inhibitors have demonstrated synergy with a variety of targeted agents in mutationally driven cancers.

Then in a cell-line-derived xenograft model which evaluated the addition of ZN-c3 to encorafenib and cetuximab, antitumor activity was enhanced, highlighting the potential benefit of combining these targeted therapies for metastatic colorectal cancer.

The trial is expected to begin enrolling patients in the start of 2023.

“We are excited to unite Pfizer’s capabilities and development expertise with Zentalis’ innovation to aid the success of this important study,” said Adam Schayowitz, PhD, MBA, vice president and development head for breast cancer, CRC, and melanoma at Pfizer, who joined the Zentalis Scientific Advisory Board as part of the Pfizer/Zentalis collaboration, in the press release. “Through this collaboration, we have the opportunity to accelerate the foundational science Pfizer has created in this space and potentially bring a second generation of therapies to patients facing BRAF-mutated colorectal cancer.”

Reference:

Zentalis Pharmaceuticals announces first ZN-c3 clinical development collaboration with Pfizer. News Release. Zentalis Pharmaceuticals. October 24, 2022. Accessed October 31, 2022.