Zentalis™ Pharmaceuticals, Inc. (NASDAQ:ZNTL), a clinical-stage biopharmaceutical company focused on discovering and developing clinically differentiated small molecule therapeutics targeting fundamental biological pathways of cancers, today announced plans to initiate the first study of its collaboration with Pfizer on Zentalis’ product candidate ZN-c3, a selective Wee1 inhibitor designed to induce synthetic lethality in cancer cells. The study is one component of Zentalis’ strategic collaboration with Pfizer, which was previously announced along with Pfizer’s $25 million equity investment in Zentalis.
Zentalis and Pfizer will initiate a Phase 1/2 dose escalation study of ZN-c3 in combination with encorafenib and cetuximab—an FDA-approved standard of care known as the BEACON regimen—in patients with BRAF V600E-mutated metastatic colorectal cancer (mCRC). Published studies indicate that up to 21% of mCRC patients have BRAF mutations and that the V600E mutation accounts for more than 95% of BRAF mutations.1 BRAF-mutated mCRC constitutes a more aggressive malignancy than non-BRAF-mutated mCRC, generally conferring worse survival outcomes. While the BEACON regimen established a new standard of care for patients with BRAF V600E-mutated mCRC—demonstrating statistically significant and clinically meaningful improvement in overall survival—all patients taking this regimen eventually progress, at which point they have limited additional treatment options. BRAF-mutated mCRC therefore continues to represent an area of significant unmet medical need.
“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, M.D., Chief Medical Officer of Zentalis. “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 (DDR) agents could be another potential treatment option to help improve the lives of people living with BRAF-mutated metastatic colorectal cancer.”
“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, Ph.D., 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. “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.”
Preclinical evidence supports the rationale for combining inhibition of BRAF, Wee1 and EGFR. Wee1 inhibition has shown synergy with many targeted agents in mutationally driven cancers, and the addition of ZN-c3 to encorafenib and cetuximab enhanced anti-tumor activity in a cell-line-derived xenograft (CDX) model. These observations highlight the potential synergy combining a number of molecularly targeted therapies.
Zentalis anticipates initiating patient enrollment in the first quarter of 2023.
