OncoMed reports positive data on tarextumab’s anti-cancer stem cell activity in clinical cancer research

The article details tarextumab’s anti-tumor effects alone and in combination with chemotherapy and elucidates the drug candidate’s mechanisms of activity. Additionally, data is presented describing the basis for biomarker identification of tumors with increased sensitivity to treatment with tarextumab.

"The early evidence of activity that we are seeing for tarextumab in our clinical trials is consistent with results of our preclinical studies. For instance, the Phase 1b biomarker-delineated response rates and survival data for tarextumab in pancreatic cancer is similar to the preclinical evidence that tumors with high Notch3 gene expression are more likely to respond to treatment," said Paul J. Hastings, OncoMed’s Chairman and Chief Executive Officer.

"Tarextumab is currently being studied in two randomized Phase 2 clinical trials for pancreatic cancer and small cell lung cancer. We look forward to reporting additional clinical and biomarker data from our tarextumab program in the months to come."

Key findings from the paper, titled "Targeting Notch signaling with a Notch2/Notch3 antagonist (tarextumab) inhibits tumor growth and decreases tumor initiating cell frequency", include:

Tarextumab was efficacious in inhibiting the growth of preclinical patient-derived xenografts from various solid tumor types, including lung, ovarian, breast and pancreatic cancers, indicating the potential for broad utility of tarextumab.

Tarextumab demonstrated a dual mechanism of action: inhibiting signaling of Notch2 and Notch3 in tumor cells and modulating the function of tumor vasculature through its action on pericytes.

Inhibition of Notch signaling in tumor cells was associated with a reduction in cancer stem cell frequency, promotion of tumor cell differentiation and a delay in tumor recurrence following chemotherapy treatment.

Tumor sensitivity to treatment with tarextumab in combination with chemotherapy was significantly higher in pancreatic tumors that had a higher level of Notch3 gene expression. Based on these data, Notch3 gene expression is being evaluated as a potential predictive biomarker for tarextumab in ongoing clinical trials.

"In this paper, we show that the blockade of Notch signaling with tarextumab sensitizes tumors to chemotherapy and reduces cancer stem frequency, delaying cancer recurrence as compared to chemotherapy alone," said Tim Hoey, Ph.D., Senior Vice President, Cancer Biology and a co-author of the paper.

"Preclinical data for tarextumab, particularly as part of a combination regimen, provide a strong rationale for the utility of targeting Notch2 and Notch3 for cancer treatment, and suggest that this therapeutic approach may improve clinical outcomes. We are currently exploring the impact of this targeted anti-cancer stem cell agent in our Phase 2 clinical trials."

Tarextumab (anti-Notch2/3, OMP-59R5) is a fully human monoclonal antibody that targets the Notch2 and Notch3 receptors. Preclinical studies have suggested that tarextumab exhibits two mechanisms of action: (1) by downregulating Notch pathway signaling, tarextumab appears to have anti-cancer stem cell effects, and (2) tarextumab affects pericytes, impacting stromal and tumor microenvironment.

Tarextumab is currently being studied in two randomized Phase 2 clinical trials. The "Alpine" study is assessing tarextumab with Abraxane (paclitaxel protein-bound particles for injectable suspension) (albumin bound) plus gemcitabine in first-line advanced pancreatic cancer patients.

The "Pinnacle" study is testing tarextumab in combination with etoposide and cisplatin and etoposide and carboplatin in first-line extensive stage small cell lung cancer patients. Data from OncoMed’s Phase 1a and Phase 1b clinical trials of tarextumab indicate that the antibody is well tolerated, with on-target modulation of the Notch signaling pathway and signs of anti-tumor activity. Tarextumab is part of OncoMed’s collaboration with GlaxoSmithKline (GSK).

GSK has an option to obtain an exclusive license to tarextumab during certain time periods through completion of the proof-of-concept Phase 2 trials.