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Aveo Oncology's Ficlatuzumab Improves Response, Survival for AML Patients, Study Finds

NEW YORK – Researchers from the University of California, San Francisco evaluated Aveo Oncology's HGF inhibitor ficlatuzumab plus chemotherapy in patients with acute myeloid leukemia and found it successfully suppressed HGF signaling and identified biomarkers of resistance and response for AML patients.

The Phase Ib study results, published in Blood Cancer Discovery on Friday, showed that the HGF inhibitor ficlatuzumab and chemo improved response and survival for some patients with relapsed and refractory AML.

The small investigator-sponsored study enrolled 17 AML patients and evaluated three dose levels of ficlatuzumab. The participants also underwent next-generation sequencing using the ARUP Laboratories Myeloid Malignancies Mutation panel. The researchers also conducted minimal residual disease, or MRD, testing using the commercial University of Washington multiparameter flow cytometry assay.

In the study, the overall response rate based on bone marrow biopsy was 53 percent, and all nine patients who responded achieved complete remission. However, based on MRD testing, only four of the nine patients who responded were MRD negative. At the data cutoff of June 30, 2020, the median progression-free survival for responders was 31.2 months and overall survival for responders was not reached. For all patients, including non-responders, the progression-free survival and overall survival was 6.6 months and 18 months, respectively.

Compared to a study using similar enrollment criteria — the Phase III VALOR trial studying Sunesis Pharmaceuticals' TOP2 inhibitor vosaroxin plus chemo in AML — ficlatuzumab performed better in these high-risk patients. That study showed a complete remission rate of 30 percent and median overall survival of 7.5 months.

"The 53 percent response rate was quite striking to us since historical response rates for the standard-of-care treatment are in the 30 percent range," senior author Charalambos Andreadis said in a statement. "While these results need to be validated in a larger study, they suggest that ficlatuzumab in combination with single-agent chemotherapy may lead to better responses with less toxicity in patients with relapsed/refractory AML."

The researchers probed further into the mechanism of response for patients treated with ficlatuzumab in this study. Ficlatuzumab binds to HGF, an extracellular pathway, to prevent it from activating MET signaling and stimulating tumor growth. Therefore, the researchers analyzed patients' HGF expression and MET expression for clues that could predict response to the drug.

They found that high expression of HGF after treatment was associated with resistance to ficlatuzumab because it stimulates growth of myeloid blasts. They also found that MET expression was not predictive of response in these patients. However, they noted that suppression of the p-S6 protein was associated with better clinical response.

The researchers wrote that the similarity in expression of p-S6 and HGF helps ficlatuzumab suppress the HGF receptor and slow tumor growth, making p-S6 a "bona fide biomarker of clinical response."

"Through integration of our RNA and protein data, we identified that non-responders exhibit higher expression of the p-S6 protein as well as higher transcript level of genes involved in protein translation compared with the responders," the authors wrote.

Based on these results, the researchers are considering a randomized, multicenter Phase II study to confirm the clinical activity of ficlatuzumab in AML and validate the p-S6 as a biomarker of response for these patients.