Ficlatuzumab (formerly known as AV-299), a potent hepatocyte growth factor (HGF) immunoglobulin G1 (IgG1) inhibitory antibody that binds to the HGF ligand with high affinity and specificity, in combination with cytarabine (also known as arabinofuranosyl cytidine or ara-C), demonstrates signs of clinical efficacy in patients with relapsed/refractory acute myeloid leukemia (AML).
The investigational drug is currently being evaluated in a number of clinical trials for the treatment of both solid and hematological malignancies, including squamous cell carcinoma of the head and neck (HNSCC), metastatic pancreatic ductal cancer (PDAC), and acute myeloid leukemia (AML).
Results of a study were published in Blood Cancer Discovery, a journal of the American Association for Cancer Research (AACR) shows that the investigational drug being developed by Aveo Oncology, nine of 17 patients (53%) participating in the trial, had a complete response, and four of the responding patients had no signs of minimal residual disease. 
The study was funded by the National Cancer Institute (NCI), the Damon Runyon Postdoctoral Award, the American Society for Clinical Oncology (ASCO) Young Investigator Award, the Department of Defense, and a Gateway for Cancer Grant.
Long term results
Patients diagnosed with acute myeloid leukemia (AML) who are refractory to induction therapy or relapsed within 1 year have poor outcomes.
“Only about half of patients with acute myeloid leukemia (AML) will achieve long-term disease control,” said senior author Charalambos Andreadis, MD, professor of clinical medicine at the University of California, San Francisco (UCSF).
“Patients whose AML relapses or does not respond to initial therapy have worse outcomes, Andreadis explained. These patients typically undergo subsequent multi-agent chemotherapy, a toxic treatment with limited success in this population,” he added.
“Unfortunately, patients whose cancers relapse or don’t respond to initial therapy face a poor outlook, as only 30 to 40 percent of these patients respond to subsequent multi-agent chemotherapy and even fewer develop long-term remissions. Most patients will eventually succumb to their disease,” Andreadis further noted.
Unmet medical needs
Although New therapies targeting AML-specific mutations have been developed in recent years, Andreadis noted that these target select patients, highlighting the need for new, widely applicable therapies.
In their study, Andreadis and colleagues evaluated the safety and efficacy of an investigational agent targeting a shared chemical pathway in combination with single-agent chemotherapy in patients with relapsed/refractory AML.
The investigational therapy, ficlatuzumab, is a first-in-class monoclonal antibody that binds the extracellular hepatocyte growth factor (HGF) to prevent it from activating MET signaling and stimulating tumor growth. “Unlike most existing targeted cancer therapies, ficlatuzumab targets an extracellular factor instead of a cancer-specific mutation,” Andreadis explained, adding that some patients with refractory AML have higher levels of circulating HGF.
The phase I clinical trial enrolled 17 adult patients with AML that was either refractory to prior treatment or that had relapsed within 12 months of prior treatment. Patients received four doses of ficlatuzumab, administered 14 days apart, along with the chemotherapeutic cytarabine.
A total of nine of 17 participating patients (53 percent) had a complete response, and four of the responding patients had no signs of minimal residual disease. Among responding patients, the progression-free survival was 31.2 months, and the overall survival was not reached.
Ten patients (eight responders and two non-responders) proceeded to allogeneic hematopoietic cell transplantation; six of these patients remained in remission at the most recent follow-up.
The most common adverse event was febrile neutropenia. Serious adverse events occurred in two patients, and there was one death unrelated to the investigational therapy. Dose-limiting toxicities were not observed, and 20 mg/kg was established as the recommended phase II dose.
“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,” Andreadis said. “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.”
Treatment-induced molecular changes
To identify molecular changes associated with treatment response, Andreadis and colleagues analyzed peripheral blood mononuclear cells collected at baseline and at several time points after treatment initiation. Using phospho-proteomic mass cytometry they found that ficlatuzumab treatment led to attenuated phosphorylation of MET, the receptor for HGF, thereby confirming on-target inhibition of HGF.
Clinical response to ficlatuzumab treatment was associated with reduced phosphorylation of the S6 protein and increased expression of genes involved in myeloid and leukocyte activation, whereas non-responding patients were more likely to have increased expression of HGF, increased phosphorylation of S6, and expression of genes involved in protein translation, cell adhesion, and type I interferon signaling.
“By comparing pre-treatment to post-treatment blood samples using state-of-the-art single-cell mass cytometry and RNA sequencing, we observed that ficlatuzumab successfully suppressed HGF signaling, and we also identified biomarkers of treatment response and resistance,” said Victoria Wang, MD, Ph.D., an assistant professor of hematology and oncology at UCSF and first author of the study.
“This approach provided novel insight into the molecular changes that occur upon treatment, which could have clinical implications for tracking treatment response or identifying patients likely to respond,” Wang added.
The study results demonstrated a favorable safety profile and promising clinical activity of ficlatuzumab and cytarabine in high-risk AML patients, supporting further investigation of this combination in a randomized trial. The results also showed the utility of a novel application using multiplexed single-cell analyses to detect on-target activity and identify biomarkers of response. 
“Together, our findings suggest that targeting an extracellular factor in conjunction with existing cancer therapies could be an effective therapeutic strategy for AML treatment,” Andreadis concluded.
The study’s authors recognized that the small sample size and its single-arm design is one of the limitations of the study. Andreadis and Wang also noted that since the study was designed to assess safety and dosing, rather than efficacy, additional studies to validate the efficacy findings will be needed.
A phase II clinical trial to evaluate ficlatuzumab plus chemotherapy has been initiated. An additional limitation was the lack of bone marrow specimens for the gene expression analyses.
Earlier results from an unrelated randomized confirmatory Phase 2 study of ficlatuzumab as a single agent (20 mg/kg IV) or in combination with cetuximab (Erbitux®; Merck KGaA; 500 mg/m2 IV every two weeks), an EGFR-targeted antibody, in patients who relapsed or were refractory to prior immunotherapy, chemotherapy, and cetuximab (pan-refractory) with metastatic head and neck squamous cell carcinoma (HNSCC) demonstrated that the ficlatuzumab and cetuximab combination arm met the study’s primary endpoint of median PFS, with the 32 evaluable patients in the arm demonstrating a median PFS of 3.6 months (lower bound 90% confidence interval [CI] 2.3 months; p=0.04), and 1.8 months (lower bound 90% CI: 1.7 months) for the 26 evaluable patients receiving ficlatuzumab alone. For the key secondary endpoint of overall response rate (ORR), the combination arm demonstrated an ORR of 19% and 4% for ficlatuzumab alone.
Of note, patients with Human papillomavirus (HPV) negative disease, which is associated with poorer outcomes compared to HPV positive disease, who received the combination demonstrated prolonged PFS (4.1 months; versus 2.3 months for HPV positive, p=0.03) and a response rate of 38% (versus 0% for HPV positive, p=0.02), which included 18% CRs. The results of this study were presented earlier this year during the annual meeting of the American Society of Clinical Oncology (ASCO) which was held June 4-8, 2021. 
Ficlatuzumab With High Dose Cytarabine in Relapsed and Refractory AML – NCT02109627
Ficlatuzumab and Cetuximab in Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma (HNSCC) NCT02277197
Ficlatuzumab w/wo Cetuximab in Patients w/Cetuximab-Resistant, Recurrent or Metastatic Head/Neck Squamous Cell Carcinoma – NCT03422536
Highlights of Prescribing Information
Cetuximab (Erbitux®; Merck KGaA)[Prescribing Information]
Cytarabine (Cytosar-U®; Pfizer/Hospira) [Prescribing Information]
Cytarabine (DepoCyt®; Sigma-Tau Pharmaceuticals)[Prescribing Information]
 Wang VE, Blaser BW, Patel RK, Behbehani GK, Rao AA, Durbin-Johnson B, Jiang T, Logan AC, et al. Inhibition of MET Signaling with Ficlatuzumab in Combination with Chemotherapy in Refractory AML: Clinical Outcomes and High-Dimensional Analysis Blood Cancer Discov July 16, 2021, DOI: 10.1158/2643-3230.BCD-21-0055
 Bauman JE, et al. Randomized Phase II trial of ficlatuzumab with or without cetuximab in pan-refractory, advanced head and neck squamous cell carcinoma (HNSCC). Abstract #6015; Presented at: American Society of Clinical Oncology (ASCO; Virtual Congress) held June 4-8, 2021.