Ficlatuzumab plus chemotherapy effective in relapsed or refractory acute myeloid leukemia
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Ficlatuzumab plus single-agent chemotherapy showed encouraging efficacy and appeared safe among patients with relapsed or refractory acute myeloid leukemia, according to phase 1 study results published in Blood Cancer Discovery.
“Patients with relapsed or refractory AML have poor outcomes, with response rates of between 30% and 40% to intensive salvage chemotherapy. Durable complete responses are even more uncommon,” Bradley W. Blaser, MD, PhD, assistant professor of leukemia research at The Ohio State University Comprehensive Cancer Center, told Healio. “Ficlatuzumab could be a promising option for patients with relapsed or refractory AML, particularly those lacking targetable mutations, but larger randomized studies will need to confirm this.”
Ficlatuzumab (Aveo Oncology) is an investigational, first-in-class monoclonal antibody that binds the extracellular hepatocyte growth factor (HGF) to prevent activation of MET signaling and stimulation of tumor growth.
Blaser and colleagues assessed the safety and efficacy of a four-dose regimen of 20 mg/kg ficlatuzumab given 14 days apart in combination with high-dose cytarabine in a cohort of 17 patients (median age, 58 years; 58.8% men) with AML who were either refractory to or had relapsed within 1 year of previous therapy.
Thirteen patients had de novo AML, three had secondary AML and one had myelodysplastic syndrome, refractory anemia with excess blasts category 2 (RAEB-2). In addition, 41.2% of patients exhibited a complex karyotype and 23.5% harbored 5q deletion. Safety and maximum tolerated dose of the combination served as primary objectives. Secondary objectives included the rate of complete remission, PFS and OS.
Researchers assessed response through next-generation sequencing with the ARUP Myeloid Malignancies Mutation panel and minimal residual disease using the University of Washington multiparameter flow cytometry assay.
Results showed the ficlatuzumab-chemotherapy combination induced an overall response rate of 53%, with all responders experiencing complete remission and four having no signs of minimal residual disease.
Median PFS was 6.6 months (31.2 months among responders) and median OS was 18.1 months (not reached among responders). Eight responders and two nonresponders underwent hematopoietic stem cell transplantation, of whom six remained in remission at last follow-up.
The combination also appeared safe. Febrile neutropenia was the most common adverse event, with nine patients experiencing grade 3 or greater febrile neutropenia. Two patients experienced serious adverse events. One patient death occurred that was unrelated to the combination treatment.
Researchers additionally examined peripheral blood mononuclear cells pooled at baseline and at various other timepoints during the study. Results confirmed on-target inhibition of HGF, with ficlatuzumab leading to attenuation of phosphorylation of MET.
“High-dimensional correlative studies with mass cytometry and single-cell RNA sequencing associated response to ficlatuzumab with induction of genes involved in leukocyte activation,” Bradley said. “Resistance to ficlatuzumab was associated with expression of genes involved in protein translation, cell adhesion and type 1 interferon signaling. Prospective clinical studies benefit from high-dimensional correlative science for identifying biomarkers of response and resistance. Genetic multiplexing, as performed here, is one way to reduce cost and increase sample throughput in this type of study.”
Ficlatuzumab could be a treatment option for patients with relapsed or refractory AML if larger randomized studies confirm its efficacy, according to Bradley.
“In correlative studies, resistance to ficlatuzumab was associated with pathways known to be important in leukemia biology,” Bradley said. “These data provide hypotheses for the lab and for future clinical trials. A phase 2 clinical study has been initiated based on these findings, and work aimed at understanding mechanisms of resistance to anti-HGF therapy is ongoing in the lab.”
For more information:
Bradley W. Blaser, MD, PhD, can be reached at The Ohio State University Comprehensive Cancer Center, 460 W. 10th Ave., Columbus, OH 43210; email: bradley.blaser@osumc.edu.
Perspective
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Primary refractory AML carries a particularly poor prognosis. There are no reliable salvage options for this difficult disease, and allogeneic HSCT offers the only real potential for durable remission and possible cure.
Wang and colleagues report promising results. The authors used several sophisticated analyses, including mass cytometry and single-cell RNA sequencing, to explore potential biomarkers for and mechanisms of response. Responses appeared to correlate with successful inhibition of the HGF/MET pathway, specifically the downstream PI3K/AKT and MAPK pathways, as measured by suppression of p-S6 by ficlatuzumab. In contrast, elevated expression of HGF was associated with nonresponse. In addition, gene module analysis showed transcriptional signatures that differed between responders and nonresponders.
The results of this novel regimen appear to be superior to most historical controls for primary refractory AML and suggest an important contribution of the HGF/MET pathway to AML resistance. However, some caution is warranted given the small sample size and the fact that nearly half of patients were still refractory to this combination. Further, most patients in this trial were aged younger than 65 years; these results are less applicable to older adults, who comprise the majority of those with AML and for whom options are especially limited. It also remains to be seen whether ficlatuzumab may have curative potential or whether it simply is a bridge to allogeneic HSCT.
More data — ideally in the form of larger, randomized trials — are needed to confirm the efficacy and safety of this regimen, as well as to better elucidate the mechanisms and predictors of response. Other combinations of ficlatuzumab, such as with hypomethylating agents and/or venetoclax [Venclexta; AbbVie, Genentech], would be interesting to explore for potential synergy and to extend treatment to older and/or unfit patients. Despite recent progress in AML, there is still much work to be done to improve outcomes. Novel approaches to therapy and correlative analyses like those employed in this study may serve as a model going forward.
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Wang VE, et al. Blood Cancer Discov. 2021;doi:10.1158/2643-3230.BCD-21-0055.
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