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Phase II study of sorafenib in children with recurrent or progressive low-grade astrocytomas
Matthias A Karajannis1, Geneviève Legault1, Michael J Fisher1
1NYU Comprehensive Neurofibromatosis Center, Division of Pediatric Hematology/Oncology, Department of Pediatrics and Laura and Isaac Perlmutter Cancer Center at NYU Langone Medical Center, New York, New York (M.A.K., G.L., A.M., J.C.A.); Division of Oncology, Children's Hospital of Philadelphia and the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania (M.J.F., A.J.S.); Department of Radiology, NYU Langone Medical Center, New York, New York (S.S.M., M.C.B.); The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland (K.J.C.); Division of Pediatric Neurosurgery, Department of Neurosurgery, NYU Langone Medical Center, New York, New York (J.H.W., D.H.H.); Division of Biostatistics, Department of Population Health and The Laura and Isaac Perlmutter Cancer Center at NYU Langone Medical Center, New York, New York (J.D.G., T.H.); Department of Neurosurgery, Children's Hospital of Philadelphia and the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania (A.C.R); Division of Hematology/Oncology, Children's Hospital Los Angeles, Los Angeles, California (G.D.); German Cancer Research Center and University Hospital, Heidelberg, Germany (D.T.W.J., A.K., S.M.P.); Division of Neuropathology, Department of Pathology, Johns Hopkins University, Baltimore, Maryland (C.G.E.); Division of Neuropathology, Department of Pathology, Department of Neurosurgery and Laura and Isaac Perlmutter Cancer Center at NYU Langone Medical Center, New York, New York (D.Z.).
Background:
Activation of the RAS-RAF-MEK-ERK signaling pathway is thought to be the key driver of pediatric low-grade astrocytoma (PLGA) growth. Sorafenib is a multikinase inhibitor targeting BRAF, VEGFR, PDGFR, and c-kit. This multicenter phase II study was conducted to determine the response rate to sorafenib in patients with recurrent or progressive PLGA.
Methods:
Key eligibility criteria included age ≥ 2 years, progressive PLGA evaluable on MRI, and at least one prior chemotherapy treatment. Sorafenib was administered twice daily at 200 mg/m(2)/dose (maximum of 400 mg/dose) in continuous 28-day cycles. MRI, including 3-dimensional volumetric tumor analysis, was performed every 12 weeks. BRAF molecular testing was performed on tumor tissue when available.
Results:
Eleven patients, including 3 with neurofibromatosis type 1 (NF1), were evaluable for response; 5 tested positive for BRAF duplication. Nine patients (82%) came off trial due to radiological tumor progression after 2 or 3 cycles, including 3 patients with confirmed BRAF duplication. Median time to progression was 2.8 months (95% CI, 2.1-31.0 months). Enrollment was terminated early due to this rapid and unexpectedly high progression rate. Tumor tissue obtained from 4 patients after termination of the study showed viable pilocytic or pilomyxoid astrocytoma.
Conclusions:
Sorafenib produced unexpected and unprecedented acceleration of tumor growth in children with PLGA, irrespective of NF1 or tumor BRAF status. In vitro studies with sorafenib indicate that this effect is likely related to paradoxical ERK activation. Close monitoring for early tumor progression should be included in trials of novel agents that modulate signal transduction.
Insights
Sorafenib unexpectedly accelerated tumor growth in pediatric low-grade astrocytoma (PLGA) patients, regardless of BRAF status. This suggests paradoxical ERK activation, necessitating close monitoring in future signal transduction inhibitor trials.
Area of Science:
- Pediatric oncology
- Molecular targeted therapy
- Cancer signaling pathways
Background:
- Pediatric low-grade astrocytoma (PLGA) growth is driven by the RAS-RAF-MEK-ERK pathway.
- Sorafenib, a multikinase inhibitor, targets key components of this pathway.
- This study investigated sorafenib's efficacy in recurrent or progressive PLGA.
Purpose of the Study:
- To determine the response rate of sorafenib in pediatric patients with recurrent or progressive PLGA.
- To evaluate the safety and efficacy of sorafenib in this patient population.
Main Methods:
- A multicenter phase II study enrolled patients aged ≥2 years with progressive PLGA.
- Sorafenib was administered at 200 mg/m(2) twice daily.
- Tumor response was assessed via MRI with volumetric analysis every 12 weeks; BRAF testing was performed when available.
Main Results:
- Eleven patients were evaluable; 9 (82%) experienced radiological tumor progression, leading to early trial termination.
- Median time to progression was 2.8 months.
- Tumor progression occurred irrespective of NF1 status or BRAF duplication.
Conclusions:
- Sorafenib demonstrated an unexpected acceleration of tumor growth in pediatric low-grade astrocytoma.
- Paradoxical ERK activation is the likely mechanism for this accelerated growth.
- Future trials of signal transduction inhibitors require close monitoring for early tumor progression.
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