Study demonstrates efficacy of new treatment for neurofibromatosis type 1-related tumors

Date:
January 14, 2021
Source:
Children's Hospital of Philadelphia
Summary:
Based on preclinical studies of an investigational drug to treat
peripheral nerve tumors, researchers have shown that the drug,
cabozantinib, reduces tumor volume and pain in patients with the
genetic disorder neurofibromatosis type 1 (NF1).



FULL STORY ========================================================================== Based on preclinical studies of an investigational drug to treat
peripheral nerve tumors, researchers at Children's Hospital of
Philadelphia (CHOP) as part of the Neurofibromatosis Clinical Trials
Consortium have shown that the drug, cabozantinib, reduces tumor volume
and pain in patients with the genetic disorder neurofibromatosis type 1
(NF1). The results of the Phase 2 clinical trial, co-chaired by Michael
J. Fisher, MD at CHOP, were published recently in Nature Medicine.


========================================================================== "This is the second class of drugs to demonstrate a very promising
response rate for NF1 patients with these tumors," said first
author Fisher, Chief of the Section of Neuro-Oncology and Director
of the Neurofibromatosis Program at CHOP, and Group Chair for the
NF Clinical Trials Consortium, which includes 25 sites developing
innovative biologically-based clinical trials for complications of
NF. "Collectively, the data presented in this study illustrate a true bench-to-bedside approach, coordinating translational and clinical
efforts to advance targeted therapies for a rare disease like NF1."
NF1 is a rare tumor predisposition syndrome, affecting approximately 1
in 3000 people worldwide. The condition involves the proliferation of
tumors throughout the central and peripheral nervous system. One of the
most prevalent type of tumors in NF1 are plexiform neurofibromas (PN), multicellular tumors composed of tumorigenic Schwann cells, fibroblasts, perineural cells, macrophages, mast cells, and secreted collagen. The
tumors arise within nerves, affect up to half of patients with NF1, grow rapidly during childhood, and can lead to motor and sensory dysfunction,
pain, and disfigurement. When the tumors impinge on vital structures
like the airway or the spinal cord, they can be life-threatening, and
although the tumors are not malignant, they can become so over time.

Because chemotherapy and radiation are ineffective at treating these
tumors, surgery is the current standard of care. However, given that
the tumors can be intertwined with nerves and other vital structures,
surgery is often not possible. Recent studies have shown that a MEK
inhibitor called selumetinib can be an effective treatment in some
children with NF1-related PNs, but not all patients respond to this
treatment, so there is a need for more treatment options.

Based on preclinical studies of cabozantinib, a tyrosine kinase inhibitor
that targets both the tumorigenic Schwann cells in PNs as well as the
complex tumor microenvironment, the researchers enrolled patients in a
single arm, multicenter Phase 2 clinical trial. Twenty-three patients
between the ages of 16 and 34 enrolled in the trial; twenty-one were
evaluable for drug toxicity and 19 were evaluable for their response
to the treatment. Of the 19 patients studied for response, eight (42%)
had a partial response, defined as having greater than a 20% decrease in
tumor volume, and 11 had stable disease after 12 rounds of treatment. No patient had disease progression while participating in the trial. The
eight patients who had a partial response to treatment also reported a significant reduction in tumor pain intensity and pain interference in
daily life.

Patients enrolled in the trial reported several adverse events, including diarrhea, nausea, asymptomatic hypothyroidism, fatigue, and palmar
plantar erythrodysesthesia, a condition that causes redness, swelling,
and pain on the palms of the hands and/or the soles of the feet. However,
none of the side effects were reported as being severe.

Based on the benefit of cabozantinib demonstrated in this study, the NF Clinical Trials Consortium opened a pediatric cohort as well, enrolling patients ages 3 to 15. Enrollment is complete, and the study is ongoing.

"It's incredibly exciting that we now have two classes of drugs that
result in tumor responses, given that we had no promising agents only
a few years ago," Dr. Fisher said. "However, despite this excitement,
neither cabozantinib nor MEK inhibitors shrink all tumors or make them
go away completely. Therefore, we are building on these results as well
as ongoing laboratory studies and are planning future exploration of combination therapies, so that we can further improve outcomes for these patients with these debilitating and life- threatening tumors."

========================================================================== Story Source: Materials provided by
Children's_Hospital_of_Philadelphia. Note: Content may be edited for
style and length.


========================================================================== Journal Reference:
1. Michael J. Fisher, Chie-Schin Shih, Steven D. Rhodes, Amy
E. Armstrong,
Pamela L. Wolters, Eva Dombi, Chi Zhang, Steven P. Angus, Gary L.

Johnson, Roger J. Packer, Jeffrey C. Allen, Nicole J. Ullrich,
Stewart Goldman, David H. Gutmann, Scott R. Plotkin, Tena Rosser,
Kent A.

Robertson, Brigitte C. Widemann, Abbi E. Smith, Waylan K. Bessler,
Yongzheng He, Su-Jung Park, Julie A. Mund, Li Jiang, Khadijeh
Bijangi- Vishehsaraei, Coretta Thomas Robinson, Gary R. Cutter,
Bruce R. Korf, Jaishri O. Blakeley, D. Wade Clapp. Cabozantinib
for neurofibromatosis type 1-related plexiform neurofibromas:
a phase 2 trial. Nature Medicine, 2021; 27 (1): 165 DOI:
10.1038/s41591-020-01193-6 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/01/210114130119.htm

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