Can we change the landscape of pediatric diffuse intrinsic pontine glioma (DIPG)? First demonstration of clinical and radiographic response in a pediatric H3-K27M mutated DIPG to the DRD2-antagonist ONC201
,2, Yazmin Odia1, Joshua Allen3, Rohinton Tarapore3, Ziad Khatib2, Ossama Maher2, Toba Niazi2, Doured Daghistani1, Lee Schalop3, Andrew Chi4, Wolfgang Oster3, Minesh Mehta1
1Miami Cancer Institute, Miami, FL, USA, 2Nicklaus Children's Hospital, Miami, FL, USA, 3Oncoceutics, Philadelphia, PA, USA, 4NYU Langone Medical Center and School of Medicine, New York, NY, USA
INTRODUCTION: DIPG is uniformly fatal, with a median survival of 8-9 months. We report the first pediatric patient with H3-K27M mutated DIPG treated with conventional radiotherapy and the small molecule DRD2-antagonist ONC201, with a sustained radiographic and clinical response after 8 months of therapy. CASE: A 10-year-old female presented with House-Brackmann Grade IV facial palsy and unilateral hearing loss in 2/2017. MRI demonstrated a 2.3x2.1x2.7 cm medullopontine tumor. Stereotactic biopsy confirmed H3-K27M mutated diffuse midline glioma. She completed intensity-modulated radiotherapy (59.4 Gy/33 fractions) in 5/2017. MR imaging 1-month post-radiotherapy demonstrated reduction in tumor volume (2.0x1.9x2.7 cm) with persistent Grade IV facial palsy.The patient began oral ONC201 (500 mg weekly) as a single agent in 6/2017 on an IRB-approved compassionate use protocol with MRI every 2 months. ONC201 is a first-in-class DRD2-antagonist that crosses the blood-brain barrier and has shown efficacy in high grade glioma preclinical models through a p53-independent mechanism. Tumor volume sequentially decreased by 30.6, 33.2, and 41.9% over the next three MRIs, reaching 1.8x1.7x1.9 cm at 6 months from initiation of ONC201. Ipsilateral hearing was restored and the facial palsy improved to House-Brackmann Grade I by 16 weeks after starting ONC201. CONCLUSION: The patient remains clinically improved and without adverse events 8 months after starting ONC201 and 11 months from diagnosis. This case provides initial proof-of-concept for this novel agent targeting H3-K27M DIPG. Phase II trials are ongoing to evaluate the efficacy of ONC201 in adult and pediatric patients with H3-K27M gliomas.