Dr Sumrall on the Clinical Efficacy of ONC201 in H3K27M -Mutant Diffuse Midline Gliomas

Ashley Sumrall, MD, FACP, clinical assistant professor, medicine, University of North Carolina at Chapel Hill, medical oncologist, section chief, Neuro-Oncology, Atrium Health, Levine Cancer Institute, discusses the clinical efficacy of ONC201 in 

The investigational small molecule ONC201 functions as a dopamine receptor D2 antagonist, and has shown preclinical activity when treating gliomas and other solid tumors through dopaminergic activation integrated stress response, as well as inactivation of AKT and ERK. Patients with 

-mutant diffuse midline glioma have achieved promising outcomes when treated with ONC201, Sumrall begins. Furthermore, prior research has shown that patients with disease affecting the thalamus experience better responses with ONC201 due to an enriched presence of dopamine receptors in this structure, Sumrall notes. 

According to results from a phase 2 pilot study (NCT02525692), ONC201 treatment without molecular stratification did not improve progression-free survival compared with historical controls in patients with recurrent, bevacizumab (Avastin)–naive, IDH1/2 wild-type glioblastoma. However, the agent showed signs of anti-tumor activity in 2 of 4 patients with 

 mutations who were enrolled in the 2 glioblastoma arms of this trial. Subsequent findings from a follow-up study showed that treatment with ONC201 prolonged responses among multiple patients with 

-mutant disease in a mixed cohort of several ongoing studies (n = 18).

To further elucidate the efficacy of and mechanism underlying responses to ONC201 in this population investigators evaluated data from a completed phase 1 study (NCT03416530) and a completed expanded access study (NCT03134131), Sumrall details. Results show that patients treated with ONC201 post-initial radiation, but before recurrence, exhibited a median overall survival (OS) of 21.7 months, whereas those treated following disease recurrence had a median OS of 9.3 months. The agent was deemed well tolerated with minimal adverse effects, Sumrall adds.

The mechanistic insights from this study reveal that ONC201 disrupts integrated metabolic and epigenetic pathways, thereby addressing the pathognomonic reduction in H3K27me3. Overall, this comprehensive study supports ONC201 as a potential monotherapy for improving outcomes in 

-mutant diffuse midline glioma beyond radiation.

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Ashley Sumrall, MD, FACP, medical oncologist, section chief, Neuro-Oncology, clinical assistant professor, medicine, Atrium Health, Levine Cancer Institute, discusses the clinical efficacy of ONC201 in H3K27M-mutant diffuse midline gliomas.

As I faced my final year of fellowship for medical training, stressed was the best word to describe how I felt. I was not stressed by lack of training, inexperience, or confidence. It was the decision that loomed ahead. Where would I work? How would I choose between academics or private practice? What type of career and life did I want to build? Until this time, my decisions were largely dictated for me through matching processes. Now I would be responsible for my own decision, for better or worse. 

I scoured the internet, interviewed attendings, and made pros and cons lists. I still felt uneasy as I narrowed my field of choices. Nothing seemed to fit. 

Then a unique opportunity presented itself in the form of a hybrid role. Interested, I decided to learn more about a position that I did not even know existed. I learned that I could marry an academic interest with a private practice style of clinic. I could teach both residents and fellows, while also having my own panel of patients. Not only would I not need to secure grant funding, but I could pursue it if desired. The compensation would be competitive with room to grow. When the position was offered to me, I jumped at the chance. 

Now, 12 years later, I am still working in my first attending role and loving the hybrid nature. But why? Most hybrid roles combine aspects of private practice with academics, but individual programs vary in how they allot responsibilities. In my role, I am given an expected level of clinical productivity. With planning, this has allowed me to decide how many patients per day I would like to see. In my model, I never have a day of more than 20 outpatients, and most days I see fewer than that. 

My clinic days are limited during the handful of weeks per year I serve on our inpatient service, and my partners assist with juggling schedules on those weeks. The time I have away from the office falls within a generous allowance for vacation and continuing medical education. 

Now on the academics front, I am able to teach residents and fellows via outpatient clinic, inpatient service, and didactics. Our section keeps a roster of clinical trials—including phase 1—available for patients, and I have been fortunate to open clinical trials quickly at our center. I am encouraged to publish papers and write clinical trials and I have a team of colleagues who work on these projects alongside me. We hold section meetings to review clinical trials that we would like to open and/or close, and to update our treatment guidelines for our cancer center accordingly to ensure we are providing optimal and appropriate cancer care. 

As I considered the hybrid model, I also wanted to be able to fit in leadership roles at my cancer center and volunteer involvement with the American Society of Clinical Oncology. I have been able to fulfill all of these passions as well as participate in leadership development opportunities. As I progress through my career, I may choose to increase leadership activities and decrease academic activities. This is the only career model where you can have freedom to make those adjustments, maintain a clinical presence, and seek balance. 

As time passes, more hybrid cancer centers are forming. This creates more opportunities for fellows and early-career oncologists. As you seek career opportunities, be sure to look for these roles. Professional and personal satisfaction are both possible with this option that optimizes work-life balance.

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Professional and personal satisfaction are both possible with a hybrid option that optimizes work-life balance.

Ashley Sumrall, MD

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Dr Sumrall on the Clinical Efficacy of ONC201 in H3K27M -Mutant Diffuse Midline Gliomas

Marrying Career Interests