Radiation oncologist and clinical trials leader Jonathan T. Yang, MD, PhD, has joined NYU Langone Health’s Perlmutter Cancer Center as director of clinical research at the Brain and Spine Tumor Center. He also serves as associate vice chair of clinical research and developmental therapeutics in the Department of Radiation Oncology.

Dr. Yang has been at the forefront of driving innovation in the treatment of metastatic cancers and central nervous system (CNS) malignancies, leading several pivotal studies in leptomeningeal metastases (LM), systemic metastatic disease, and primary brain tumors.

Here, Physician Focus speaks with Dr. Yang about the latest developments in metastatic disease and CNS malignancies. He also discusses upcoming clinical trials, two of which are set to open at Perlmutter Cancer Center later this year.

Proton Therapy for Leptomeningeal Metastasis

Physician Focus: Dr. Yang, you recently presented encouraging data from a phase 2 trial suggesting that proton therapy is more effective than conventional radiation at treating LM. Why are these results important, and what’s next for this work?

Dr. Yang: Exciting progress has been made in the treatment of LM. Prior to our study, photon involved-field radiotherapy was the standard of care for patients with LM from solid tumors. Although the choices have traditionally been limited for LM, we now have a better option—proton craniospinal irradiation —for a disease that is notoriously difficult to treat.

“With the arrival of proton therapy, LM can be detected and be effectively treated earlier in its disease course, allowing patients to live longer without neurologic compromise.”

Jonathan T. Yang, MD, PhD

While conventional radiotherapy effectively treats local symptoms, craniospinal irradiation treats the entire leptomeningeal compartment. Protons deposit the bulk of their energy at the last few millimeters of their range, leading to significantly less toxicity.

Furthermore, advancements in imaging technology and novel cerebrospinal fluid diagnostic tools have enabled better detection of LM. So now, with the arrival of proton therapy, LM can be detected and be effectively treated earlier in its disease course, allowing patients to live longer without neurologic compromise.

Building on these findings, we’re analyzing molecular data from patients to pinpoint biomarkers that can aid in patient selection. We also plan to validate these results in a larger group of patients in an upcoming national trial.

Trailblazing in Clinical Trials

Physician Focus: Beyond LM, what other promising trials are on the horizon?

Dr. Yang: There are several in progress, but I’ll highlight two. The first is a phase 1 trial evaluating AZD1390, an ataxia telangiectasia mutated (ATM) kinase inhibitor, in combination with radiotherapy for patients with glioblastoma.

Despite efforts to improve survival in glioblastoma, a backbone of radiotherapy with or without temozolomide has remained the standard of care for the past two decades. AZD1390 showed promising preclinical results by offering antitumor effects without worsening radiotherapy toxicity in the healthy brain tissue.

At the AACR Annual Meeting 2024, I presented early safety and efficacy results for the combination approach, showcasing its potential utility as a radiosensitizing treatment in glioblastoma. I am continuing to work with the sponsor in not only the development of AZD1390 with radiotherapy in brain tumors, but also in systemic metastatic disease, for which we are in the process of opening a trial here at NYU Langone.

The second is a national trial that will investigate the use of prophylactic radiation therapy—compared with standard of care—for asymptomatic, high-risk bone metastases. In most cases, radiation therapy is utilized to treat painful bone metastases, but we’re interested in examining the potential advantages of a proactive strategy.

The study protocol, which builds upon a previous phase 2 trial, is currently being finalized, with plans to open later this year.

Physician Focus: What excites you about combining targeted therapy with radiotherapy?

Dr. Yang: Drug–radiotherapy combinations have reached a defining moment. With multiple trials in progress, we’re on the cusp of breakthroughs, but still working towards overcoming obstacles and improving patient outcomes.

“Drug-radiotherapy combinations have reached a defining moment. With multiple trials in progress, we’re on the cusp of breakthroughs.”

To overcome barriers, such as the perceived impracticality of conventional regulatory end points and comparatively more-limited collaborations among sponsors and radiation oncologists, we’ll have to prioritize communication among key stakeholders. In addition, there is still a considerable amount of work needed to reduce attrition rates of novel radiosensitizers in the clinic.

In a nutshell, we’re not quite there yet, but we’re moving in the right direction.

Opening the Doors to Collaboration

Physician Focus: Looking ahead, what are your plans for the next three to five years?

Dr. Yang: We plan to open more clinical trials. To achieve this goal, we plan to pursue further public and private research funding, strengthen relationships with our industry partners, and build collaborations with experts within and outside of the cancer center.

Our main focus will be on developing novel therapeutic strategies for primary brain tumors and systemic metastatic disease. Health outcomes studies, particularly those incorporating quality of life assessments, will also be a priority. In addition, we will further enhance our understanding of tumor biology through investigation of genomics and changes to the tumor microenvironment in the setting of novel therapeutics. This will help us to better personalize treatments.

Unlike standalone cancer centers, Perlmutter Cancer Center’s placement within a larger healthcare system offers unique opportunities for research collaborations. Few institutions prioritize research to the level that NYU Langone does.