Guest Column | May 6, 2024

Multidisciplinary Collaborations Fuel New Glioma Treatment Breakthroughs

By Susan Pandya, MD, vice president, head of cancer metabolism global development oncology & immuno-oncology, Servier

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Pursuit of novel treatments for difficult and hard to treat cancers, where investment in research has been historically limited, can be challenging. Successful clinical development strategies must: 1) recognize — and confront — the limitations of existing knowledge, 2) be grounded in rigorous scientific hypotheses to enable smart risk takings, and 3) reflect an acute understanding of the patient experience from diagnosis onward.

These were the strategies that were deployed when developing the Phase 3 INDIGO study, evaluating vorasidenib in the treatment of patients with IDH-mutant gliomas, and they represent what can be achieved when scientists from various disciplines, patients, clinical investigators, and advocacy groups collaborate to create an innovative clinical trial design and accelerate the development of a potential breakthrough therapy.

Collaborating To Forge A New Path In The Treatment Of IDH-Mutated Glioma

Adult-type diffuse gliomas represent approximately 81% of primary malignant brain tumors. Of those, approximately 20% harbor an IDH mutation, including 100% of grade 2 and grade 3 adult-type diffuse gliomas, as well as a much smaller portion of the grade 4 tumors.1,2 The current treatment paradigm for this disease consists of maximal surgical resection, followed by radiation and chemotherapy, which can be associated with treatment-related toxicities. Historically, developing treatment advances in this area has struggled due to the difficulty in designing treatments that could penetrate the blood-brain barrier and/or due to the lack of a known molecular druggable target.

The INDIGO study (NCT04164901), the first Phase 3 clinical trial of its kind, assessed the safety and efficacy of vorasidenib, an orally administered inhibitor of mutant IDH enzymes, to treat IDH-mutant diffuse glioma. The trial enrollment completed rapidly, despite being launched a few months prior to the start of the COVID-19 pandemic, highlighting the significant unmet patient need in the disease area. The successful results of the Phase 3 study have led to vorasidenib receiving priority review by the FDA.

Here is how an approach based on humility and eagerness to learn from others, as well as a willingness to engage in healthy debate and question the status quo, led to the first significant advance in low-grade gliomas in a quarter century.

Recognizing — And Addressing — Limitations In Existing Knowledge

In 2016, the use of targeted therapies in IDH mutant gliomas, where the experiences of patients who are relatively young and otherwise healthy, was not deeply explored in scientific literature or in clinical research. The available aggressive non-curative treatment approaches led to acute and chronic toxicities that could potentially alter patient quality of life. Additionally, these treatments were often not initiated as many patients elected active observation post-resection even in the context of residual or recurrent disease in order to avoid the potential toxicities.

We undertook an immense thought leader engagement effort based on advisory panels, evolving scientific literature, and in-depth data review from our early first-in-human studies to identify knowledge gaps and define the best setting to intervene with a targeted mutant IDH inhibitor. By creating an avenue for scientific discourse and debate, one that took both fact and nuance into account, we were able to identify unanswered questions and develop new ways of thinking about the disease and its treatment.

Another key factor in optimizing the INDIGO trial design was the recognition that a placebo control would require the option for crossover. We discussed and agreed upon this feature in collaboration with thought leaders. Given the limited studies in this disease setting, we felt it important to understand as much as we could from the data to support our understanding of the disease’s natural history. One of the features to support our understanding of the natural history and the impact of this targeted therapy included a novel imaging endpoint to assess tumor growth rates before and during treatment using 3D volume measurements. Accordingly, a collaboration with brain tumor imaging experts led to the inclusion of 3D measurements using MRI as another way to explore tumor growth and regression in the study.

Forming A Sound Scientific Basis Of A Novel Therapeutic Approach

As part of my clinical team, Servier Pharmaceuticals Senior Director of Clinical Science Lori Steelman, MS, and Senior Medical Director and vorasidenib clinical lead Islam Hassan, MD, were instrumental in building our scientific collaborations and bringing clinical and imaging expertise to the vorasidenib program from the first Phase 1 studies to the Phase 3 INDIGO study. This included evaluating the brain penetrant properties of vorasidenib in a window of opportunity perioperative study, poring over the early safety, clinical and imaging data, and leading the execution of the Indigo trial alongside a group of dedicated cross-functional team members. In the critical perioperative study, vorasidenib was administered pre-operatively to patients who were to undergo surgical resection as part of their treatment plan. This study allowed access to the tumor tissue to evaluate the drug’s concentration and pharmacodynamic effect on an important biomarker linked to its mechanism of action. This study was key in providing demonstrable evidence of vorasidenib’s mechanism of action and in establishing a biologically active and safe dose which bolstered our confidence in progressing the development of vorasidenib to the Phase 3 study.

Putting The Patient Experience At The Center — From Diagnosis Onward

Patients, advocacy groups, and advisory committees convened early in the design process to provide their unique perspectives about how diagnosis and treatment decisions were made and how IDH-mutated gliomas affect patients’ daily lives. The resulting understanding of the patient journey was crucial to the success of the INDIGO study. Though diagnosis of glioma can occur at any age, the majority of diagnoses occur when patients are in their 30s or 40s — the prime of life where personal and professional trajectories evolve rapidly — so when they hear the prognosis of this disease will impact their longevity, their outlook and priorities are significantly altered.  Patients with IDH-mutant gliomas often experience seizures as a presenting symptom, which can limit their independence and quality of life. While the treatments, including surgical resections and systemic and radiation-based therapies, can improve the presenting symptoms, they also come with side effects that limit quality of life. Thus, many patients face hard choices when deciding whether to wait and observe, despite knowing the disease is incurable, or undergo aggressive interventions. Preserving quality of life is essential to patients, as is treating the disease and minimizing side effects.

In recognition of the impact of the disease as well as priorities of prospective participants, we designed INDIGO as a crossover study that allowed participants who were randomized to the placebo arm to switch to treatment with vorasidenib if the disease had progressed radiographically based on a blinded independent review of the imaging. This was critical to meet the needs of participants, who would be understandably reluctant to enter a study knowing they could receive only placebo. Investigators also appreciated this design from an ethical standpoint, as clinical trial participants already demonstrated an exceptional level of courage in dedicating themselves to this research, and healthcare providers want to ensure their patients are always receiving the best possible care. Thus, ensuring that all eligible participants could have the option to receive the potential treatment was essential.

The patient-centered nature of the INDIGO trial design proved important in adapting the study during the COVID-19 pandemic. Appreciation of patients’ needs and safety during that time led to focused efforts on risk mitigations, including remote assessments and direct shipping to patients, which also ensured ongoing participation and enrollment. What’s more, the early involvement of advocacy groups and investigators in the trial design enhanced recruitment efforts, allowing the trial to complete enrollment ahead of schedule.

INDIGO’s Successes For Scientific Research And For Patients

Investing resources in drug development addressing difficult to treat cancers like IDH-mutated gliomas can be challenging, as not all endeavors result in success. However, when there is an identified and actionable target that is considered disease-defining such as IDH mutations in diffuse gliomas and there are few available, yet often deferred, treatments, there is an immense opportunity to fundamentally change the way the disease is approached. As IDH mutations occur early in gliomagenesis, it was important to consider the impact of targeting the mutant protein before additional therapies could alter the genetic signature of the disease. This also favored a monotherapy approach that could potentially allow for preservation of quality of life for patients. Innovations in development strategies can significantly increase the overall chance of success and potentially increase the speed with which novel treatments are brought to market.

The INDIGO study demonstrates that sound scientific approaches paired with appreciation of patients’ experiences and enlistment of multidisciplinary experts can increase stakeholder confidence, lead to a thoughtful patient-centric study design, expedite study enrollment and completion, and achieve transformative results that can facilitate the approval of novel drugs.


  1. Louis, D. et. al (2021). The 2021 WHO Classification of Tumors of the Central Nervous System: a summary, Neuro-Oncology, 23(8): 1231–1251. Accessed February 2024.
  2. Ostrom, Q. T., Price, M., Neff, C., Cioffi, G., Waite, K. A., Kruchko, C., & Barnholtz-Sloan, J. S. (2022). CBTRUS Statistical Report: Primary Brain and Other Central Nervous System Tumors Diagnosed in the United States in 2015-2019. Neuro-oncology, 24(Suppl 5), v1–v95. Accessed February 2024.

About The Author:

Susan Pandya, M.D., is the Head of Cancer Metabolism Global Development Oncology & Immuno-Oncology at Servier Pharmaceuticals. She leads Servier’s Oncology clinical development from early clinical studies to pivotal phase 3 programs and successful FDA approvals, including TIBSOVO®’s supplemental approval for advanced or metastatic cholangiocarcinoma in 2021, newly diagnosed acute myeloid leukemia (AML) in 2022 and relapsed or refractory (R/R) myelodysplastic syndromes (MDS) in 2023. Her leadership also extends to early and late phase clinical development of vorasidenib, including the pivotal Phase 3 INDIGO trial for vorasidenib, which was selected for a plenary at ASCO 2023 and is currently under review by the U.S. FDA and European Commission for the treatment of IDH-mutant diffuse glioma.

She is a passionate and innovative oncologist with over a decade of oncology drug development experience in both academic and biotech settings. Prior to Servier, she held leading roles at Agios Pharmaceuticals and Acceleron Pharma.