ASCO Perspective

"This study highlights the significant benefits of vorasidenib in minimizing the disabling long-term effects of current therapies for low grade gliomas, particularly in younger patients, and has the potential to revolutionize care for this disease,” said Glenn Lesser, MD, FASCO, ASCO Expert.

ALEXANDRIA, Va. —  Vorasidenib, an oral dual inhibitor of mutant IDH1/2 enzymes, significantly improved progression-free survival in patients with grade 2 gliomas, a type of malignant brain tumor with poor long-term prognosis. This treatment delayed disease progression and was well-tolerated. These findings represent a significant step forward in the treatment of grade 2 glioma with IDH mutations. The research will be presented at the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting.

Study at a Glance

Key Findings

In patients with grade 2 gliomas with IDH mutations, vorasidenib treatment showed a significant improvement in progression-free survival (median was 27.7 months compared to 11.1 months for placebo and a delay in the time to next treatment (median time to next treatment not yet reached, compared to 17.4 months for placebo), as demonstrated by the results of the phase III INDIGO study. Vorasidenib was tolerable with a manageable safety profile, with reported side effects in both the placebo and treatment groups. Although there were adverse events in the treatment group (fatigue, headache, diarrhea, nausea, COVID-19, and reversible liver transaminase elevations), most of them were manageable and resolved with appropriate medical attention. The increase of liver enzyme alanine aminotransferase was the most common grade ≥3 adverse event, occurring in 9.6% of patients receiving vorasidenib.

“Our study shows that targeting IDH mutations with vorasidenib significantly delays tumor growth and the need for more toxic therapies. This is clinically meaningful because patients diagnosed with grade 2 glioma with IDH mutations are typically young, otherwise healthy individuals. The results of this trial offer a chance to change the treatment paradigm for this type of glioma and could bring the first new targeted therapy for low-grade glioma,” said lead author Ingo Mellinghoff, MD, FACP, of Memorial Sloan Kettering Cancer Center.

About the Study

In this global, randomized, double-blind, placebo-controlled phase III study, 331 eligible patients (16-71 years) from 10 countries with grade 2 gliomas and IDH mutations were enrolled. Patients were randomized to receive a daily oral dose of vorasidenib or placebo in 28-day cycles, with 168 patients in the vorasidenib arm and 163 in the placebo arm. The primary endpoint was progression-free survival based on centrally reviewed brain MRIs. The key secondary endpoint was time to next treatment.  Crossover to vorasidenib from placebo was permitted upon confirmed imaging-based disease progression.

Next Steps

Vorasidenib is under evaluation in combination with pembrolizumab in an ongoing phase I study in grade 2/3 glioma. Future rational combination therapy efforts in both low- and high-grade glioma are under consideration.  

The study was funded by Servier Pharmaceuticals.

View the full embargoed abstract: 

LBA1: INDIGO: A global, randomized, double-blinded, phase 3 study of vorasidenib versus placebo in patients with residual or recurrent grade 2 glioma with an IDH1/2 mutation.  

Authors: Ingo K. Mellinghoff, Martin J. Van Den Bent, Deborah T. Blumenthal, Mehdi Touat, Katherine B. Peters, Jennifer Leigh Clarke, Joe Sammy Mendez, Liam Welsh, Warren P. Mason, Andreas Felix Hottinger, Juan Manuel Sepulveda Sanchez, Wolfgang Wick, Riccardo Soffietti, Steven Schoenfeld, Dan Zhao, Shuchi Sumant Pandya, Lori Steelman, Islam Hassan, Patrick Y. Wen, Timothy Francis Cloughesy; Memorial Sloan Kettering Cancer Center, New York, NY; Erasmus MC Cancer Institute, Rotterdam, Netherlands; Tel-Aviv Sourasky Medical Center/Tel-Aviv University, Tel Aviv, Israel; Pitié Salpêtrière Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Sorbonne Université, Paris, France; Duke University Medical Center, Durham, NC; University of California, San Francisco, San Francisco, CA; University of Utah, Salt Lake City, UT; The Royal Marsden NHS Foundation Trust, London, United Kingdom; Princess Margaret - University Health Network, Toronto, ON; Department of Clinical Neurosciences, Centre Hospitalier Universitaire Vaudois & Lausanne University, Lausanne, Switzerland; Hospital Universitario 12 Octubre, Madrid, Spain; University of Heidelberg, Heidelberg, Germany; University of Turin, Torino, Italy; Servier Pharmaceuticals, Boston, MA; Dana-Farber Cancer Institute, Boston, MA; University of California, Los Angeles, CA  

Background: Grade 2 gliomas are slowly progressive, malignant brain tumors with a poor long-term prognosis. Current treatments (surgery followed by observation or adjuvant radiation and chemotherapy) are not curative and can be associated with short- and long-term toxicities.  Mutations in isocitrate dehydrogenase (IDH) 1 or 2 occur in approximately 80% and 4% of grade 2 gliomas, respectively, and are a disease defining characteristic in the World Health Organization (WHO) 2021 definition. Vorasidenib (VOR) – an oral, brain-penetrant, dual inhibitor of mutant (m)IDH1/2 enzymes has shown a tolerable safety profile and preliminary clinical activity in phase 1 studies.  Methods: In this randomized, double-blind, placebo-controlled phase 3 study (NCT04164901) patients (pts) were randomized 1:1 to receive VOR 40 mg daily or placebo (PBO) daily in 28-day cycles. Patients were stratified by 1p19q status and baseline tumor size. Key eligibility criteria included: age ≥12; KPS > 80; residual or recurrent grade 2 IDH1m or IDH2m oligodendroglioma or astrocytoma; measurable non-enhancing disease; no prior treatment for glioma with most recent surgery 1-5 years from randomization; and not in immediate need of chemotherapy/radiation. Primary endpoint: radiographic progression-free survival (PFS) by blinded independent radiology committee (BIRC). Key secondary endpoint: time to next intervention (TTNI).  Results: As of 6Sep2022 (2nd planned interim analysis data cutoff), 331 pts were randomized across 10 countries: 168 to VOR and 163 to PBO. Of the 331 pts: median age: 40.4 years (range, 16 to 71); KPS = 100: 53.5%; histological subtype: oligodendroglioma: 172 and astrocytoma: 159; median time from last surgery until randomization: 2.4 years. Two hundred twenty-six (68.3%) pts remained on treatment (131VOR; 95PBO). PFS by BIRC was statistically significant in favor of the VOR arm (HR, 0.39; 95% CI, (0.27, 0.56); P= 0.000000067). Median PFS: VOR: 27.7 mos; PBO: 11.1 mos. TTNI was statistically significant in favor of the VOR arm (HR, 0.26; 95% CI, (0.15, 0.43); P= 0.000000019). Median TTNI: PBO: 17.8 mos; VOR: not reached. All reported P values are one-sided. All-grade adverse events (AEs) occurring in > 20% pts receiving VOR vs PBO were alanine aminotransferase increased (38.9% vs 14.7%), COVID-19 (32.9% vs 28.8%), fatigue (32.3% vs 31.9%), aspartate aminotransferase increase (28.7% vs 8.0%), headache (26.9% vs 27.0%), diarrhea (24.6% vs 16.6%), nausea (21.6% vs 22.7%). Common grade ≥3 AEs ( > 5%): ALT increased (9.6% vs 0%).  Conclusions: This is the first prospective, randomized phase 3 study of a targeted therapy in grade 2 mIDH glioma. VOR significantly improved PFS by BIRC compared with PBO with a manageable safety profile. These data demonstrate the clinical benefit of VOR in this pt population for whom chemotherapy and radiotherapy are being delayed.   

View disclosures for:

• Authors – in the abstract (will be available on May 30)
• ASCO Cancer Communications Committee 
• Dr. Lesser
• Dr. Gralow

For your readers:

• Brain Tumors
• Caring for a Person with a Brain Tumor or Metastatic Brain Cancer
• What is Targeted Therapy?

ATTRIBUTION TO THE AMERICAN SOCIETY OF CLINICAL ONCOLOGY ANNUAL MEETING IS REQUESTED IN ALL COVERAGE.

###