SIGMA Scales Post-RT Maintenance Bet Without Efficacy or Clean Precedent

Nuvation Bio Expands Phase III SIGMA Trial for Safusidenib into Europe

Nuvation Bio is expanding its pivotal Phase III SIGMA trial for the investigational oral IDH1 inhibitor safusidenib into six European countries: France, Germany, Italy, Spain, Sweden, and the UK. This expansion builds on existing trial activity in Australia, Canada, China, Japan, and the US. The randomized, placebo-controlled study evaluates safusidenib as maintenance therapy for patients with high-risk IDH1-mutant astrocytoma who have undergone radiotherapy or chemoradiotherapy. The primary endpoint is progression-free survival, measured via blinded independent central review, with approximately 300 participants planned for the main pivotal segment. Safusidenib also received FDA fast track designation in August 2026 for IDH1-mutant glioma treatment.

• Nuvation Bio's pivotal Phase III SIGMA trial for safusidenib is significantly expanding its geographical footprint by adding six new study sites across Europe, specifically in France, Germany, Italy, Spain, Sweden, and the UK. This strategic move complements ongoing recruitment efforts in Australia, Canada, China, Japan, and the US, demonstrating a global commitment to reaching more patients with IDH1-mutant glioma. The expansion aims to accelerate patient enrollment and gather diverse data, reinforcing the company's goal to develop therapies with a profound, positive impact on patients' lives worldwide.
• The SIGMA trial is a randomized, placebo-controlled study designed to evaluate safusidenib as a maintenance therapy. It targets patients diagnosed with high-risk IDH1-mutant astrocytoma who have previously undergone standard-of-care radiotherapy or chemoradiotherapy, often alongside adjuvant temozolomide. The trial's primary endpoint is progression-free survival, which will be rigorously assessed through blinded independent central review. Approximately 300 participants are slated for enrollment in this crucial main pivotal segment, aiming to establish the drug's efficacy in this specific patient population.
• Safusidenib has already received Fast Track designation from the US Food and Drug Administration (FDA) in August 2026 for the treatment of IDH1-mutant glioma, underscoring its potential to address an unmet medical need. Beyond the SIGMA trial, safusidenib is also being investigated in the Phase III G307 study in regions where vorasidenib is not approved or available, and in the Phase II G209 trial for patients whose cancer has progressed after vorasidenib therapy. This multi-pronged development approach highlights Nuvation Bio's comprehensive strategy for the drug.

Addressing Unmet Needs in IDH1-Mutant Glioma Treatment

Current treatment for IDH1-mutant glioma remains constrained by limited options at recurrence and highly context-dependent benefit from targeted inhibition. Ivosidenib was associated with longer PFS in lower-grade, non-enhancing tumors that received little or no prior anticancer treatment and less complex genomic profiles, underscoring the challenge of extending benefit to broader populations.

• Context-dependent activity of IDH inhibition in recurrent disease: In predominantly recurrent, pretreated CNS WHO grade 2-4 astrocytoma IDH-mutant or grade 2-3 oligodendroglioma, IDH-mutant and 1p/19q codeleted, median PFS was 15.2, 4.6, and 2.1 months for astrocytoma grades 2-4, and 14.0 and 6.9 months for oligodendroglioma grades 2-3, supporting a context-dependent benefit of IDH inhibition in recurrent disease with infiltrative tumors with limited treatment options at recurrence.

• Reduced benefit with genomic complexity and CDKN2A/B deletion: Increasing genomic complexity was associated with shorter PFS in univariate analysis, while patients without CDKN2A/B homozygous deletion had median PFS of 19.2 months compared with median PFS of 0.6 months in two patients with homozygous deletion.

• Limited effectiveness in enhancing disease: The presence of enhancing disease at ivosidenib initiation was associated with lower disease control rates (DCR), and findings highlight limited effectiveness in patients with enhancing disease, with DCR differences not detected based on grade, tumor histology, or age.

• Toxicity trade-offs of chemoradiation and need for delivery strategies: Chemoradiation can cause detrimental late neurocognitive morbidities and an accelerated disease course, while future advances will likely depend on innovative drug-delivery technologies designed to overcome the blood-brain barrier to enhance efficacy of conventional and targeted therapies.

• Persistent risk of recurrence and malignant transformation: After primary surgical resection, the median recurrence and malignant transformation times were 14 and 24 months, and the 5-year recurrence-free and malignant-free survival rate was 50% and 68%, with radiotherapy followed by PCV, or selected temozolomide-based approaches when PCV is not feasible, remaining appropriate for rapid growth, new or nodular enhancement, neurological decline, uncontrolled seizures, high-risk molecular pathology such as CDKN2A/B homozygous deletion, or suspected grade transformation.

SIGMA Trial: Design, Endpoints, and European Expansion

Key trials in IDH1-mutant glioma range from retrospective off-label cohorts to first-in-human phase I dose-escalation and a randomized phase 3 trial. Populations focus on nonenhancing versus enhancing disease and grade 2 versus grades 2-4 tumors, with endpoints spanning radiographic response, progression-free survival, seizure control, tolerability, and pharmacodynamics.

• Retrospective off-label ivosidenib experience from October 2020 through February 2022 assessed radiographic response, seizure control, tolerability, and access to the medication, with all patients initially receiving single-agent IVO dosed at 500 mg orally once daily.

• Phase 3 randomized, multicenter, double-blind INDIGO trial compared vorasidenib to placebo in non-enhancing grade 2 IDH-mutant gliomas following surgery, with primary efficacy based on radiographic progression-free survival (PFS) per blinded independent central review (BICR) according to the modified Response Assessment for Neuro-oncology for Low-Grade Gliomas (RANO-LGG) criteria in 331 patients with hazard ratio (HR) 0.39 (95% CI: 0.27, 0.56; p-value <0.0001), plus time to the next anticancer intervention and exploratory seizure analyses showing on-treatment seizure rate of 18.2 per person-year with vorasidenib vs. 51.2 with placebo [rate ratio 0.36, 95% confidence interval (CI) 0.14-0.89].

• Multicenter, open-label, phase I, dose-escalation study of vorasidenib (NCT02481154) enrolled 93 patients with mutant IDH1/2 solid tumors including 52 patients with glioma that had recurred or progressed following standard therapy, administering vorasidenib orally, once daily, in 28-day cycles until progression or unacceptable toxicity, with safety and dose-limiting toxicities of elevated transaminases at doses ≥100 mg, objective response rate per Response Assessment in Neuro-Oncology criteria for LGG of 18% in nonenhancing glioma, and median progression-free survival of 36.8 months [95% confidence interval (CI), 11.2-40.8] for nonenhancing glioma and 3.6 months (95% CI, 1.8-6.5) for enhancing glioma.

• Multicenter, open-label, phase I, dose escalation and expansion study of ivosidenib in mutant IDH1 solid tumors included 66 patients with advanced gliomas treated orally daily in 28-day cycles with 500 mg once per day selected for the expansion cohort and no dose-limiting toxicities reported, reporting grade ≥3 adverse event rate of 19.7%, objective response rate of 2.9% with 1 partial response in nonenhancing glioma (n = 35), stable disease in 30 of 35 patients (85.7%) with nonenhancing glioma compared with 14 of 31 (45.2%) with enhancing glioma, and median progression-free survival of 13.6 months (95% CI, 9.2 to 33.2 months) and 1.4 months (95% CI, 1.0 to 1.9 months) for nonenhancing and enhancing cohorts, respectively, with exploratory analysis of volume and growth rates of nonenhancing tumors.

• Phase II study of ivosidenib 500 mg by mouth daily with nivolumab 480 mg intravenously every 4 weeks (NCT04056910) enrolled 15 patients with advanced or refractory mIDH1 solid tumors (glioma, 46.7%) using a composite primary endpoint including either six-month progression-free survival (PFS6) or overall response rate (ORR), with 3 out of 15 patients meeting the primary endpoint (3/15; 20%), median PFS of 1.94 months, assessment of plasma (R)-2HG reduction, and exploratory serum proteomic and tumor spatial transcriptomic analyses.

• Retrospective real-world ivosidenib monotherapy cohort from 2020 to 2024 reviewed clinical and radiographic data in 74 patients with IDHm glioma including 49, 23, and 2, grade 2, 3, and 4 tumors, respectively, reporting median progression-free survival of 31 months with median overall survival not reached, 7 patients (9%) with partial response, 3 (4%) with minor response, 47 (64%) with stable disease, and 17 (23%) with progressive disease, with disease control rates lower with enhancing disease at initiation.

Safusidenib's Expanding Clinical Program Beyond Glioma

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Safusidenib's Global Trial: A Strategic Move in IDH1-Mutant Glioma

The global expansion of Nuvation Bio's pivotal Phase III SIGMA trial for safusidenib signals a critical advancement in the targeted treatment of IDH1-mutant astrocytoma. This move positions safusidenib to address a significant unmet need in patients with high-risk disease who have completed initial radiotherapy or chemoradiotherapy, aiming to extend progression-free survival as a maintenance therapy. The underlying biology of IDH1-mutant gliomas, characterized by the production of the oncometabolite 2-hydroxyglutarate (2HG), offers a clear therapeutic target, as studies consistently show IDH inhibitors rapidly reduce 2HG levels and can reprogram tumor metabolism.

This strategic expansion, coupled with FDA fast track designation, underscores a clear intent for accelerated global market entry and broad patient access. However, the landscape for IDH-mutant glioma therapies is rapidly evolving. The recent FDA approval of vorasidenib for IDH1/2-mutant Grade 2 gliomas post-surgery sets a high bar and introduces a competitive dynamic. Safusidenib must demonstrate compelling efficacy and a favorable safety profile specifically within its maintenance setting to carve out a distinct and valuable position. A key risk lies in proving robust efficacy in a high-risk, pre-treated population, where prior evidence suggests IDH inhibitors may have limited effectiveness in patients with enhancing disease or more complex genomic profiles. Furthermore, as an oral agent, ensuring optimal blood-brain barrier penetration and long-term tolerability will be paramount for a maintenance therapy. Success for safusidenib would not only establish a new standard of care for this specific patient group but also further validate the precision medicine approach in glioma, potentially paving the way for integrated treatment strategies and the use of advanced biomarkers like 18F-DOPA-PET and MR spectroscopy for monitoring response.