IDO1 Inhibition Combined With Radiotherapy and Nivolumab Demonstrates Safety in Newly Diagnosed Glioblastoma

Clinical Summary: 

• Design/Population: This single-arm, phase 1 trial evaluated the IDO1 inhibitor BMS-986205 in combination with radiotherapy and nivolumab in patients with newly diagnosed IDH-wildtype glioblastoma. Separate cohorts enrolled patients with MGMT-unmethylated disease receiving radiotherapy, nivolumab, and escalating doses of BMS-986205, and patients with MGMT-methylated tumors receiving the combination with concurrent and adjuvant temozolomide.
• Key Outcomes: The combination demonstrated a manageable safety profile and established 50 mg daily as the recommended phase 2 dose of BMS-986205 for patients with MGMT-unmethylated glioblastoma. Exploratory correlative analyses provided insight into potential biologic mechanisms associated with response to IDO1 inhibition.
• Clinical Relevance: These findings establish the feasibility of combining IDO1 inhibition with radiotherapy and immune checkpoint blockade in newly diagnosed glioblastoma and support further evaluation of this immunotherapy strategy in future clinical trials.

Rimas Lukas, MD, Northwestern University Feinberg School of Medicine, Chicago, Illinois, discusses results from a phase 1 trial evaluating the IDO1 inhibitor BMS-986205 in combination with radiotherapy and nivolumab for patients with newly diagnosed IDH-wildtype glioblastoma. The study was designed to target the immunosuppressive tumor microenvironment created by IDO1 signaling while integrating immune checkpoint inhibition with standard radiotherapy.

The trial established the recommended phase 2 dose of BMS-986205 in combination with radiotherapy and nivolumab and demonstrated a manageable safety profile in both MGMT-methylated and MGMT-unmethylated glioblastoma. Exploratory biomarker analyses and the observation of durable responses in selected patients provide a rationale for continued investigation of IDO1 inhibition and biomarker-driven immunotherapy strategies in glioblastoma.

Transcript: 

Hi, my name is Rimas Lukas, I'm associate chief of the neuro-oncology division and vice chair of neurology at the Malnati Brain Tumor Institute in the Northwestern University department of neurology. Thank you for taking the time to hear about our recently published study.

This clinical trial, recently published in Clinical Cancer Research, evaluated the role of IDO inhibition in patients with newly diagnosed IDH wild-type glioblastoma, an aggressive primary central nervous system tumor. Glioblastoma, IDH wild type, arises within a very immunosuppressed tumor microenvironment.

This immunosuppression is driven, in part, by the activity of the enzyme IDO, as well as possible nonenzymatic activities. My colleague, Derek Wainwright, had conducted a number of pre-clinical studies evaluating the role of this key enzyme. In one such study, he evaluated the potential of blocking this pathway with the addition of radiation therapy and an immune checkpoint inhibitor, specifically a PD-1 antibody, in murine models. The results of that preclinical study were quite favorable, with a large number of mice surviving and surviving tumor rechallenge, pointing toward the concept that immune memory can play a role in helping eradicate these tumors.

We then moved forward with a phase 1 clinical trial combining radiation therapy, which is part of the standard of care, with the PD-1 antibody nivolumab and the novel IDO inhibitor BMS-986205. 

BMS-986205 is an oral agent that was investigated in a dose-escalation manner.Initially, patients with MGMT promoter-unmethylated glioblastoma—those with a less favorable prognosis and a lower likelihood of benefiting from alkylating chemotherapy, specifically temozolomide—received this treatment. This was followed by the same regimen in patients with MGMT promoter-methylated glioblastoma. Those patients also received temozolomide chemotherapy as part of standard treatment. Patients also had, at the discretion of the treating physician and the patient, the option of receiving adjuvant tumor-treating fields.

Within the framework of this study, dose escalation was completed, and a recommended phase 2 dose was established for both the MGMT-unmethylated and MGMT-methylated cohorts. The treatments in both cohorts were generally safe and tolerable. Most treatment-emergent adverse events were related to radiation therapy, temozolomide, or the underlying disease and tumor progression.

In the MGMT-unmethylated cohort, serious adverse events and treatment-emergent adverse events were predominantly lower grade, with no major differences between the different dose-escalation cohorts. Dose-limiting toxicities consisted primarily of grade 3 transaminase elevations at the higher dose levels of BMS-986205, and the 50 mg daily dose was established as the recommended phase 2 dose in combination with radiation therapy and nivolumab. 

Median overall survival was generally in line with what has previously been observed in this patient population. However, we did observe a number of long-term survivors who remained free of tumor progression.

There may be a clue as to why some of those patients did particularly well. One such patient harbored a BRAF mutation. BRAF mutations are relatively uncommon in glioblastoma—I would estimate fewer than 5% of patients harbor these alterations. However, we know that abnormalities in the MAP kinase pathway, including BRAF mutations, may influence susceptibility to immunotherapeutic approaches, so it's possible that this contributed to that patient's outcome.

This is a therapeutic strategy that we're excited about and one that I think helps us begin to understand why certain immunotherapeutic approaches may be beneficial while others may not. I think it's important for us in the neuro-oncology field to keep in mind the negative feedback loops that contribute to immunosuppression. 

Many of our therapeutic modalities, such as radiation therapy, stimulate interferon signaling. In turn, that interferon activates the immunosuppressive IDO-driven brake, which is then further augmented by a number of additional mechanisms. I'm thankful for the opportunity to tell you a little bit about our clinical trial, and I look forward to future endeavors.

Source: 

Lukas RV, Zhai L, Lauing KL, et al. Phase I evaluation of patients with newly diagnosed glioblastoma treated with radiation, nivolumab, and IDO1 enzyme inhibitor BMS-986205. Clin Cancer Res. Published online: June 12, 2026. doi: 10.1158/1078-0432.CCR-26-1124