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-wild-type 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, 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 the context of 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 1 such study, he evaluated the potential of blocking this with the addition of radiation therapy and an immune checkpoint inhibitor, specifically a PD-1 antibody, in murine models. The results of that pre-clinical study were quite favorable, with a large number of mice surviving and surviving rechallenge, pointing toward the concept that immune memory can play a role in helping eradicate these tumors.

We then moved forward with conducting a phase 1 clinical trial combining radiation therapy, which is part of the standard of care, in conjunction with aPD-1 antibody, nivolumab, and the novel IDO inhibitor BMS-986205. This 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 received temozolomide chemotherapy as part of standard treatment. Patients 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 conducted and a recommended phase 2 dose was established for both the MGMT-unmethylated and MGMT-methylated cohorts. The median overall survival was in line with what had been previously observed in this patient population, although there were a number of long-term survivors that had survived without evidence of tumor progression. 

There may be a hint of why some of those patients did particularly well, 1 such patient had a mutation in the BRAF gene. BRAF mutations are relatively rare within the context of glioblastoma, I'd say less than 5% of patients with that disease harbor these, but we know that aberrancies in the MAP kinase pathway, including BRAF mutations, can play a role with regards to susceptibility to immunotherapeutic approaches. So it's possible that this may have been a contributing factor. 

This is a therapeutic strategy which we are excited about and one which I think helps us begin to understand why certain types of immunotherapeutic approaches may be of benefit or may lack benefit. I think it's important for us in the neuro-oncology field to keep in mind the negative feedback loops that lead to immunosuppression, so many of our therapeutic modalities such as radiation therapy lead to interferon stimulation, in turn, that interferon turns on the immunosuppressive break, the IDO-driven break, which then is further augmented by a number of other different 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