Nivolumab Combinations Feasible for Newly Diagnosed GBM


The PD-1 inhibitor nivolumab was successfully combined with radiotherapy alone or concurrently with temozolomide for patients with newly-diagnosed glioblastoma multiforme in cohorts 1c and 1d from the phase I CheckMate-143 study. 

“The research question was if treatment with nivolumab to block immune checkpoint pathways could potentiate an antitumor immune response and have synergistic effects with radiotherapy or chemoradiotherapy in patients with newly diagnosed GBM,” stated first author by Antonio Omuro, MD, of the Memorial Sloan Kettering Cancer Center.

Cohorts 1c and 1d included patients with newly diagnosed GBM. Patients in cohort 1c (n = 57) were enrolled regardless ofMGMTstatus and those in cohort 1d had unmethylated MGMT(n = 53).All patients were treated with nivolumab at 3 mg/kg every 2 weeks in combination with standard radiotherapy. Those in cohort 1c also received concurrent and adjuvant temozolomide. Those in cohort 1d did not receive temozolomide.

In cohort 1c,MGMTwas methylated (n = 11), unmethylated (n = 39), and indeterminate (n = 7). In cohort 1d, MGMTstatus was indeterminate for 2 patients and unmethylate for 52. The median age of patients was 59 years (range, 25-79) in cohort 1c and 58 years in cohort 1d (range, 28-78). More than 1 measurable lesion was present in 27 patients in cohort 1c (47.4%) and in 24 patients in cohort 1d (45.3%). In cohort 1d, 1 patient received prior radiotherapy and 1 had prior systemic anticancer therapy with anastrozole.

At the data cutoff of September 16, 2016, 51 patients in cohort 1c (89%) and 47 (89%) in cohort 1d continued on the study. Treatment was discontinued in 6 patients in cohort 1c due 3 cases of increased transaminases and 1 case each of asthenia, fatigue, and hypotension. In cohort 1d, 4 patients discontinued treatment due to 1 case each of increased alanine transaminase, increased lipase, herpes simplex virus (HSV) encephalitis, and acute kidney injury.

There were 10 deaths on study (5 in each cohort). The causes of death in cohort 1c were progressive disease (n = 4) and unknown (n = 1). In cohort 1d the causes of death were progressive disease (n = 3), related to HSV encephalitis and clinical decline (n = 1), and unknown (n = 1).

Treatment-related serious adverse events were experienced by 22.8% and 15.1% of patients treated with nivolumab with radiotherapy with temozolomide and without, respectively. There were no new safety signals observed.

The median duration of treatment was 3.25 months (range, 0-14.9) in cohort 1c and 3.71 months (range, 0-11.8) in cohort 1d. Subsequent anticancer therapy was received by 31.6% of the patients in cohort 1c and by 26.4% in cohort 1d, which included systemic therapy, radiotherapy, and surgical resection. ​In 20 evaluable patients across both arms, the 12-month overall survival rate was 80%.

"Results suggest that the combination of nivolumab with radiotherapy with or without temozolomide is feasible and well tolerated, raising no new safety concerns," the authors wrote in their abstract. "These data support continued clinical investigation in this population."

Nivolumab is a fully human IgG4 monoclonal antibody against the PD-1 receptor. It was first FDA approved for advanced melanoma in December 2014, and it has been subsequently approved for advanced lung cancer, renal cell carcinoma, head and neck cancer, Hodgkin lymphoma, and further melanoma indications.

The interim analysis from the CheckMate-143 study support further clinical evaluation of nivolumab plus radiotherapy with or with temozolomide in patients with newly diagnosed GBM. Two other studies are also investigating nivolumab in combination with radiotherapy: CheckMate-498 for patients with unmethylatedMGMTand CheckMate-548 for patients with methylated or indeterminateMGMT.

Omuro A, Gordana V, Baehring J, et al. Nivolumab combined with radiotherapy with or without temozolomide in patients with newly diagnosed glioblastoma: Results from phase 1 safety cohorts in CheckMate 143.Neuro-Oncology. 2016; 18: abstract ATIM-16.

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