A combination of the immunotherapeutic agent nivolumab plus standard radiotherapy with or without temozolomide is safe in patients with newly diagnosed glioblastoma, supporting further development for treatment of these patients, who currently have a poor prognosis and few treatment options, according to findings presented at ESMO 2017, the Annual Congress of the European Society for Medical Oncology in Madrid, Spain.
Michael Lim, of The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA, presented updated safety data from 2 exploratory cohorts of the CheckMate 143 trial (NCT02017717). The study assessed the safety and tolerability of nivolumab in combination with standard radiotherapy with and without temozolomide in patients with newly diagnosed glioblastoma. Nivolumab, a fully human IgG4 monoclonal antibody that inhibits the programmed death-1 (PD-1) receptor, has been approved for the treatment of numerous other cancers.
CheckMate 143 assigned patients to cohort 1c or 1d based on the methylation status of the promoter region of the MGMT gene, which when methylated has been linked to improved outcomes when temozolomide is added to radiotherapy in patients with newly diagnosed glioblastoma.1 Cohort 1c included patients with either methylated or unmethylated MGMT, whereas cohort 1d included only patients with unmethylated MGMT. After the initial evaluation, 55 additional patients with unmethylated MGMT were randomised 1:1 to cohort 1c or 1d.
Cohort 1c included 12 patients with methylated MGMT and 43 patients with unmethylated MGMT, who received nivolumab at 3 mg/kg once every 2 weeks plus standard radiotherapy and concurrent temozolomide at 75 mg/m2 daily followed by adjuvant temozolomide at 150 to 200 mg/m2 for 5 days per 28-day cycle for ≥ 6 cycles. Fifty-eight patients with unmethylated MGMT were treated in cohort 1d with the same dose of nivolumab and standard radiotherapy, but without temozolomide.
Nivolumab was continued in both cohorts until confirmed progression or unacceptable toxicity occurred.
The safety profile of nivolumab combined with radiotherapy with or without temozolomide supports further evaluation in patients with newly diagnosed glioblastoma
Dr Lim presented safety data from all 113 treated patients.
In cohort 1c, 67% of patients with methylated MGMT and 93% of patients with unmethylated MGMT who received nivolumab, radiotherapy, and temozolomide discontinued treatment compared to 97% of patients in cohort 1d with unmethylated MGMT, who received nivolumab plus radiotherapy.
In cohort 1c, treatment discontinuation due to radiographic progression occurred in 50% of patients with methylated MGMT and 58% of patients with unmethylated MGMT. In addition, discontinuation due to treatment-related toxicity and patient decision each occurred in 8% and 14% of patients with methylated and unmethylated MGMT, respectively.
In cohort 1d, 78% of patients with unmethylated MGMT discontinued treatment due to radiographic progression, and 12% of patients were discontinued because of treatment-related toxicity.
No deaths due to study drug toxicity were reported.
The most commonly reported adverse events (AEs) of any cause were fatigue, headache, nausea, seizure, and constipation in cohorts 1c and 1d.
Grade 3/4 decreases in lymphocyte counts occurred in 17% (methylated) and 12% (unmethylated) of patients in cohort 1c and 3% of patients in cohort 1d. The omission of temozolomide in cohort 1d, which was associated with a lower incidence of lymphopenia, was not associated with any significant additional immune-mediated AEs. Other commonly reported grade 3/4 AEs included increased ALT/transaminases and increased AST.
Immune-mediated AEs occurring in ≥ 15% of patients in any arm included increased ALT/transaminases, diarrhoea, rash, increased AST, and maculopapular rash. Increased ALT/transaminases was reported in 25% (methylated) and 23% (unmethylated) of patients in cohort 1c and 16% of patients in cohort 1d. Diarrhoea was reported in 0% (methylated) and 16% (unmethylated) of patients in cohort 1c and 19% of patients in cohort 1d.
In cohorts 1c (methylated and unmethylated MGMT) and 1d, the most common neurological AEs were headache, which occurred in 42%, 49%, and 43% of patients, and seizure, which occurred in 25%, 19%, and 31% of patients, respectively.
The most common serious AEs included seizure, which occurred in 25% (methylated) and 9% (unmethylated) of patients in cohort 1c and 12% of patients in cohort 1d, and pneumonia, which was reported in 17% (methylated) and 5% (unmethylated) of patients in cohort 1c and 3% of patients in cohort 1d.
Nivolumab in combination with radiotherapy with and without temozolomide was well tolerated, with the incidence of high-grade neurological AEs being consistent with those previously reported in glioblastoma, according to the authors. In addition, the use of temozolomide in combination with nivolumab and radiotherapy was not associated with any significant additional AEs other than those that are associated with temozolomide alone.
These safety data support further clinical development of nivolumab in combination with radiotherapy with and without temozolomide in patients with newly diagnosed glioblastoma.
M.J. van den Bent of The Brain Tumor Center at Erasmus MC Cancer Center, Rotterdam, the Netherlands, who discussed the study findings said that it is still needed to see the first well-designed positive immunotherapy trial in neuro-oncology. The flurry of uncontrolled studies reporting very promising initial data have so far not been confirmed once rigorously tested. No unexpected toxicity of adding nivolumab to radiotherapy/temozolomide was observed. There is no signal yet for anti-PD-L1 therapy in recurrent glioblastoma but the trial in newly diagnosed patients is ongoing. PD-L1 immunohistochemistry may not be the optimal test to identify responsive patients.
The CheckMate 143 trial was sponsored by Bristol-Myers Squibb.
- Hegi ME, et al. N Engl J Med 2005;352(10):997–1003.
325O - Lim M, et al. Nivolumab (nivo) in Combination With Radiotherapy (RT) ± Temozolomide (TMZ): Updated Safety Results From CheckMate 143 in Pts With Methylated or Unmethylated Newly Diagnosed Glioblastoma (GBM).