Primary Endpoint Not Met in Phase III CheckMate498 Trial of MGMT-Unmethylated GBM

Fouad Namouni, MD

Fouad Namouni, MD

Final results from the phase III CheckMate 498 trial demonstrated that nivolumab (Opdivo) in combination with radiation failed to demonstrate a significant improvement in overall survival (OS) compared with temozolomide (Temodar) and radiation in patients with newly diagnosedMGMT-unmethylated glioblastoma multiforme (GBM).¹

Although the primary endpoint of OS was not met, the safety profile with nivolumab was still tolerable in patients with GBM, as had been seen in previous reports of nivolumab, according to a press release from Bristol-Myers Squibb.

“While we are disappointed the CheckMate 498 trial did not meet its primary endpoint, GBM is a notoriously aggressive cancer,” said Fouad Namouni, MD, head of the Oncology Department, Bristol-Myers Squibb. “We are grateful to all those who participated in this trial and remain committed to researching the potential of immunotherapy to address the important unmet medical need of patients who suffer from this devastating disease.”

Approximately 550 adult, treatment-naïve patients were enrolled in the phase III trial and randomized to either nivolumab plus radiation or temozolomide plus radiation. Eligible patients had centrally confirmedMGMT-unmethylated disease and a Karnofsky performance status ≥70. Patients who had received prior treatment for GBM, had additional tumors, or known or suspected autoimmune disease were excluded from the trial.

To meet the primary endpoint, the study had to show a 90% power to detect a hazard ratio of less than 0.72 after at least 397 events.

Evidence for the phase III trial in this population came from 2 cohorts of the phase I CheckMate 143 trial.²Cohort 1c consisted of newly diagnosed patients with either methylated (n = 12) or unmethylated (n = 43)MGMTstatus, and these patients received treatment with nivolumab at 3 mg/kg once every 2 weeks plus radiation and temozolomide. Temozolomide was given concurrently with radiation at 75 mg/m²and then was given as adjuvant treatment at 150 to 200 mg/m²for 5 days of the 28-day cycle for at least 6 cycles. Only patients with newly diagnosedMGMTunmethylated GBM were included in cohort 1d (n = 58) and were treated with nivolumab and radiation alone.

In findings presented at the 2017 ESMO Congress, nivolumab plus radiation with or without temozolomide was well tolerated in patients with newly diagnosed GBM in the phase I study. The most common adverse events (AEs) included fatigue, headache, nausea, seizure, and constipation in the 2 cohorts. The most common immune-mediated AEs were increased ALT, diarrhea, rash, increased AST, and maculopapular rash. Diarrhea was more common among the unmethylated patients.

The most common neurological AEs were headache and seizure, and frequent serious AEs included seizure and pneumonia. The investigators noted that nivolumab and radiotherapy did not come with any significant additional AEs compared with temozolomide treatment alone. No deaths were reported due to study drug toxicity.

However, 97% of patients in cohort 1d discontinued treatment compared with 93% of unmethylated patients in cohort 1c and 67% of methylated patients. In cohort 1d, 78% of the patients discontinued treatment due to radiographic progression and 12% due to treatment-related toxicity.

Based on cohort 1c of the phase I trial, nivolumab is continuing to be studied in GBM in the ongoing phase III CheckMate 548 trial of patients with newly diagnosedMGMT-methylated GBM (NCT02667587). In this trial, nivolumab is being investigated in combination with temozolomide and radiation.

References:

1. Bristol-Myers Squibb Announces Phase 3 CheckMate -498 Study Did Not Meet Primary Endpoint of Overall Survival with Opdivo (nivolumab) Plus Radiation in Patients with Newly Diagnosed MGMT-Unmethylated Glioblastoma Multiforme [press release]. Princeton, NJ: Bristol-Myers Squibb Company; May 9, 2019. https://bit.ly/2V9ceag. Accessed May 9, 2019.
2. Lim M, Omuro A, Vlahovic G, 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).Ann Oncol.2017;38(suppl 5; abstr 325O):v109-v121. doi: 10.1093/annonc/mdx366.