Upfront Nivolumab Not Additive in Phase III Trial of MGMT-Methylated GBM

Fouad Namouni, MD

Fouad Namouni, MD

The addition of nivolumab (Opdivo) to the standard of care temozolomide (Temodar) and radiation therapy was not additive in terms of progression-free survival compared with standard of care alone in patients with newly diagnosed glioblastoma multiforme (GBM) that is O6-methylguanine-DNA methyltransferase (MGMT)-methylated, according to results released from the phase III CheckMate 548 trial.¹

Although this did not meet the primary endpoint for the trial, the data monitoring committee recommended that the trial continue as planned to analyze for overall survival data, the other primary endpoint of the trial, according to a press release from Bristol-Myers Squibb.

“Though CheckMate 548 did not show statistically significant improvement in progression-free survival, we are continuing to evaluate the benefit the addition of Opdivo to the standard of care treatment regimen may bring to patients suffering from GBM, an extremely aggressive and difficult disease to treat. We look forward to seeing the overall survival data when they are available,” said Fouad Namouni, MD, head, Oncology Development, Bristol-Myers Squibb, in the press release.

The CheckMate 548 trial (NCT02667587) is a randomized, single-blind, multicenter study that is exploring the use of the PD-1 inhibitor nivolumab in addition to temozolomide and radiation therapy, as the current standard of care, versus standard of care and placebo in patients with newly diagnosed MGMT-methylated GBM.

Investigators expected to enroll about 693 patients into the phase III trial who had recovered from prior surgical resection and had a Karnofsky performance status of ≥70. Patients who had received prior therapy beyond surgery for GBM, those who had tumors outside of the brain, and those who had active or suspected autoimmune disease were excluded from enrolling in the trial.

Patients in both arms were administered 75 mg/m²temozolomide daily during radiation treatment followed by a 4-week treatment break, then 150 mg/m²of temozolomide for days 1 to 5 of cycle 1, which was then increased to 200 mg/m²for days 1 to 5 for cycles 2 through 6 as tolerated. Radiotherapy consisted of 2 Gy 5 times a week for 6 weeks.

The primary endpoints of the trial were both progression-free survival by blinded independent central review assessment and overall survival. Secondary outcomes included overall survival at 2 years and progression-free survival by investigator assessment.

Nivolumab also failed to demonstrate a benefit in combination with radiation therapy compared with temozolomide and radiation in the phase III CheckMate 498 trial, which looked at patients with newly diagnosed MGMT-unmethylated GBM. The PD-1 inhibitor combination failed to meet the primary endpoint of overall survival in the trial.²

References

1. Bristol-Myers Squibb Provides Update on Phase 3 Opdivo(nivolumab) CheckMate -548 Trial in Patients with Newly Diagnosed MGMT-Methylated Glioblastoma Multiforme [press release]. Princeton, NJ: Bristol-Myers Squibb Company; September 5, 2019. https://bit.ly/2ktBxYb. Accessed September 5, 2019.
2. 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 September 5, 2019.