Immunotherapy Combo Falls Short in Brain Cancer Treatment


Nivolumab plus radiation did not improve overall survival compared to temololomide in patients with newly diagnosed glioblastoma.

Immunotherapy Combo Falls Short in Brain Cancer Treatment

Immunotherapy Combo Falls Short in Brain Cancer Treatment

The combination of nivolumab (Opdivo) plus radiation therapy compared with temozolomide did not improve overall survival (OS) in patients with newly diagnosed O6-methylguanine-DNA methyltransferase (MGMT)-unmethylated glioblastoma multiforme (GBM), missing the coprimary endpoint of the phase III CheckMate-498 trial.1

Results of the final analysis also showed that the safety profile was consistent with prior studies of nivolumab in solid tumors. Full findings will be presented at an upcoming medical meeting and submitted for publication, Bristol-Myers Squibb, the manufacturer of nivolumab, stated in a press release.

“While we are disappointed the CheckMate-498 trial did not meet its primary endpoint, GBM is a notoriously aggressive cancer,” Fouad Namouni, MD, head, oncology development, Bristol-Myers Squibb, said in the press release. “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.”

GBM remains the most common and most aggressive type of primary malignant tumor of the CNS. Standard therapies for newly diagnosed patients include surgery followed by radiation and chemotherapy, but treatments are overall limited. MGMT methylation status, which is a common biomarker in GBM, may be predictive of response to temozolomide. Patients with MGMT-unmethylated GBM have a worse prognosis than those with MGMT-methylated disease.

In the multicenter, phase III CheckMate-498 trial (NCT02617589), investigators randomized 550 patients with newly diagnosed MGMT-unmethylated GBM to receive nivolumab intravenously in combination with radiation or temozolomide/radiation. Following surgery, those on the experimental arm were given nivolumab every 2 weeks concurrent with radiation, followed by maintenance nivolumab every 4 weeks until disease progression or unacceptable toxicity. The primary endpoint was OS; secondary endpoints were progression-free survival (PFS) and a 2-year OS rate.

To be eligible for enrollment, patients were aged ≥18 years old and had newly diagnosed glioblastoma or GBM, MGMT unmethylated disease, and a Karnofsky performance status ≥70. Exclusion criteria included prior treatment for GBM beyond surgical resection, any known tumor outside of the brain, recurrent or secondary GBM, active known or suspected autoimmune disease, and a biopsy with <20% of the tumor resected.

A prior study evaluating nivolumab in patients with GBM also demonstrated disappointing findings.2 In the phase III CheckMate-143 trial, results of which were presented at the 2017 World Federation of Neuro-Oncology Societies, nivolumab did not improve OS in patients with first recurrence of GBM compared with bevacizumab (Avastin) alone.

In the trial, patients were randomized to receive nivolumab (n = 182) or bevacizumab (n = 165). At baseline, most patients in the nivolumab (83%) and bevacizumab (84%) arms had measurable disease, and 40% and 43% patients with nivolumab and bevacizumab, respectively, required corticosteroids. There were 154 deaths on the nivolumab arm and 147 in the bevacizumab group. The median OS was 9.8 and 10.0 months with nivolumab and bevacizumab, respectively, and the 12-month OS rate was 42% in both arms.

The median PFS with nivolumab was 1.5 months compared with 3.5 months with bevacizumab. Among evaluable patients treated, the overall response rates were 8% with nivolumab and 23% with bevacizumab; however, the median durations of response were 11.1 months and 5.3 months with nivolumab and bevacizumab, respectively.

Regarding safety, treatment-related adverse events (TRAEs) were comparable in the nivolumab and bevacizumab arms, at 57% and 58%, respectively. The most common TRAEs (≥10%) were fatigue (21% with nivolumab vs 14% with bevacizumab) and hypertension (1% vs 22%, respectively).

Grade 3/4 TRAEs occurred in 18% and 15% of patients with nivolumab and bevacizumab, respectively. Seizers (8% vs 6%) and malignant neoplasm progression (11% vs 7%) were the only serious AEs reported in ≥5% of patients in either group. Treatment discontinuations due to AEs occurred in 10% and 15% of patients on nivolumab and bevacizumab, respectively.

The ongoing phase III CheckMate-548 trial (NCT02667587) is evaluating nivolumab in combination with radiation therapy and temozolomide in patients with newly diagnosed MGMT-methylated GBM.


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. Bristol-Myers Squibb. Published May 9, 2019. Accessed May 9, 2019.

2. Reardon DA, Omuro A Brandes AA, et al. Randomized phase 3 study evaluating the efficacy and safety of nivolumab vs bevacizumab in patients with recurrent glioblastoma: CheckMate 143. Neuro-Oncol. 2017;19(3):iii21. doi: 10.1093/neuonc/nox036.071.

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