Nivolumab Combo Misses PFS Endpoint in Newly Diagnosed MGMT-Methylated GBM

Fouad Namouni, MD

The combination of nivolumab (Opdivo) plus standard temozolomide and radiation therapy did not show a statistically significant improvement in progression-free survival (PFS) compared with temozolomide/radiation therapy alone in patients with newly diagnosed glioblastoma multiforme (GBM) that is O6-methylguanine-DNA methyltransferase (MGMT)-methylated, missing one of the primary endpoints of the phase III CheckMate-548 trial.¹

A data monitoring committee did recommend, however, that the trial should continue as planned to allow overall survival (OS), the other primary endpoint, to mature. Bristol-Myers Squibb (BMS), the developer of the PD-1 inhibitor nivolumab, stated in a press release that it remains blinded to all study data.

"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," Fouad Namouni, MD, head, Oncology Development, BMS, stated in the press release. "We are grateful to the patients, caregivers and investigators participating in this trial who make this research possible."

GBM is defined as the most common and most aggressive type of primary malignant tumor of the central nervous system, with a global incidence of <10 per 100,000 people. MGMT methylation status is a commonly used biomarker in GBM for treatment guidance, and data suggest MGMT methylation status may be predictive factor for treatment response.

The multicenter, single-blind, CheckMate-548 study (NCT02667587) evaluated nivolumab in combination with standard temozolomide and radiation therapy versus temozolomide/radiation therapy alone in 693 patients with newly diagnosed GBM that is MGMT-methylated. In the control arm, patients received 75 mg/m² of temozolomide daily during radiation therapy, followed by a 4-week treatment-free interval, and then continued with 150 mg/m² on days 1 to 5 for cycle 1, and increased to 200 mg/m² on days 1 to 5 for cycles 2 through 6 as tolerated. Radiotherapy was given as 2 Gy 5 times per week for 6 weeks. In the experimental arm, patients were treated with nivolumab at specified doses on specified days, plus the same temozolomide/radiation therapy regimen.

To be eligible for enrollment, patients with newly diagnosed GBM must have been ≥18 years old, had a Karnofsky performance status ≥70, substantial recovery from surgery resection, and have a MGMT-methylated tumor. Those with a biopsy-only of GBM with <20% of tumor removed, had prior therapy for their GBM, any known tumor outside of the brain, had recurrent or secondary GBM, or active known or suspected autoimmune disease, were excluded from enrolling on the study.

The primary endpoints of the trial are PFS as per blinded independent central review and OS; secondary endpoints are investigator-assessed PFS and OS rate ≤2 years.

Disappointing topline findings were announced in May 2019 with the phase III CheckMate-498 trial, which evaluated nivolumab plus radiation therapy versus temozolomide in patients with MGMT-unmethylated GBM.² Results showed that the nivolumab regimen did not improve OS over temozolomide, missing the coprimary endpoint of this multicenter study.

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 PFS and a 2-year OS rate. Results of the final analysis also showed that the safety profile was consistent with prior studies of nivolumab in solid tumors.

Earlier phase I data demonstrated activity with a similar combination regimen with nivolumab. Cohorts from the CheckMate-143 study evaluated the PD-1 inhibitor plus radiation with or without concurrent temozolomide in patients with newly diagnosed GBM.

Cohorts 1c and 1d of the phase I study included patients with newly diagnosed GBM. Patients in cohort 1c (n = 57) were enrolled regardless of MGMT status while 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, and patients in cohort 1d did not receive temozolomide.

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 radiation and 1 had prior therapy with anastrozole.

Findings showed that of 20 evaluable patients across both arms, the 12-month OS rate was 80%.³ 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. No new safety signals were observed.

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.

Ten deaths occurred 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, deaths were caused by progressive disease (n = 3), related to HSV encephalitis and clinical decline (n = 1), and unknown (n = 1).

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.

References

1. Bristol-Myers Squibb Provides Update on Phase 3 Opdivo (nivolumab) CheckMate-548 Trial in Patients with Newly Diagnosed MGMT-Methylated Glioblastoma Multiforme. Bristol-Myers Squibb. Published 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. Bristol-Myers Squibb. Published May 9, 2019. https://bit.ly/2V9ceag. Accessed May 9, 2019.
3. 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(suppl_6). doi: 10.1093/neuonc/now212.081.