Clinical trialPhase 3Brain tumours

Lomustine and Bevacizumab in Progressive Glioblastoma

N Engl J Med · 2017437 patients

Wick W, Gorlia T, Bendszus M, Taphoorn M, Sahm F, Harting I, et al. N Engl J Med. 2017. 377:1954-1963

Study type: Clinical trial
Study name: EORTC 26101
Phase: Phase 3
Design: Randomised open-label 2:1 trial comparing lomustine plus bevacizumab with lomustine alone
Sample size: 437 patients
Source: N Engl J Med · 2017
Trial registration: NCT01290939

In plain words

In this study, patients with glioblastoma whose disease had progressed after initial treatment received either the drug lomustine alone or lomustine together with bevacizumab. Adding bevacizumab slightly lengthened the time the disease stayed without progressing, but did not help patients live longer. Serious side effects were more common in the group that received both drugs, but patients' quality of life and mental function did not change.

Key results

9.1 months vs 8.6 months (combination vs monotherapy)

Median overall survival

HR for death 0.95 (95% CI 0.74 to 1.21); P=0.65

4.2 months vs 1.5 months

Median progression-free survival (local assessment)

HR for progression or death 0.49 (95% CI 0.39 to 0.61); P<0.001

329 events (75.3%)

Number of overall survival events

Adding bevacizumab affected neither

Quality of life and neurocognitive function

Drugs in this study:Bevacizumab (Avastin)

Dose and schedule cards

Lomustine + bevacizumab (EORTC 26101)

First progression of glioblastoma at least 3 months after chemoradiotherapy; no prior bevacizumab or nitrosoureaEach drug’s schedule in the tableOn the page “Brain tumours” · Recurrent or progressive glioblastoma

First progression of glioblastoma at least 3 months after chemoradiotherapy; no prior bevacizumab or nitrosourea

Drug	Dose	Route	Schedule
Lomustine	90 mg/m² (maximum 160 mg); in the absence of haematologic toxicity above grade 1 in the first cycle, 110 mg/m² (maximum 200 mg) from the second cycle	Oral	Day 1 every 6 weeks
Bevacizumab	10 mg/kg	IV	Every 2 weeks

Cycle schedule: Lomustine every 6 weeks; bevacizumab every 2 weeks
Duration: Until progression or unacceptable toxicity

Improved progression-free survival but not overall survival. The FDA-labelled bevacizumab dose in recurrent glioblastoma is 10 mg/kg every 2 weeks; do not give it for at least 28 days before and after major surgery; monitor blood pressure and urine protein; discontinue for grade 3 to 4 haemorrhage, gastrointestinal perforation, severe arterial thromboembolism or posterior reversible encephalopathy syndrome (PRES). Lomustine points as in the “Common safety considerations”. Dose source: protocol NCT01290939.

On the page “Brain tumours” · Recurrent or progressive glioblastoma

Doses follow the trial protocol, guideline or official drug label (source given in the notes of each regimen). Before prescribing, check blood counts, renal and hepatic function, drug interactions and the patient’s condition, and adjust the dose according to the drug label.

Treatment arms and regimens

1Combination group

Lomustine 90 mg/m² orally (maximum 160 mg) every 6 weeks + bevacizumab 10 mg/kg IV every 2 weeks; in the absence of haematological toxicity above grade 1 in the first cycle, lomustine was escalated from the second cycle to 110 mg/m² (maximum 200 mg). 288 patients; median number of 6-week cycles: 3.

2Monotherapy group

Single-agent lomustine 110 mg/m² orally (maximum 200 mg) every 6 weeks. 149 patients; median number of cycles: 1.

Source of the regimen details: Abstract of the paper and ClinicalTrials.gov NCT01290939 (lomustine dose, dose cap and dose escalation; bevacizumab dose)

Doses are given for the information of specialists, as in this study’s protocol, and are not a prescription. Every drug must be prescribed by the treating physician for the individual patient.

Study population

Patients with glioblastoma at first progression after chemoradiotherapy.

Per ClinicalTrials.gov: primary glioblastoma with first unequivocal progression at least 3 months after the end of the concurrent part of chemoradiotherapy; at most one prior line of chemotherapy; no prior treatment with bevacizumab or other VEGF inhibitors and no prior nitrosourea; surgery for recurrence was allowed.

Endpoints

Primary endpoint: overall survival. Progression-free survival, adverse events, health-related quality of life and neurocognitive function (at baseline and every 12 weeks) and MGMT promoter methylation status were also assessed.

Safety and side effects

Grade 3 to 5 adverse events occurred in 63.6% of patients in the combination group and 38.1% of patients in the monotherapy group.

Clinical significance and place in guidelines

According to the abstract, adding bevacizumab to lomustine in progressive glioblastoma at first progression conferred no overall survival advantage, although it slightly increased progression-free survival. This finding is important for evaluating the place of bevacizumab in these patients, for whom it had previously been approved on the basis of uncontrolled data. The current status of clinical guidelines and drug approvals should be checked separately.

Limitations

According to the abstract, progression-free survival was assessed locally. The monotherapy group had half as many patients as the combination group (2:1 design). Other limitations should be checked in the full text of the paper.

Original article (DOI)PubMed ClinicalTrials.gov

This summary was prepared by the editorial team from the published paper; the original paper is the final reference. Read the original abstract on PubMed.