A Randomized Phase II Trial (TAMIGA) Evaluating the Efficacy and Safety of Continuous Bevacizumab Through Multiple Lines of Treatment for Recurrent Glioblastoma

Abstract

Background: We assessed the efficacy and safety of bevacizumab (BEV) through multiple lines in patients with recurrent glioblastoma who had progressed after first-line treatment with radiotherapy, temozolomide, and BEV.

Patients and methods: TAMIGA (NCT01860638) was a phase II, randomized, double-blind, placebo-controlled, multicenter trial in adult patients with glioblastoma. Following surgery, patients with newly diagnosed glioblastoma received first-line treatment consisting of radiotherapy plus temozolomide and BEV, followed by six cycles of temozolomide and BEV, then BEV monotherapy until disease progression (PD1). Randomization occurred at PD1 (second line), and patients received lomustine (CCNU) plus BEV (CCNU + BEV) or CCNU plus placebo (CCNU + placebo) until further disease progression (PD2). At PD2 (third line), patients continued BEV or placebo with chemotherapy (investigator's choice). The primary endpoint was survival from randomization. Secondary endpoints were progression-free survival in the second and third lines (PFS2 and PFS3) and safety.

Results: Of the 296 patients enrolled, 123 were randomized at PD1 (CCNU + BEV, n = 61; CCNU + placebo, n = 62). The study was terminated prematurely because of the high drop-out rate during first-line treatment, implying underpowered inferential testing. The proportion of patients receiving corticosteroids at randomization was similar (BEV 33%, placebo 31%). For the CCNU + BEV and CCNU + placebo groups, respectively, median survival from randomization was 6.4 versus 5.5 months (stratified hazard ratio [HR], 1.04; 95% confidence interval [CI], 0.69-1.59), median PFS2 was 2.3 versus 1.8 months (stratified HR, 0.70; 95% CI, 0.48-1.00), median PFS3 was 2.0 versus 2.2 months (stratified HR, 0.70; 95% CI, 0.37-1.33), and median time from randomization to a deterioration in health-related quality of life was 1.4 versus 1.3 months (stratified HR, 0.76; 95% CI, 0.52-1.12). The incidence of treatment-related grade 3 to 4 adverse events was 19% (CCNU + BEV) versus 15% (CCNU + placebo).

Conclusion: There was no survival benefit and no detriment observed with continuing BEV through multiple lines in patients with recurrent glioblastoma.

Implications for practice: Previous research suggested that there may be value in continuing bevacizumab (BEV) beyond progression through multiple lines of therapy. No survival benefit was observed with the use of BEV through multiple lines in patients with glioblastoma who had progressed after first-line treatment (radiotherapy + temozolomide + BEV). No new safety concerns arose from the use of BEV through multiple lines of therapy.

Keywords: Clinical trial; Continuous bevacizumab; Overall survival; Recurrent glioblastoma.

Conflict of interest statement

Disclosures of potential conflicts of interest may be found at the end of this article.

© AlphaMed Press 2018.

Figures

Figure 1.

TAMIGA study design. Stratification factors: occurrence of PD1 relative to completion of first‐line maintenance therapy (before vs. after completion) and Eastern Cooperative Oncology Group performance status at randomization (0 vs. 1 or 2). Abbreviations: *, start of TAMIGA study; BEV, bevacizumab; CCNU, lomustine; CIC, chemotherapy (investigator's choice); PD1, first disease progression; PD2, second disease progression; PD3, third disease progression; PFS1, first‐line progression‐free survival; PFS2, second‐line progression‐free survival; PFS3, third‐line progression‐free survival; RT, radiotherapy; TMZ, temozolomide.

Figure 2.

OS from randomization with multiple‐line BEV treatment versus placebo (primary efficacy endpoint). Abbreviations: BEV, bevacizumab; CCNU, lomustine; CI, confidence interval; HR, hazard ratio; OS, overall survival.

Figure 3.

PFS2 and PFS3 with multiple‐line BEV treatment versus placebo. (A): PFS2. (B): PFS3. Abbreviations: BEV, bevacizumab; CCNU, lomustine; CI, confidence interval; HR, hazard ratio; PFS2, second‐line progression‐free survival; PFS3, third‐line progression‐free survival.

Figure 4.

Time‐to‐event analysis of corticosteroid initiation in second‐line treatment with BEV versus placebo. A deterioration in health‐related quality of life (HRQoL) was defined as a decrease of ≥10 points from randomization on the respective functional scale/global health status or an increase of ≥10 points from randomization on the respective symptom/neurological deficit subscales; time to HRQoL deterioration was defined as the time from randomization to HRQoL deterioration or second‐line progression or death due to any cause. Abbreviations: BEV, bevacizumab; CCNU, lomustine; CI, confidence interval; HR, hazard ratio.