Second-line temozolomide in first recurrent MGMT-methylated glioblastoma after lomustine/temozolomide: Efficacy and safety

Abstract

Background: The optimal salvage therapy for recurrent MGMT-methylated glioblastoma (GBM), IDH wildtype, remains undefined. While lomustine is often used in clinical trials and considered standard-of-care, cumulative toxicity precludes its use in patients previously treated with lomustine/temozolomide. The role of temozolomide rechallenge in this setting is unclear.

Methods: This monocentric retrospective study included 70 patients with MGMT-methylated GBM, IDH wildtype, who received lomustine/temozolomide as first-line therapy. Descriptive data on second-line therapies were collected, and therapy responses were assessed. Survival outcomes were evaluated using Kaplan-Meier analysis.

Results: Of 55 patients with documented tumor progression, 40 patients received second-line therapy. The most frequently used systemic therapy was temozolomide (n = 33, 79% of patients with second-line therapy), with a median number of 6 cycles and hematotoxicity grade 3 or 4 observed in <20% of patients. Among patients receiving temozolomide only, stable disease or partial response was achieved in 53.3%, with a progression-free survival rate at 6 months after first recurrence of 50% and a 1-year OS rate of 45%.

Conclusions: Temozolomide rechallenge is a common, safe, and effective second-line option for patients with MGMT-methylated, IDH wildtype GBM following first-line lomustine/temozolomide therapy. These findings support its consideration as a salvage therapy in appropriate clinical scenarios.

Keywords: Glioblastoma; MGMT; progression; salvage therapy; temozolomide.

Figure 1.

The treatment modalities employed for recurrence therapies. On the left, a Venn diagram depicts the distribution of different treatment approaches, including systemic therapy, re-irradiation (re-RT), and re-resection, with overlapping regions indicating combination therapies. In the upper right corner, a pie chart shows the distribution of systemic therapies, highlighting temozolomide (TMZ) as the most frequently used agent (78.8%). The bottom right corner presents the spectrum of TMZ rechallenge and its combination with other modalities, such as re-RT and/or re-resection.

Figure 2.

(A) A swimmer’s plot displaying patients receiving TMZ rechallenge. Each bar represents 1 patient, with the x-axis indicating the number of completed cycles. An asterisk denotes tumor progression as the reason for discontinuation before the eighth cycle. A triangle marks discontinuation due to hematotoxicity, while a square represents other reasons for early discontinuation (withdrawal in 1 case and symptomatic varicella zoster infection in the other). (B) The frequency of hematotoxicity during TMZ rechallenge, assessed using CTCAE v5, is illustrated. For 1 patient, data on hematotoxicity were unavailable and are shown as a white proportion.

Figure 3.

(A) A pie chart illustrating the frequency of achieved therapy responses in patients receiving TMZ rechallenge, with categories defined in detail in the Methods section. (B) and (C) present Kaplan-Meier curves for PFS-2 (progression-free survival from first to second progression, measured in months) and OS (overall survival from first progression to death), respectively. The dotted lines represent the 95% confidence intervals (CI). Numbers at risk are provided below the curves, indicating how many patients remained in follow-up at 6-month intervals. Within the Kaplan-Meier curves, PFS-6 (progression-free survival rate after 6 months) and 1-year-OS rate is highlighted.