Pembrolizumab/Bevacizumab Combination Satisfies Safety Criteria in Recurrent Glioblastoma

David Reardon, MD

David Reardon, MD

An immunotherapy/antiangiogenesis combination proved to be safe and tolerable for patients with recurrent glioblastoma, preliminary data from an ongoing trial showed.

Safety lead-in data for the trial of pembrolizumab and bevacizumab showed only two grade >1 adverse events: one case each of grade 3 dizziness and grade 2 fatigue. None of the 6 patients involved in the lead-in phase achieved objective responses, although 2 patients lived more than a year after enrollment in the study.

The results satisfied safety criteria for proceeding with an 80-patient, randomized, phase II trial of the combination in patients with recurrent glioblastoma, as reported at the 2016 ASCO Annual Meeting.¹

“Pembrolizumab and bevacizumab can be safely coadministered at established dose levels for each individual agent,” said David A. Reardon, MD, clinical director of neuro-oncology at the Dana-Farber Cancer Institute. “The side effects of standard pembrolizumab plus bevacizumab are tolerable and manageable and there do not appear to be unexpected adverse events associated with this combination of therapy.”

Several lines of evidence support the combination of an immunotherapeutic agent and an angiogenesis inhibitor in recurrent glioblastoma. The tumors are highly angiogenic and associated with elevated expression of VEGF. Inhibition of VEGF has been shown to prolong progression-free survival (PFS) in newly diagnosed and recurrent glioblastoma, said Reardon.

Glioblastomas also exhibit substantial immunosuppression, which is associated with tumor cell expression of PD-L1 and expression of the PD-1 receptor by tumor-infiltrating lymphocytes.

Additionally, preclinical evidence has demonstrated that VEGF blockade enhances immunotherapeutic strategies. The preclinical evidence has translated into clinical evidence in the case of metastatic melanoma, as the combination of bevacizumab and the CTLA-4 inhibitor ipilimumab led to substantial improvement in objective response rate, PFS, and overall survival compared with ipilimumab monotherapy.²

The supporting evidence provided the basis for the study reported by Reardon. The trial had 2 primary objectives: (1) determine phase II dose and maximum tolerated dose of pembrolizumab administered in combination with bevacizumab in patients with recurrent glioblastoma and (2) to evaluate the antitumor activity of pembrolizumab in patients with bevacizumab-naïve glioblastoma treated with the combination.

“We hypothesized that the administration of pembrolizumab with and without bevacizumab would be well tolerated and result in a clinically meaningful benefit compared to the appropriate historical controls, as measured by 6-month PFS among subjects with bevacizumab-naïve recurrent glioblastoma,” said Reardon.

For the safety lead-in, the first 3 patients received standard doses of pembrolizumab (200 mg every 3 weeks) and bevacizumab (10 mg/kg every 2 weeks). If no dose-limiting toxicities (DLT) occurred, 3 additional patients were treated at the same doses. Absence of DLT allowed the evaluation to move forward with the randomized phase II trial.

Reardon reported only the data from the safety lead-in, although the 80 patients for the phase II trial have been accrued. Eligibility criteria included age ≥18, glioblastoma in first or second recurrence, good performance status, no prior VEGF/VEGFR-directed therapy, ≥12 weeks from completion of radiotherapy, 4 weeks from prior chemotherapy, and 4 weeks from prior surgery.

The 6 patients had a median age of 48, and 4 of the 6 were in second recurrence of glioblastoma. Median time from initial glioblastoma diagnosis was 11.2 months.

Aside from 1 grade 3 adverse event and 1 grade 2, 1 more patients had grade 1 episodes of multiple adverse events that were considered possibly/probably related to treatment. The events included abdominal pain, decreased absolute neutrophil count, cough, chest pain, diarrhea, dry mouth, headache, hyperglycemia, hyperinsulinemia, hyper- and hypothyroidism, leukopenia, lymphopenia, nausea, pruritus, rash, thrombocytopenia, and transaminase increase.

Four of the 6 patients had stable disease. No patient had an objective response. Median PFS was 3.5 months and ranged from 1.4 to 9.8 months. Median overall survival was 6.9 months and ranged from 3.5 to 14.4 months. Two patients lived for more than a year.

Patient accrual has completed for the randomized phase II trial (NCT02337491) which will compare the pembrolizumab/bevacizumab (n = 49) combination versus bevacizumab monotherapy (n = 29). The patients have a median age of 55, and most (65%-70%) are in first recurrence. Median time since initial diagnosis is approximately 1 year.

References

1. Reardon DA, De Groot JF, Colman H, et al. Safety of pembrolizumab in combination with bevacizumab in recurrent glioblastoma (rGBM).J Clin Oncol. 2016;34(suppl; abstr 2010).
2. Hodi FS, Lawrence D, Lezcano C, et al. Bevacizumab plus ipilimumab in patients with metastatic melanoma.Cancer Immunol Res. 2014;7:632-642.