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Neoadjuvant pembrolizumab confers survival benefit among patients with glioblastoma
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Administering pembrolizumab to patients with glioblastoma before surgery appeared to significantly improve OS compared with administration after surgery, according to results of a randomized, multi-institution trial published in Nature Medicine.
“The results are very encouraging,” Robert M. Prins, PhD, professor of molecular and medical pharmacology at David Geffen School of Medicine at UCLA, said in a press release. “This is the first hint that immunotherapy can have clinical benefit for patients with malignant brain tumors — and help prevent future recurrences.”
Prins and colleagues sought to determine whether neoadjuvant pembrolizumab (Keytruda, Merck), an anti-PD-1 monoclonal antibody, would change the functional immune landscape and improve survival in patients with glioblastoma, which has 3-year survival rate of only 10.1%.
The researchers randomly assigned 35 patients with recurrent, resectable glioblastoma to neoadjuvant (n = 16) or adjuvant-only (n = 19) pembrolizumab. Three patients in the adjuvant-only group withdrew consent before surgery.
Estimated median follow-up was 15.6 months (interquartile range, 13.6-17.2).
Results showed that patients in the neoadjuvant group had a significant increase in OS compared with patients in the adjuvant group (13.7 months vs. 7.5 months; HR = 0.39; 95% CI, 0.17-0.94). Patients in the neoadjuvant group also experienced longer PFS (3.3 months vs. 2.4 months; HR = 0.43; 95% CI, 0.2-0.9).
The OS advantage with neoadjuvant pembrolizumab was similar among the 15 patients in each group who underwent surgery and had histologic evidence of tumor (13.2 months vs. 6.3 months; HR = 0.35; 95% CI, 0.14-0.88).
Neoadjuvant PD-1 blockade appeared associated with upregulation of T cell– and interferon-γ-related gene expression, as well as with downregulation of cell-cycle-related gene expression within the tumor, changes not observed among patients who received only adjuvant therapy.
The neoadjuvant group more frequently demonstrated induction of PD-L1 in the tumor microenvironment, enhanced clonal expansion of T cells, reduced PD-1 expression on peripheral blood T cells and a decreasing monocytic population.
Pembrolizumab generally was well-tolerated among the patients, 10 of whom in the neoadjuvant group and seven of whom in the adjuvant group experienced grade 3 to grade 4 adverse events deemed unlikely, possible, probable or likely attributable to the immunotherapy. The most common treatment-related adverse events included muscle weakness (50%), headache (47%), and hyperglycemia (37%). Two patients in the neoadjuvant group stopped taking pembrolizumab because of adverse events.
Researchers noted that larger trials are needed to confirm the results.
“This isn’t a very big study, and our data need to be replicated, but we have a foot in the door,” Timothy F. Cloughesy, MD, professor of neuro-oncology at Geffen School of Medicine, said in the release. “We have found a way to use these checkpoint inhibitors in glioblastoma that we previously thought were ineffective. We now have a rational and logical way to develop immunotherapies going forward and a clinical development process for doing it.”– by John DeRosier
Disclosures: Cloughesy reports compensation for an advisory board consultant role with Merck. Prins reports no relevant financial disclosures. Please see the study for all other authors’ relevant financial disclosures.
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