Patients with glioblastoma, the most common malignant brain tumor, experienced tumor control after complete in-situ vaccination and anti-PD-1 immunotherapy, which resulted in T-cell expansion and clonal replacement, study findings showed.
At the 2024 Society for Immunotherapy of Cancer Annual Meeting, results were highlighted from the phase 2 2-THE-TOP trial, analyzing the safety and efficacy of adjuvant Temodar (temozolomide) plus tumor treating fields (TTFields; Optune) and Keytruda (pembrolizumab) for patients with newly diagnosed glioblastoma. The data from the trial were compared with a matched-control cohort of patients who received TTFields plus Temodar. Investigators found the median progression-free survival (PFS) in the experimental arm reached 12 months versus 5.8 in the control arm. The median overall survival (OS) was 24.8 months versus 14.6 months.
A longer survival was noted when patients underwent biopsy only versus maximal resection. The median PFS was 27.2 months versus 9.6 months. The median OS was 31.6 months versus 18.8 months. A high objective response was also noted for patients with biopsy-only tumors
The most common grade 1 (mild)/2 (moderate) side effects included nausea (29 patients), rash (22 patients), vomiting (14 patients) and pruritus/itching (14 patients). Additionally, grade 3 (severe)/4 (life-threatening) effects were minimal, with the most common being fatigue (six patients).
Glossary:
Complete in-situ vaccination: Injection of immune-activating drugs into a tumor.
Anti-PD-1 immunotherapy: Treatment that helps a body’s immune system kill cancer cells.
T-cell expansion: When T cells, which are part of the immune system, activate and multiply.
Clonal replacement: When T cells are replaced by new T cells.
Adjuvant: Treatment that follows the primary treatment, such as surgery.
Progression-free survival: The time a patient lives without their disease spreading or worsening.
Overall survival: The time a patient lives, regardless of disease status.
Maximal resection: Surgically removing as much of the tumor as possible.
Unresectable: Cannot be removed by surgery.
T lymphocytes: A type of white blood cell, which are part of the body’s immune system.
“The hypothesis was created that TTFields plus [Keytruda] creates a therapeutic synergy,” Dr. David D. Tran stated during the presentation. “Patients with bulky, unresectable tumors are associated with more robust in-situ vaccination, enhanced anti-tumor immunity and longer survival compared with those with maximally reduced tumors.”
Tran is the chief of the Division of Neuro-Oncology and co-director of the Brain Tumor Center at the University of Southern California.
The 2-THE-TOP trial enrolled patients with newly diagnosed glioblastoma. At week 1, concurrent radiotherapy and Temodar were given. At two weeks to 24 months, Keytruda was given for up to 34 cycles.
Patients who received biopsy only and were given Keytruda underwent clonal replacement, which investigators found correlated with survival.
Tran discussed that immuno-oncology has shown limited efficacy in glioblastoma because of the non-inflamed “cold” tumor microenvironment. This could be because of the low infiltration of T cells or TILs that are tolerized and exhausted.
Reasons leading to this limited efficacy could be intrinsic resistance with a failure to initiate an immune reaction, adaptive resistance with a failure to initiate an immune reaction an inactivation of tumor-specific cytotoxic T lymphocytes or acquired resistance with an escape from detection.
Tran introduced the phase 3 EF-14 trial, which assessed adjuvant Temodar plus TTFields for patients with newly diagnosed glioblastoma. Specifically, the TTFields used was Optune, which is a mobile device that attaches to the top of the head to directly target the tumor.
The median OS from randomization was 20.9 months in the TTFields and Temodar arm versus 16 months in the Temodar alone arm. Additionally, the median OS from diagnosis was 24.5 months versus 19.8 months in each arm, and the two-year OS rates were 43.1% versus 30.7%.
Reference:
“In-situ vaccination by tumor treating fields and anti-PD-1 immunotherapy in patients with large residual GBM results in robust T cell selection and expansion, high response rate, and extended survival,” by Dr. David D. Tran, et al., presented at the 2024 Society for Immunotherapy of Cancer Annual Meeting.
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