Abstract
Prospective phase I study of checkpoint blockade for the treatment of patients with newly diagnosed high-grade glioma prior to radiochemotherapy: Results of nivolumab plus ipilimumab treatment arm.
Author
Santosh Kesari
Saint John's Cancer Institute at Providence Saint John's Health Center, Santa Monica, CA
info_outline
Santosh Kesari, Alexandre Wojcinski, Jaya M. Gill, Jose Arganda Carrillo, Naveed Wagle, Minhdan Nguyen, Judy Dang Truong, Tiffany M. Juarez
Full text
Authors
Santosh Kesari
Saint John's Cancer Institute at Providence Saint John's Health Center, Santa Monica, CA
info_outline
Santosh Kesari, Alexandre Wojcinski, Jaya M. Gill, Jose Arganda Carrillo, Naveed Wagle, Minhdan Nguyen, Judy Dang Truong, Tiffany M. Juarez
Organizations
Saint John's Cancer Institute at Providence Saint John's Health Center, Santa Monica, CA, Pacifica Neuroscience Institute and Saint John's Cancer Institute at Providence Saint John's Health Center, Santa Monica, CA, Pacific Neuroscience Institute and Saint John's Cancer Institute at Providence Saint John’s Health Center, Santa Monica, CA, Pacific Neuroscience Institute and Saint John's Cancer Institute at Providence Saint John's Health Center, Santa Monica, CA
Abstract Disclosures
Research Funding
Other Foundation
PHASE ONE – The Road to Curing Cancer, Glen Turner, Jamie Siminoff
Background:
The limited success of checkpoint inhibitors (CPI) targeting the programmed death-1 (PD-1) axis in the adjuvant setting for glioblastoma has prompted a deeper understanding of the brain tumor and immune microenvironment and evaluating how the sequence of immunotherapy administration impacts antitumor response. We initiated a feasibility study (NCT03425292) of postoperative nivolumab (anti-PD-1) monotherapy and combination therapy in adults with newly diagnosed high-grade gliomas (HGG) prior to radiotherapy.
Methods:
Within six weeks from surgical resection of newly diagnosed HGG, patients in study Arm 3 received nivolumab 300 mg every 2 weeks and ipilimumab 1 mg/kg every 6 weeks until disease progression or unacceptable toxicity. The primary endpoint was the rate of dose-limiting toxicities (DLT). Secondary objectives included adverse events, antitumor activity and pharmacodynamic effects of study treatment. Next-generation sequencing (NGS) was performed on archival tumor specimens before treatment and at the time of subsequent surgery.
Results:
Fifteen patients were treated with nivolumab plus ipilimumab. 27% (4/15) of patients were receiving dexamethasone at treatment initiation. MGMT promoter was methylated in 5 tumors, unmethylated in 9, and equivocal in one. The most common treatment-related adverse events (AEs) were rash, pruritus, fatigue, nausea, and anorexia. Grade 3 AEs were lipase increased (n = 2), anorexia (n = 1), pruritus (n = 1), and rash (n = 3), and Grade 4 cerebral edema occurred in 1 patient. Median progression-free survival (mPFS) was 1.3 months and median overall survival (mOS) was 19.3 months. Paired tumor specimens obtained before and after treatment were analyzed in six patients and revealed molecular changes in response to treatment as well as differences between patients with shrinking tumors versus progressing tumors.
Conclusions:
We show that nivolumab plus ipilimumab can be safely administered prior to radiation. To our knowledge, this is the first study in which checkpoint blockade therapy was administered for newly diagnosed glioblastoma prior to standard radiotherapy. Despite the short mPFS, mOS was suggestive of a potential long-term benefit from early CPI exposure, and three patients deferred chemoradiation greater than seven months. Analysis of other study arms is ongoing. Clinical trial information: NCT03425292.
Clinical status
Clinical
1 clinical trial
4 organizations
2 drugs
2 targets
Clinical trial
A Longitudinal Assessment of Tumor Evolution in Patients With Brain CancerStatus: Completed, Estimated PCD: 2022-09-12
Organization
Saint John's Cancer InstituteOrganization
Pacifica Neuroscience InstituteOrganization
Pacific Neuroscience Institute and Saint John’s Cancer Institute at Providence Saint John’s Health CenterOrganization
Saint John's Health CenterDrug
nivolumabDrug
ipilimumabTarget
CTLA-4Target
PD-1