Researchers examine genomic mutations with tumor response to Keytruda and Opdivo in patients with GBM, highlighting the potential for a molecular, personalized approach to treat certain patients.
Certain patients with glioblastoma
(GBM) who had mutations in genes involved in a signaling pathway in the cell known as MAPK may benefit from treatment with immunotherapy, according to recent study findings published in Nature Medicine
“(The researchers’) results…suggest that it may be beneficial to combine PD-1 inhibitors with targeted drugs against the MAPK pathway,” the American Association for Cancer Research issued in a press release.
A team of researchers examined the genomics of patients with GBM and how that affects responses to Keytruda (pembrolizumab) and Opdivo
(nivolumab), both immune checkpoint inhibitors
that target PD-1, a protein found on T cells. They studied 66 patients with GBM, including 17 long-term responders, during standard therapy and after treatment with either Keytruda or Opdivo.
Immune checkpoint inhibitors have shown success across many tumor types, such as melanoma, non-small cell lung cancer, kidney cancer, bladder cancer, head and neck cancers and Hodgkin lymphoma, but their efficacy in GBM is still not well known.
“There has been considerable interest in utilizing immunotherapy in GBM, but a recent clinical trial of (PD-1) immune checkpoint inhibitors in recurrent glioblastoma showed that only a small subset of patients (8%) demonstrated objective responses,” the researchers wrote.
Higher mutational burdens in tumors have been associated with improved response to anti-PD-1 therapy, they explained. Therefore, the researchers collected DNA, RNA, tissue imaging and clinical data from the patients to evaluate genomic features and clinical outcomes associated with immunotherapy in GBM. Then they analyzed genes and proteins to check for possible disease-causing mutations. They identified 11 IDH1 R132G/H mutated tumors and 23 PTEN mutations. “Within the cohort, PTEN was significantly more frequently mutated in the nonresponsive tumors than in the responsive ones,” the researchers wrote.
Four mutations, including BRAF and PTPN11, were found in the MAPK pathway, which is a chain of proteins in the cell that communicates a signal from a receptor on the surface of the cell to the DNA.
Median overall survival was 15.5 months in responders compared with 5.7 months in non-responders. Overall, the researchers discovered that patients who responded to the PD-1 inhibitors had mutations in genes that involved the MAPK pathway. Patients who had more mutations in the PTEN gene did not respond to treatment.
“We have confirmed that GBM patients who were responsive to anti-PD-1 immunotherapy (as evaluated through radiology and pathology) had significantly better overall survival after treatment,” the researchers wrote. “In our cohort, tumors from non-responders were significantly enriched for PTEN mutations; furthermore, RNA-sequence analysis indicated that these PTEN mutations may induce a distinct immunosuppressive microenvironment.”
Glioblastomas represent about 15% of all primary brain tumors, according to the American Brain Tumor Association
. GBM most commonly affects men with diagnosis occurring at a median age of 64.
“Our study identified multiple genomic features related to response to anti-PD-1 therapy in patients with GBM and depicted distinct evolutionary patterns of GBM under immunotherapy,” the researchers wrote. “While overall PD-1 inhibitors do not provide a survival benefit for patients with GBM, our study showed that a subgroup of patients might benefit from this therapy, suggesting a molecular, personalized approach for refining patient selection for immunotherapy.”