Scientists report that several patients with recurring glioblastoma survived for more than a year in a clinical trial the researchers believe was the first to use DNA and RNA sequencing of a patient's tumor to provide treatment for these patients in real time. The study (“Prospective Feasibility Trial for Genomics-Informed Treatment in Recurrent and Progressive Glioblastoma”), published in Clinical Cancer Research, was led by the Translational Genomics Research Institute (TGen), University of California, San Francisco (UCSF), and the Ivy Foundation Early Phase Clinical Trials Consortium.
“We conducted a prospective genomics-informed feasibility trial in adults with recurrent and progressive glioblastoma. Following surgical resection, genome-wide tumor/normal exome-sequencing and tumor RNA-sequencing was performed to identify molecular targets for potential matched therapy. A multi-disciplinary molecular tumor board issued treatment recommendations based on the genomic results, blood brain barrier penetration of the indicated therapies, drug-drug interactions, and drug safety profiles. Feasibility of generating genomics-informed treatment recommendations within 35 days of surgery was assessed,” write the investigators.
“Of the 20 patients enrolled in the study, 16 patients had sufficient tumor tissue for analysis. Exome-sequencing was completed for all patients and RNA-sequencing was completed for 14 patients. Treatment recommendations were provided within the study's feasibility time frame for 15 of 16 (94%) patients. Seven patients received treatment based on the tumor board recommendations. Two patients reached 12-month progression-free survival, both adhering to treatments based on the molecular profiling results. One patient remained on treatment and progression-free 21 months after surgery, three-times longer than the patient's previous time to progression. Analysis of matched non-enhancing tissue from 12 patients revealed overlapping as well as novel putatively actionable genomic alterations.
“Use of genome-wide molecular profiling is feasible and can be informative for guiding real-time, central nervous system (CNS)-penetrant, genomics-informed treatment recommendations for patients with recurrent glioblastoma.”
“To our knowledge, this is the first report of a prospective profiling study in recurrent glioblastoma to show patients with extended time to progression following treatment with genomics-informed therapy,” said Sara Byron, Ph.D., research assistant professor in TGen's Integrated Cancer Genomics Division and the study's lead author. “This is a primary example of the benefits of genomics-driven precision medicine being applied for patients with aggressive and refractory tumors.”
Key to this study was the fact that all genomic sequencing, genetic analysis, and recommendations for treatment were completed in less than 35 days after surgery, ensuring that suggested therapies could begin within “a clinically acceptable time frame.”
Glioblastoma is an aggressive disease, with a median overall survival of only 15 months for newly diagnosed patients. One of the major difficulties in treating glioblastoma is its intrusive penetration into adjoining tissues, which prevents the complete surgical removal of the tumors from the brain, even with follow-up radiation and chemotherapy. As a result, nearly all glioblastomas recur. Patients whose brain cancer returns are often encouraged to enter experimental clinical trials. However, even on clinical trials, further progression of the disease is seen, on average, within four months.
“Notably, two of the patients experienced progression-free survival—meaning their tumor did not return or increase in size—for more than a year, with one of these patients progression-free at 21 months, three times longer than the time to progression on their previous therapy,” said Michael D. Prados, M.D., the Charles B. Wilson Endowed Chair in Neurological Surgery at UCSF, and the study's senior author.
Another major challenge in treating brain tumors is finding drugs that can penetrate the blood–brain barrier, which buffers the brain from the rest of the body's blood-circulatory system. Located along small capillaries, the blood–brain barrier protects the brain from rapid changes in the body's metabolic conditions and minimizes exposure to large molecules that are toxic to neurons in the brain.
The only FDA-approved standard-of-care drugs to treat glioblastoma are temozolomide, nitrosoureas, and bevacizumab.
In this study, more than 180 FDA-approved agents were reviewed, including all FDA-approved oncology drugs and a selection of repositioned agents that are approved by the FDA for other indications but show promising activity against cancer pathways. The tumor board considered the drugs supported by the genomic data for each patient, and discussed each drug's ability to penetrate the blood–brain barrier, potential opportunities to combine treatments, drug-to-drug interactions, and drug-safety profiles.
One of the patients was a 58-year-old woman with recurrent glioblastoma. Genomic sequencing showed several alterations with potential therapeutic relevance. Based on mutations in her NF1 and PALB2 genes, the UCSF Molecular Tumor Board recommended treatment with a combination of trametinib, olaparib, and carboplatin. “This patient continued on treatment without disease progression (for more than) 665 days after surgery,” according to the new study which adds, “Additional preclinical and clinical studies will be needed to determine the role of genomic context and combination therapy in the response observed for this patient.”
Another patient was a 35-year old man with recurrent glioblastoma. The study's tumor board, focusing on the tumor's mutations in the IDH1 and ATRX genes, recommended treatment with a combination of CCNU (lomustine), carboplatin, and metformin. The patient and treating oncologist decided to pursue treatment with CCNU and metformin. “This patient remained on treatment and progression-free for just over one year,” the study reported.
“This precision-medicine study provides one of the first prospective demonstrations of using genome-wide molecular profiling to guide treatment recommendations for patients with recurrent glioblastoma within a clinically actionable time frame,” said Michael Berens, Ph.D., TGen deputy director for research resources, and professor and director of TGen's Cancer and Cell Biology Division. “These findings provide a rationale and framework for larger prospective studies to further assess the efficacy of employing genomics-guided treatment for patients with recurrent glioblastoma.”
