Precision Medicine in Recurrent Glioblastoma

At recurrence, survival for glioblastoma patients is approximately nine months even with additional treatment, pointing to an urgent need to identify more effective combination therapies against these genetically complex brain tumors. 

Researchers at UC San Francisco have now demonstrated the feasibility of implementing a personalized treatment regimen using multiple targeted therapies in a phase 1 clinical trial for recurrent glioblastoma.

“The idea behind the trial was to try to really assess what precision medicine should be: looking at the genetic profile of an individual’s tumor at the time of tumor regrowth and then selecting treatments based on their own tumor,” said Jennifer Clarke, MD, MPH, a UCSF neuro-oncologist and the UCSF Brain Tumor Center principal investigator leading the trial.

The findings were recently published in Clinical Cancer Research.

Between 2018 and 2023, the trial enrolled patients with recurrent glioblastoma who underwent surgery and had their tumor genomically sequenced with the UCSF500 Cancer Gene Panel. Then, a multidisciplinary tumor board that included experts in neuro-oncology, neuropathology, clinical pharmacy, and pharmacology met to decide on the patient’s treatment plan.

For each patient, Clarke and her colleagues chose one chemotherapy plus an additional two or three targeted therapies tailored the patient’s history and tumor profile. 

All the drugs used in the trial were approved by the U.S. Food and Drug Administration, but many had not been extensively studied in glioblastoma before, especially as a combination therapy. Generous philanthropic support from the Sandler family to the Glioblastoma Precision Medicine Program, also meant that Clarke and her colleagues did not have to worry about whether a trial participant’s health insurance would cover the cost of the different medications.

With an initial 15-patient cohort, the researchers demonstrated that they could successfully get patients onto a personalized treatment regimen within 35 days of surgery. By including a second 15-patient cohort and bringing the total number of trial participants up to 30, the researchers were also able to evaluate the efficacy of this precision medicine approach. They studied a total of 12 drugs and 18 drug combinations — highlighting the variation observed in the genetic features of these brain tumors.

Overall survival at nine months from trial enrollment was 73 percent, and the median overall survival for the study participants was 12.7 months. Although the survival outcomes were longer than expected in this patient population, they were not significantly different than a comparison cohort of 43 patients who only received traditional chemotherapy.

Part of the challenge with the multidrug regimen Clarke says was in negotiating a balance between maximizing the effectiveness and minimizing overlapping toxicities.

“The combinations were tough for the patients to tolerate,” Clarke said. “A lot of drugs that are used to fight cancer have similar side effects, so we did have to hold medications and pull back on some doses.”

As more targeted anti-cancer therapies become available, future clinical trials that use an adaptive platform to evaluate multiple therapies more quickly may help refine the choice of drugs and their effective dose.

Clarke and her colleagues also showed that sequencing tumor specimens following the treatment regimens revealed some mechanisms that could be underlying drug resistance, pointing to the continuing importance of genomic profiling in identifying new potential therapies.

Since 2017, patients who have surgery at the UCSF Brain Tumor Center have their tumor routinely sequenced — information that Clarke says has been extremely beneficial to the management of their disease.

“It’s helpful to have greater confidence in their exact tumor diagnosis,” she said. “There’s also a subset of people where we see an actionable abnormality or mutation that changes their treatment options or significantly changes our understanding of their likely prognosis. That has been a huge positive.”

Reference: Chen J, Oberheim Bush NA, Grabowsky JA, Kline C, Kroetz DL, Taylor JW, Villanueva-Meyer J, Molinaro AM, de Groot JF, Butowski NA, Tedesco M, Rabbitt J, Phillips JJ, Hervey-Jumper S, Aghi MK, Berger MS, Chang EF, Chang SM, Solomon DA, Clarke JL. A genomically-tailored multi-agent precision medicine clinical trial for adults with recurrent glioblastoma. Clin Cancer Res. 2026 Feb 6. doi: 10.1158/1078-0432.CCR-25-4080. Epub ahead of print.