Drug Combination Sees Median 91% Brain Tumor Shrinkage in Small Trial

Results from a new Phase 2 clinical trial show that a combination of targeted drugs led to a median 91% shrinkage of a rare type of brain tumor – papillary craniopharyngioma (PCP) – in a small study of 16 participants. The research is published in the New England Journal of Medicine.

Investigating new treatments for rare tumors

PCPs are a rare type of brain tumor, occurring at a rate of 0.5–2 cases per million people per year, but cause considerable morbidity for patients, and treatment almost always results in other illnesses or conditions.

Incomplete surgical removal of tumors and toxic side effects from radiation can lead to neuroendocrine dysfunction – i.e., problems with how the brain controls the body’s hormonal activity – or loss of vision or memory.

Investigations into the genetics of these tumors have revealed that over 90% harbor a mutation in the BRAF gene called V600E. This causes BRAF – an enzyme involved in cell proliferation – to increase its activity and subsequently drive tumor growth.

Drugs such as vemurafenib (an inhibitor of BRAF V600E) and cobimetinib (an inhibitor of MEK, a protein activated by BRAF) are extremely effective in targeting cells with this mutation to block BRAF activity, particularly for cancers such as melanoma. However, there is not much data on the safety and efficacy of these drugs for the treatment of PCPs, which researchers from Mass General Cancer Center sought to address in the current study.

91% median reduction in tumor size

Investigators recruited into their Phase 2 clinical trial 16 patients with PCPs positive for BRAF V600E and who had not received previous radiotherapy.

Patients received a combination of vemurafenib and cobimetinib in 28-day cycles, with 15 patients receiving at least 1 full cycle (1 patient dropped out due to side effects), and a median of 6 cycles being administered.

Over the course of 4 treatment cycles, there was a 91% median reduction in tumor size, with a range of 68–99%. All patients who completed at least one cycle showed a response to treatment within four months.

After the trialed vemurafenib–cobimetinib cycles, seven patients received no further treatment, six received radiotherapy alone, one received radiotherapy followed by surgery, one received radiotherapy followed by dabrafenib (another BRAF inhibitor) and one received a different protocol of vemurafenib–cobimetinib treatment.

After 12 months of follow-up, 87% of patients showed no progression of their disease, and 58% of patients showed no progression by 24 months. Though three patients showed progression during follow-up, there was no progression during treatment, and none have died.

Nonetheless, patients did experience side effects from the treatment, leading three patients to discontinue. The most common side effects were rashes, which were reported by six patients. Despite side effects, many patients continued therapy beyond the initial four prescribed cycles as a result of their positive response to it.

“All patients who completed one or more cycles of therapy responded to treatment, which is the highest response rate to date of any medical therapy for brain tumors,” said Dr. Priscilla Brastianos, lead author of the study and director of the Central Nervous System Metastasis Center within Mass General Cancer Center. “These unprecedented results signal a paradigm shift for targeting brain tumors because they show that, with the right target and the right drugs, precision medicine can have a dramatic impact on brain tumors.”

Driving precision medicine

“This study demonstrated that national, biomarker-driven trials are feasible for patients with brain tumors,” Brastianos continued. “Moving the needle on treating rare brain tumors truly requires a multidisciplinary and multi-institution effort, and we were able to highlight that through our research.”

Future studies may determine the optimal number of vemurafenib–cobimetinib cycles for PCP patients. The researchers are also working on additional precision medicine clinical trials for meningiomas and brain metastases, which will also use similar precision medicine approaches to screen patients for biomarkers that indicate which existing therapies may be appropriate for their tumor.

Reference: Brastianos P, Twohy E, Geyer S, et al. Phase II trial of BRAF/MEK inhibition in newly diagnosed papillary craniopharyngiomas. N Engl J Med. 2023. doi: 10.1056/NEJMoa2213329

This article is a rework of a press release issued by Mass General Brigham. Material has been edited for length and content.