A phase II clinical trial has demonstrated substantial clinical activity and promising survival outcomes for patients with untreated melanoma brain metastases (MBM) when treated with a combination of pembrolizumab and bevacizumab. The study results, published in the Journal of Clinical Oncology, suggest this regimen could represent an important therapeutic advance for a patient population with historically limited treatment options.
Significant Response Rates in Brain and Extracranial Lesions
The trial enrolled 37 patients with untreated MBM who had at least one asymptomatic, nonhemorrhagic brain metastasis measuring between 5-20 mm. All patients were anti–PD-(L)-1–naïve and did not require immediate local therapy or steroids.
Treatment consisted of four doses of bevacizumab and pembrolizumab administered every three weeks, followed by pembrolizumab monotherapy for up to two years. The results were impressive, with a brain metastasis response rate of 54.1% (95% CI, 36.9 to 70.5) and an extracranial response rate of 56.3% (95% CI, 37.7 to 73.6).
"Pembrolizumab with bevacizumab was well tolerated and demonstrated substantial activity in patients with untreated MBM with promising OS, justifying further evaluation of this regimen," stated Dr. Sarah A. Weiss, lead author from Rutgers Cancer Institute, and colleagues.
Promising Long-Term Survival Data
The survival outcomes were particularly noteworthy. The median intracranial progression-free survival reached 2.2 years (95% CI, 0.41 to not reached), while the median overall survival was 4.3 years (95% CI, 1.6 to not reached). At the four-year mark, 51.6% of patients remained alive—a significant achievement for this difficult-to-treat population.
Among the 37 patients, the overall response rate was 54%, including 10 complete responses (27%) and 10 partial responses (27%). An additional two patients (5.4%) achieved stable disease.
Favorable Safety Profile
The combination therapy demonstrated a manageable safety profile. Grade 3 treatment-related adverse events occurred in 10.8% of patients due to bevacizumab and 18.9% due to pembrolizumab. Importantly, no grade 4 or grade 5 treatment-related adverse events were reported during the study.
Patient Characteristics and Treatment Details
The study population had a median age of 66 years (range 33-88), with 76% male and 24% female participants. Most patients (68%) had an ECOG performance status of 0, while 32% had a status of 1. Regarding mutation status, 24% of patients had BRAF V600E mutations, 16% had BRAF V600K mutations, and 3% had BRAF mutations of unknown V600 type. Additionally, 11% of patients had NRAS mutations.
The majority of patients (95%) presented with new intracranial lesions, while 5% showed progression in previously irradiated lesions. Most patients (62%) had 1-2 intracranial target lesions, with the remainder (38%) having 3-5 lesions. A significant proportion (86%) also had extracranial metastases.
Potential Biomarkers Identified
The researchers identified two potential biomarkers associated with treatment response: higher pretreatment vessel density in metastatic tumors and smaller on-therapy increases in circulating angiopoietin-2. These findings could help identify patients most likely to benefit from the combination therapy in future studies.
Clinical Implications
Melanoma brain metastases represent a significant clinical challenge, with limited effective treatment options. The combination of anti-VEGF therapy (bevacizumab) with PD-1 inhibition (pembrolizumab) appears to enhance clinical activity compared to historical outcomes with either agent alone.
Dr. Robert G. Maki, Associate Editor of the Journal of Clinical Oncology, highlighted the significance of these findings: "This prospective study provides data to support a comparative trial of combined PD-1/vascular endothelial growth factor inhibition versus PD-1/CTLA-4 inhibition for untreated MBMs, and could later impact treatment of brain metastases from other diagnoses."
Future Directions
The promising results from this phase II trial support further investigation of the pembrolizumab-bevacizumab combination for patients with untreated melanoma brain metastases. Comparative studies against current standard approaches, including PD-1/CTLA-4 inhibition, will be crucial to determine the optimal treatment strategy for this challenging patient population.
Additionally, the identified biomarkers warrant further exploration to potentially enable more personalized treatment approaches based on individual patient characteristics and tumor biology.
