In a phase Ib/II trial (BTRC-GU14-003) reported in the Journal of Clinical Oncology, Dudek et al found that the combination of pembrolizumab and bevacizumab showed activity in patients with metastatic clear cell renal cell carcinoma.

As stated by the investigators, “Anti-angiogenic treatment has been shown to decrease the number of [myeloid-derived suppressor cells], increase the number of [tumor-associated macrophages] polarized to an immunostimulatory phenotype, and facilitate tumor infiltration by CD4-positive and CD8-positive T cells.” It was thus hypothesized that bevacizumab might potentiate pembrolizumab activity.

Study Details

In the phase Ib component of the study, 13 patients who experienced disease progression after at least one systemic therapy were treated with pembrolizumab at 200 mg and bevacizumab at 10 or 15 mg/kg every 3 weeks. In the phase II component of the trial, 48 treatment-naive patients were treated at dosage selected for the secondary phase of the study. The primary endpoint for phase II was an overall response rate of 42%.

Responses

No dose-limiting toxicities were observed in phase Ib, with a regimen of 200 mg of pembrolizumab and 15 mg/kg of bevacizumab being selected for phase II. The overall response rate was 41.7%.

The overall response rate among 46 evaluable patients in phase II was 60.9% (meeting the primary endpoint), with responses consisting of 1 complete response, 2 complete responses in target lesions, and 25 partial responses; an additional 18 patients (39.1%) had stable disease. Median duration of response was 832 days. Presence of tumor-infiltrating T cells—but not programmed cell death ligand 1 expression—in tumor tissue was correlated with response.

Median progression-free survival was 20.7 months. Median overall survival was not reached at a median follow-up of 28.3 months.

Adverse Events

Among all patients in both phases of the trial reported, treatment-related grade 3 or 4 adverse events occurred in 45%. The most common treatment-related grade 3 adverse events were hypertension (in 25.0%), proteinuria (10.0%), and adrenal insufficiency (6.7%); grade 4 toxicities, consisting of duodenal ulcer and hyponatremia, occurred in two patients. The most common immune-related adverse events of any grade were pruritus (23.3%), rash (21.7%), and hypothyroidism (13.3%).

The investigators concluded, “The combination of 200 mg of pembrolizumab and a 15 mg/kg dose of bevacizumab given every 3 weeks is safe and active in metastatic [renal cell carcinoma].”

Arkadiusz Z. Dudek, MD, PhD, of HealthPartners Regions Cancer Care Center, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The study was supported by Merck & Co. For full disclosures of the study authors, visit ascopubs.org.