SBRT Plus Pembrolizumab and Trametinib May Become a Promising Treatment Option in Locally Recurrent Pancreatic Cancer

Stereotactic body radiotherapy plus pembrolizumab and trametinib could potentially become a novel treatment strategy for patients with locally recurrent pancreatic cancer following surgery.

A combination of stereotactic body radiotherapy (SBRT) plus pembrolizumab (Keytruda) and trametinib (Mekinist) may be a promising novel option for patients with locally recurrent pancreatic cancer after surgery compared with SBRT plus gemcitabine, according to a study published in The Lancet Oncology.

The median overall survival (OS) for SBRT plus pembrolizumab and trametinib was 14.9 months (95% CI, 12.7-17.1) vs 12.8 months (95% CI, 11.2-14.4) in the SBRT plus gemcitabine group (HR, 0.69; 95% CI, 0.51-0.95; P = .021). At data cutoff, 2 patients in the SBRT plus pembrolizumab group were alive, and all other patients in both groups had died from cancer-specific causes. One-year OS rate in the SBRT plus gemcitabine group was 56.5% (95% CI, 51.1%-61.9%) vs 62.4% (95% CI, 57.1%-67.7%) in the SBRT plus pembrolizumab group, and the 2-year rates were 0% and 1.5% (95% CI, 0.1%-2.9%), respectively.

A total of 170 patients were enrolled on the study, 85 of whom were each randomly assigned to either the pembrolizumab group or gemcitabine group. The median follow-up was 13.1 months. Patients received a median of 11 treatment cycles in both groups. In the pembrolizumab group, treatment discontinuation occurred in 83 patients because of disease progression and 2 patients because of adverse effects (AEs) and in the gemcitabine group, 1 and 41 patients, respectively, discontinued because of AEs and disease progression.

In the experimental arm, receipt of treatment occurred 1 week after SBRT at 35 to 40 Gy for those receiving pembrolizumab at 200 mg every 3 weeks and trametinib at 2 mg orally once daily. In the control arm, treatment took place 1 week after SBRT and patients were given 1000 mg/m2 of gemcitabine intravenously on days 1 and 8 of each 21-day cycle.

The median progression-free survival (PFS) was 8.2 months (95% CI, 6.9-9.5) in the pembrolizumab group and 5.4 months (95% CI, 3.2-7.6) in the gemcitabine group (HR, 0.60; 95% CI, 0.44-0.81; P = .0009). The 1-year PFS rate was 8.2% (95% CI, 5.2%-11.2%) vs 21.2% (95% CI, 17.8%-25.6%) in the gemcitabine and pembrolizumab groups, respectively.

Grade 3 and 4 AEs occurred in 26 patients in the pembrolizumab group and 17 in the gemcitabine groups. The most common grape 3/3 AEs in the pembrolizumab and gemcitabine groups, respectively, were increased alanine aminotransferase or aspartate aminotransferase (12% vs 7%), increased blood bilirubin (5% vs 0%), neutropenia (1% vs 11%), and thrombocytopenia (1% vs 5%).

Serious AEs were observed in 19 patients in the pembrolizumab group and 12 in gemcitabine group. In the SBRT plus pembrolizumab group, drug-related serious AEs occurred in 11 patients, which included alanine aminotransferase or aspartate aminotransferase (8%), increased bilirubin (4%), and neutropenia (1%). Drug-related serious AEs in the SBRT plus gemcitabine group included neutropenia (11%) and thrombocytopenia (6%).

Treatment-related AEs resulted in a dose reduction for trametinib in 8% of patients, and 5% had their treatment with pembrolizumab interrupted. Additionally, in the SBRT plus gemcitabine group, 7% of patients had treatment-related dose reductions and 4% had delays. No treatment-related deaths occurred in either group.

The QLC-C30 patient-reported outcomes survey found that patients in both groups had improvement in physical function after 12 months of treatment. There were no clinically relevant benefits in either group. However, investigators noted that clinically significant pain relief was seen in both groups.

Reference

Zhu X, Cao Y, Liu W, et al. Stereotactic body radiotherapy plus pembrolizumab and trametinib versus stereotactic body radiotherapy plus gemcitabine for locally recurrent pancreatic cancer after surgical resection: an open-label, randomised, controlled, phase 2 trial. Lancet Oncol. 2021;22(8):1093-1102. doi:10.1016/S1470-2045(21)00286-2