SBRT plus pembrolizumab and trametinib could become a promising treatment option in locally recurrent pancreatic cancer

Stereotactic body radiation therapy combined with pembrolizumab and trametinib could potentially become a new treatment strategy for patients with locally recurrent pancreatic cancer after surgery.

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) versus 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 = 0.021). As of the data cutoff date, 2 patients in the SBRT plus pembrolizumab group were alive, and all other patients in both groups had died of cancer-specific causes. The one-year OS rate in the SBRT plus gemcitabine group was 56.5% (95% CI, 51.1%-61.9%) versus 62.4% (95% CI, 57.1% -67.7%) in the SBRT plus pembrolizumab group, and the 2-yearly rates were 0% and 1.5% (95% CI, 0.1% to 2.9%), respectively.

A total of 170 patients were recruited for the study, 85 of whom were each randomly assigned to either the pembrolizumab group or the 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 due to disease progression and 2 patients due to adverse events (AEs) and in the gemcitabine group, 1 and 41 patients, respectively, were discontinued due to AEs and disease progression.

In the experimental arm, treatment reception occurred 1 week after SBRT at 35 to 40 Gy for those receiving pembrolizumab 200 mg every 3 weeks and trametinib 2 mg orally once daily. In the control arm, treatment took place 1 week after SBRT and patients received 1000 mg/m2 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% to 11.2%) versus 21.2% (95% CI, 17.8% to 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 % versus 0%), neutropenia (1% versus 11%) and thrombocytopenia (1% versus 5%).

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

Treatment-related AEs led to a reduction in the dose of 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 outcome survey found that patients in both groups showed improvement in physical function after 12 months of treatment. There was no clinically relevant benefit in either group. However, the researchers noted that clinically significant pain relief was seen in both groups.

Reference

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

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