SBRT Plus Pembrolizumab/Trametinib Demonstrate Potential for Treatment of Recurrent Pancreatic Cancer

The use of stereotactic body radiotherapy (SBRT) plus pembrolizumab (Keytruda) and trametinib (Mekinist) could be a potential novel treatment for patients with recurrent pancreatic cancer after surgery, according to the results of a phase 2 (NCT02704156) study published in Lancet Oncology.

Patients who received SBRT plus pembrolizumab and trametinib achieved a median overall survival (OS) of 24.9 months (95% CI, 23.3-26.5) compared with SBRT plus gemcitabine (Gemzar), which yielded a median OS of 22.4 months (95% CI, 0.44-0.82; HR, 0.60; 95% CI, 0.44-0.83; P = .0012). Investigators emphasize that a phase 3 trial is still needed in order to confirm the findings. The 2-year OS rate in the SBRT plus gemcitabine was 37.6% (95% CI, 32.3%-42.9%) and 56.5% (95% CI, 51.1%-61.9%) for the SBRT plus pembrolizumab and trametinib group.

“In this trial, we found improved [OS] and progression-free survival [PFS] with SBRT plus pembrolizumab and trametinib compared with SBRT plus gemcitabine in patients with locally recurrent pancreatic cancer after surgical resection. The HR…for overall survival indicated that the combination of radiotherapy with immunotherapy and targeted therapy led to a clinically meaningful reduction in the risk of death,” the study’s investigators wrote.

The open-label trial enrolled 170 patients who were randomized to receive either SBRT plus pembrolizumab and trametinib (n = 85) or SBRT plus gemcitabine (n = 85). The median follow-up was 23.3 months, and no patients were lost to follow-up.

Patients in the SBRT plus pembrolizumab and trametinib group received a median of 18 treatment cycles (Interquartile range (IQR), 15-22) vs a median of 8 cycles (IQR, 8-8) in the SBRT plus gemcitabine group.

Treatment was discontinued in 83 (98%) patients in the SBRT plus pembrolizumab and trametinib group due to disease progression, with 2 other patients (2%) discontinuing treatment due to adverse effects (AEs). However, only 1 (1%) patient in the SBRT plus gemcitabine group discontinued due to AEs, while the other 84 (99%) remaining patients completed all 8 cycles. Additionally, 13% of those in the SBRT plus pembrolizumab and trametinib group (n = 11) and 11% in the SBRT plus gemcitabine group (n = 9) had dose modifications and treatment interruptions. A total of 2 (2%) patients in the SBRT plus pembrolizumab and trametinib group were alive. The remaining patients in either group had died due to cancer-specific causes. 

For those in the experimental cohort, the median PFS was 18.3 months (95% CI, 16.5-20.1) and 15.6 months (95% CI, 14.5-16.7) in the control cohort (HR, 0.52; 95% CI, 0.38-0.72; P = .0006). The 1-year PFS rate was 87.1% (95% CI, 83.5%-90.7%) and 90.6% (95% CI, 87.4%-93.8%). Additionally, the 2-year PFS rate was 4.7% (95% CI, 2.4-7.0) and 15.3% (95% CI, 11.4%-19.2%) in the SBRT plus gemcitabine and SBRT plus pembrolizumab and trametinib groups, respectively.

In the SBRT plus pembrolizumab and trametinib group, 82% (n = 70) of patients had at least 1 AE compared with 72% (n = 85) patients in the SBRT plus gemcitabine group. The most common AE in the SBRT plus gemcitabine group was hematological toxicity that affected 27 (32%) patients compared with 15 (18%) in SBRT plus pembrolizumab and trametinib group.

Those in the SBRT plus pembrolizumab and trametinib group had more grade 3/4 AEs (n = 26; 31%) compared with the SBRT plus gemcitabine group (n = 17; 20%). The most common AEs in the SBRT plus pembrolizumab and trametinib group were increased alanine aminotransferase or aspartate aminotransferase (12%; n = 10) vs 7% (n = 6) in the SBRT plus gemcitabine group. Additional AEs for SBRT plus pembrolizumab and trametinib and SBRT plus gemcitabine were increased blood bilirubin (5% vs 0%), neutropenia (1% vs 11%), and thrombocytopenia in (1% vs 5%).

Patients in both groups reported serious AEs. The SBRT plus pembrolizumab and trametinib group had 10 (12%) patients with increased alanine aminotransferase or aspartate aminotransferase, 4 (5%) with increased bilirubin, 1 (1%) with neutropenia, 1 (1%) with thrombocytopenia, 2 (2%) had a rash, and 1 (1%) had pneumonia. In the SBRT plus gemcitabine group, 9 (11%) had serious AEs, including neutropenia (6%; n = 5) and thrombocytopenia (5%; n = 4).

There was no treatment-related death in either group.

“Improved [OS] and [PFS] survival together with acceptable toxicity support further investigation of SBRT plus pembrolizumab and trametinib in patients with locally relapsed pancreatic cancer after surgery,” the investigators concluded.

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