First prospective evaluation demonstrates a clinical benefit and safety of stereotactic body radiotherapy (SBRT) in combination with nivolumab and ipilimumab in pretreated patients with refractory metastatic pancreatic cancer. The threshold for efficacy was met in such combination arm with 37.2% of patients achieving clinical benefit, 14% of patients had partial response (PR), which lasted for a median of 5.4 months. The treatment had favourable safety profile. However, the contribution from SBRT is unknown and further studies are warranted. Findings from a randomised, phase II study are published on 27 April 2022 in the Journal of Clinical Oncology by Dr. Inna M. Chen of the Department of Oncology, Copenhagen University Hospital—Herlev and Gentofte in Herlev, Denmark and CheckPAC colleagues.
The authors wrote in the background that immune checkpoint inhibitors (ICIs) have only shown benefits in pancreatic cancer displaying microsatellite instability or mismatch repair deficiency. Poor immunogenicity is considered to be one of the causes of poor response to immunotherapies. Considering emerging evidence that radiotherapy may modulate antitumour immune response, the authors hypothesized that the combination of ICI with radiotherapy might lead to better responses in tumours such as the historically ICI-resistant pancreatic cancer. In this study, the investigators evaluated the clinical benefits and safety of nivolumab with or without ipilimumab in combination with SBRT in patients with refractory metastatic pancreatic cancer. They also investigated blood and tumour biomarkers to identify a subset of patients who were most likely to respond to the experimental approach.
Between November 2016 and December 2019, patients with refractory metastatic pancreatic cancer were randomly assigned 1:1 to SBRT of 15 Gy with nivolumab or nivolumab plus ipilimumab stratified by performance status. The primary endpoint was the clinical benefit rate (CBR), defined as the percentage of patients with complete response or PR or stable disease, according to RECIST v1.1. Simon's 2-stage phase II optimal design was used independently for both arms, with CBR determining expansion to the second stage. Secondary endpoints included safety, response rate, duration of response, progression-free survival, and overall survival (OS). Exploratory analyses included biomarkers related to the benefits.
In total, 84 patients, of whom 41 in SBRT/nivolumab arm and 43 in SBRT/nivolumab/ipilimumab arm, received at least one dose of study treatment; CBR was 17.1% for patients receiving SBRT/nivolumab and 37.2% for SBRT/nivolumab/ipilimumab; PR was observed in 1 patient receiving SBRT/nivolumab and lasted for 4.6 months, while 6 patients receiving SBRT/nivolumab/ipilimumab achieved a PR with a median duration of response of 5.4 months.
Grade 3 or higher treatment-related adverse events occurred in 10 patients (24.4%) in the SBRT/nivolumab and in 13 patients (30.2%) in the SBRT/nivolumab/ipilimumab groups.
PD-L1 expression by tumour proportion score or combined positivity score of ≥1% was not associated with clinical benefits. On-treatment decreased serum interleukin-6, interleukin-8, and C-reactive protein levels were associated with better OS.
The authors concluded that SBRT of 15 Gy in combination with nivolumab and ipilimumab had a favourable safety profile and antitumour activity in a historically hard-to-treat group of patients with refractory metastatic pancreatic cancer. However, the contribution from SBRT is unknown. The aggressive nature of disease and its rapid progression in the targeted population resulted in the refractory course observed in most patients. Further translational studies should focus on identifying how nivolumab and ipilimumab concurrently with SBRT augments antitumour activity and facilitates remission.
The study was previously presented at the 2022 ASCO Gastrointestinal Cancers Symposium.
Bristol Myers Squibb has provided drugs and financial support for data management. The study was supported in part by Danish Comprehensive Cancer Center grant.
Chen IM, Johansen JJ, Theile S, et al. Randomized Phase II Study of Nivolumab With or Without Ipilimumab Combined With Stereotactic Body Radiotherapy for Refractory Metastatic Pancreatic Cancer (CheckPAC). Journal of Clinical Oncology; Published online 27 April 2022. DOI: 10.1200/JCO.21.02511