Abstract
BackgroundThe efficacy of immunotherapy targeting the PD-1/PD-L1 pathway has previously been demonstrated in metastatic head and neck squamous cell carcinoma (HNSCC). Stereotactic Body Radiotherapy (SBRT) aims at ablating metastatic lesions and may play a synergistic role with immunotherapy. The purpose of this study is to assess the safety and efficacy of triple treatment combination (TTC) consisting of the administration of durvalumab and tremelimumab in combination with SBRT in metastatic HNSCC.MethodThis is a phase I/II single arm study that will include 35 patients with 2–10 extracranial metastatic lesions. Patients will receive durvalumab (1500 mg IV every 4 weeks (Q4W)) and tremelimumab (75 mg IV Q4W for a total of 4 doses) until progression, unacceptable toxicity or patient withdrawal. SBRT to 2–5 metastases will be administered between cycles 2 and 3 of immunotherapy. The safety of the treatment combination will be evaluated through assessment of TTC-related toxicities, defined as grade 3–5 toxicities based on Common Terminology Criteria for Adverse Events (v 4.03), occurring within 6 weeks from SBRT start, and that are definitely, probably or possibly related to the combination of all treatments. We hypothesize that dual targeting of PD-L1 and CTLA-4 pathways combined with SBRT will lead to < 35% grade 3–5 acute toxicities related to TTC. Progression free survival (PFS) will be the primary endpoint of the phase II portion of this study and will be assessed with radiological exams every 8 weeks using the RECIST version 1.1 criteria.DiscussionThe combination of synergistic dual checkpoints inhibition along with ablative radiation may significantly potentiate the local and systemic disease control. This study constitutes the first clinical trial combining effects of SBRT with dual checkpoint blockade with durvalumab and tremelimumab in the treatment of metastatic HNSCC. If positive, this study would lead to a phase III trial testing this treatment combination against standard of care in metastatic HNSCC.Trial registrationNCT03283605. Registration date: September 14, 2017; version 1.
Highlights
The efficacy of immunotherapy targeting the PD-1/PD-L1 pathway has previously been demonstrated in metastatic head and neck squamous cell carcinoma (HNSCC)
This study would lead to a phase III trial testing this treatment combination against standard of care in metastatic HNSCC
Oncology practise has shifted towards aggressive treatment of oligometastatic cancers, with the underlying rationale that radical ablation of limited disease burden can lead to prolonged Progression free survival (PFS) and sometimes potentially achieve cure
Summary
The efficacy of immunotherapy targeting the PD-1/PD-L1 pathway has previously been demonstrated in metastatic head and neck squamous cell carcinoma (HNSCC). The purpose of this study is to assess the safety and efficacy of triple treatment combination (TTC) consisting of the administration of durvalumab and tremelimumab in combination with SBRT in metastatic HNSCC. Among patients without metastasis at diagnosis, up to 30% will develop distant failure [6, 7]. The prognosis of patients with distant metastasis is poor, and standard of care remains palliative chemotherapy. Palliative chemotherapy includes combinations of cetuximab, platinum and fluorouracil-based combinations associated with a median overall survival of 10 months and a response rate of 30% [8]. Doublet platinum chemotherapy is associated with a median overall survival (OS) of 6–8 months [9]. Patients that are refractory or progress on first-line chemotherapy have limited treatment options as response rates to second-line therapies are between 3 and 13% [10]
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