Abstract
BackgroundHypofractionated palliative radiotherapy for metastatic lung cancer patients is frequently used in order to ease pain, to increase bone stability, to treat local mass effects, or to prolong progression-free survival at critical sites. Recently introduced, immunotherapy for patients with non-squamous non-small cell lung carcinoma (NSCLC) has significantly improved outcome in this cohort. Preclinical and early clinical data suggest that the combination of photon radiation with programmed death-1 (PD-1) targeting immunotherapies may promote a strong and durable immune response against tumor manifestations both within and beyond radiation targets.Methods/designIn the present prospective, two-group, non-randomized, open-label phase II trial, 130 patients with stage IV non-squamous NSCLC in 2nd-line or 3rd-line treatment will be included. 65 patients with a clinical indication for palliative radiotherapy to non-cerebral/non-pulmonary metastatic sites will receive 240 mg nivolumab followed by palliative radiotherapy with 5 × 4 Gray (Gy) = 20 Gy photon radiation, which will be initiated within 72 h after first nivolumab administration (Group A). 65 patients without an indication for radiotherapy will only receive nivolumab (Group B). Nivolumab will be further administered every two weeks in both groups and will be continued until progression and loss of clinical benefit or until occurrence of limiting toxicities.The primary endpoint will be the objective response rate (ORR) according to response evaluation criteria in solid tumors (RECIST) 1.1. Secondary endpoints will be progression-free survival (PFS) according to RECIST 1.1, overall survival, descriptive subgroup analyses according to PD-L1 expression, toxicity and quality of life. Since response patterns following immunotherapies differ from those after conventional cytostatic agents, both objective response rate and progression-free survival will additionally be assessed according to immune-related RECIST (irRECIST) criteria.DiscussionThe FORCE study will prospectively investigate response rates, progression-free and overall survival (OS), and toxicity of nivolumab with and without hypofractionated palliative radiotherapy in a group of 130 patients with metastatic non-small cell lung cancer (non-squamous histology) in 2nd-line or 3rd-line treatment. This trial will contribute prospective data to the repeatedly published observation that the combination of hypofractionated photon radiotherapy and medical immunotherapy is not only safe but will also promote antitumoral immune responses.Trial registrationClinicaltrials.gov identifier: NCT03044626 (Date of initial registration: 05 January 2017).Eudra-CT Number: 2015–005741-31 (Date of initial registration: 18 December 2015).
Highlights
Hypofractionated palliative radiotherapy for metastatic lung cancer patients is frequently used in order to ease pain, to increase bone stability, to treat local mass effects, or to prolong progression-free survival at critical sites
Treatment of non-small cell lung carcinoma (NSCLC) has been limited to chemotherapy with a sparse impact on median progression-free survival times ranging from 3 to 4 months
programmed death-1 (PD-1)/Programmed death-ligand 1 (PD-L1)-targeting checkpoint inhibition has even advanced up to 1st-line treatment, either as a monotherapy or in combination with chemotherapy. Despite this important progress a crucial remaining question is how T-cell-mediated antitumor immune responses upon checkpoint inhibition can be activated in non-responders, which account for approximately half of the patients [3, 4, 6, 22]
Summary
Lung cancer is the most common cause of cancer death worldwide with approximately 85% of patients suffering from NSCLC. Connected to the PD-L1 expression are the underlying immune-biological mechanisms of PD-L1 targeting and the potential immune-stimulating effect of radiotherapy To this end, a systematic exploration to better understand the immune-mediated tumor-host interaction – and thereby the potential impact of PD-1/ PD-L1 antibody-treatment – in a true clinical setting is pivotal. The rationale of the FORCE trial can be synthesized into three interconnected goals: to determine the safety and feasibility of the radio-immunological treatment approach; to increase PD-1 checkpoint inhibitor efficacy in metastatic non-squamous NSCLC by inducing an immune-sensitizing effect (abscopal-like effect) with radiotherapy; to explore the fundamental immunological principles that underlie checkpoint inhibitor efficacy and the immune-stimulating effect of radiotherapy in order to elucidate tumor-host biology and to find potential novel biomarkers
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
