Fostering efficacy of anti-PD-1-treatment: Nivolumab plus radiotherapy in advanced non-small cell lung cancer: The FORCE trial

Background: 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. 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 PD-1-targeting immunotherapies may promote a strong and durable immune response against tumor manifestations both within and beyond radiation targets. Trial design: In this prospective, two-armed, non-randomized, open-label phase II trial, 130 patients with stage IV non-squamous non-small cell lung cancer 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 nivolumab 240 mg followed by palliative radiotherapy with 5 x 4 Gy = 20 Gy photon radiation, which will be initiated within 72 hours after first nivolumab administration (Group A). 65 patients without an indication for radiotherapy will receive nivolumab (Group B). Nivolumab will be administered every two weeks in both groups and will be continued until progression or until limiting toxicities. The primary endpoint will be the objective response rate according to RECIST criteria 1.1. Secondary endpoints will be progression-free survival according to RECIST 1.1, overall survival, descriptive subgroup analyses according to PD-L1 expression, toxicity and quality of life. An extensive exploratory translational research program attached to this trial will focus on mechanisms of the immune-stimulating effect of radiotherapy and the identification of potential biomarkers predicting response to nivolumab. The FORCE trial will contribute prospective data to the observation that the combination of hypofractionated photon radiotherapy and medical immunotherapy is not only safe but will also promote antitumoral immune responses. Clinical trial identification: NCT Nr: 03044626 Eudra-CT Nr: 2015-005741-31 Legal entity responsible for the study: AIO-Studien gGmbH. Funding: Bristol Myers Squibb GmbH & Co. KGaA BMBF / NCT 3.0 BMBF / NCT 3.0. Disclosure: F. Bozorgmehr: Research funding: BMS; Honoraria: MSD, Novartis. F. Lasitschka: Advisory board memberships: Roche Pharma, BMS; Corporate-sponsored research: Roche, MSD, BMS, Boehringer-Ingelheim, Morphosys, Dianova. J. Debus: Advisory board: Merck; Research support: Siemens, Accuray, Viewray. J.R. Fischer: Honoraria, Advisory boards, Presentations, Consulting: AstraZeneca, BMS, Boehringer Ingelheim, Celgene, MSD, Roche. M. Bischof: Advisory board: BMS. A. Atmaca: Honoraria for Advisory board participation and travel expenses: BMS. M. Faehling: Advisory boards: BMS, Roche, MSD, AstraZeneca. D.F. Heigener: Honoraria for presentations / Advisory board: Boehringer Ingelheim, BMS, Astra Zeneca, Roche, Lilly, Pfizer, Takeda, MSD. Travel expenses: Boehringer Ingelheim, BMS, Astra Zeneca, Roche, Lilly, Pfizer, Takeda, MSD. N. Reinmuth: Honoraria: Roche, Lilly, Novartis, MSD, BMS, Boehringer-Ingelheim, AstraZeneca, Pfizer, Takeda. C. Schumann: Advisory role and lectures: BMS, Astra, Roche, MSD. M. Wermke: Honoraria: BMS, Novartis, Roche, Bayer, Glenmark, AstraZeneca; Travel expenses: AstraZeneca, BMS, MSD, Novartis. M. Thomas: Presentations: Lilly; BMS; MSD; Roche; Pfizer; AstraZeneca; Advisory Boards: Lilly; BMS; MSD; Roche; Pfizer; AstraZeneca; Celgene; Mediolanum. S. Rieken: Honoraria and travel expenses: ELEKTA Inc., Accuray Inc., AstraZeneca GmbH, Brystol Myers Squibb, Lilly, Roche, DGP, DKG, DEGRO, Frauenselbsthilfe nach Krebs e.V., Berufsverband der Pharmaberater IITs and research funding: Brystal Myers Squibb, Accuray Inc., Merck KGaA Consulting or advisory role: Accuray Inc., AstraZeneca GmbH All other authors have declared no conflicts of interest.