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Clinical Trial
. 2025 Jul 24;42(5):42.
doi: 10.1007/s10585-025-10358-x.

Reconsidering palliative radiotherapy in addition to PD-1 blockade for non-small cell lung cancer: results from the FORCE phase II trial (AIO/YMO-TRK-0415)

Farastuk Bozorgmehr  1   2 , Inn Chung  3   4 , Jürgen R Fischer  5 , Marc Bischof  6 , Akin Atmaca  7 , Sophie Wetzel  8 , Martin Faehling  9 , Dirk Bottke  10 , Martin Wermke  11 , Esther G C Troost  12 , Cornelia Kropf-Sanchen  13 , Thomas Wiegel  14 , Bernd Schmidt  15 , Andrej Stupavsky  16 , Walburga Engel-Riedel  17 , Michaela Hammer-Hellmig  18 , Niels Reinmuth  19 , Farkhad Manapov  20 , Christian Grohe  21 , Robert Krempien  22 , Christian Schumann  23 , Florian Sterzing  24 , Martin Reck  25 , Florian Würschmidt  26 , Jochen Fleckenstein  27 , Alev Petroff  27 , Sven Henschke  28 , Rouven Behnisch  29 , Jelena Cvetkovic  3   4 , Lena Brückner  3   4 , Constantin Schwab  4   30 , Albrecht Stenzinger  4   30 , Thorsten Götze  31 , Christina Kopp  31 , Helge Schröder  32 , Jürgen Debus  33 , Petros Christopoulos  3   4 , Michael Thomas  3   4 , Stefan Rieken  34
Affiliations
Clinical Trial

Reconsidering palliative radiotherapy in addition to PD-1 blockade for non-small cell lung cancer: results from the FORCE phase II trial (AIO/YMO-TRK-0415)

Farastuk Bozorgmehr et al. Clin Exp Metastasis. .

Abstract

Introduction of immune checkpoint inhibitors (ICI) has improved overall survival (OS) for advanced non-small cell lung cancer (NSCLC). However, responses differ greatly amongst patients. Additional radiotherapy (RT) may promote tumor-specific immunity and synergize with ICI to improve tumor control. The multicenter phase II FORCE trial evaluated safety and efficacy of nivolumab with additional palliative radiotherapy (5 × 4 Gy) as clinically indicated in pre-treated metastatic non-squamous NSCLC (group A, n = 41), including pretreated patients without an indication for radiotherapy in a parallel cohort as real-world controls (group B, n = 60). With an objective response rate (ORR) of 8.3% in group A (n = 41), the primary endpoint was not met (p = 0.991). ORR in group B (n = 60) was 23.8%. Patient characteristics indicated a significantly poorer baseline clinical condition for group A compared to B, including worse Eastern Cooperative Oncology Group (ECOG) performance status (PS, p = 0.020) and more metastatic sites (p = 0.009). Consequently, group A had shorter progression-free survival (median PFS, 1.9 versus 3.7 months, hazard ratio [HR] 1.69 [95% CI (1.10, 2.58)]) and OS (median 6.0 versus 12.6 months, HR 1.75 [95% CI (1.07, 2.84)]). In multivariable analyses for the intention-to-treat (ITT) population, ORR, PFS and OS were inversely associated with the patients' ECOG PS (ORR odds ratio [OR] 0.126, p = 0.004) and correlated positively with tumor PD-L1 expression (ORR OR 12.8, p = 0.022), but not with radiotherapy administration (p = 0.169-0.854). Adverse events were distributed equally in both groups. Addition of palliative radiotherapy to nivolumab was safe and feasible, but not associated with improved efficacy. Patients with an indication for palliative radiotherapy have an inherently worse prognosis which cannot be overcome by radiation-induced immunostimulation. Clinical features and PD-L1 expression influence clinical outcomes more than radiotherapy administration and should be considered when evaluating the effectiveness of immuno-/radiotherapy combinations.ClinicalTrials.gov identifier: NCT03044626.

Keywords: Immunotherapy; Nivolumab; Non-small cell lung cancer; Palliative radiotherapy; Radioimmunotherapy.

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Conflict of interest statement

Declarations. Competing interests: Dr. Bozorgmehr received research grants from BMS, Roche and AstraZeneca and personal fees (honoraria, advisory boards, travel support) from AstraZeneca, AMGEN, Novartis, Janssen, Novocure, GSK and Daiichi Sankyo. Dr. Atmaca received personal fees (travel support, advisory boards) from BMS, MSD, Roche, Takeda, Pfizer, Novartis, Astra Zeneca, Sanofi, Amgen, and Biontech. Dr. Faehling received personal fees (advisory boards) from BMS, AstraZeneca, and MSD. Dr. Wermke received research grant from Roche and personal fees (honoraria, consulting fees, travel support) from Lilly, Boehringer Ingelheim, SYNLAB, Janssen, Merck Serono, GWT, Amgen, Novartis, BMS, ISA Pharmaceuticals, immatics, Bayer, ImCheck therapeutics, Pfizer, AstraZeneca, GEMoaB, and Sanofi/Aventis. Dr. Troost received support from IBA. Dr. Kropf-Sanchen received personal fees (consulting fees, honoraria, travel support, advisory boards) from Astra Zeneca, Amgen, Art tempi/medtoday, BMS, Boehringer Ingelheim, Daichi, Lilly, Novartis, onkowissen, MSD, Pfizer, Roche, Sanofi, StreamedUp, and Takeda. Dr. Schuman received institutional and personal fees (honoraria, advisory boards) from AstraZeneca, BMS, Boehringer Ingelheim, Pfizer, and Roche. Dr. Reck received personal fees (consulting fees, honoraria, travel support, advisory board) from Amgen, AstraZeneca, Beigene, Boehringer Ingelheim, BMS, Daiichi-Sankyo, GSK, Mirati, Merck, MSD, Lilly, Novartis, Pfizer, Sanofi, Roche, and Regeneron. Dr. Würschmidt received personal fees (honoraria, travel support) from AstraZeneca and Siemens Varian. Dr. Stenzinger received research grants from Bayer, BMS, Chugai, and Incyte and honoraria from Aignostics, Amgen, Astellas, Astra Zeneca, Bayer, BMS, Eli Lilly, Illumina, Incyte, Janssen, MSD, Novartis, Pfizer, Qlucore, QuiP, Roche, Seagen, Servier, Takeda, and Thermo Fisher. Dr. Götze received grants from German Research Foundation (DFG), Gemeinsamer Bundesausschuss, German Cancer Aid, Lilly-Pharma, AstraZeneca, and Incyte and personal fees (consulting fees, honoraria, advisory board) from Amgen, AstraZeneca, Bayer, BMS, Daiichi Sankyo, FoundationMedicine, Lilly, MCI, MSD Sharp & Dohme, Novartis, Roche, Sanofi Aventis, Servier, Deciphera, and Boehringer Ingelheim. Dr. Christopoulos received research grants from Roche, Amgen, Boehringer Ingelheim, Takeda, Amgen, Merck, AstraZeneca, and Novartis and personal fees (honoraria, travel support, advisory board) from AstraZeneca, Gilead, Janssen, Novartis, Roche, Pfizer, Thermo Fisher, Takeda, Eli Lilly, Daiichi Sankyo, Boehringer Ingelheim, Chugai, Pfizer, and MSD. Dr. Debus received research grants from RaySearch Laboratories AB, Vision RT Limited, Merck Serono GmbH, Siemens Healthcare GmbH, PTW-Freiburg Dr. Pychlau GmbH, and Accuray Incorporated. Dr. Thomas received research grants from AstraZeneca, BMS, Merck, Roche, and Takeda and personal fees (honoraria, travel support) from Amgen, AstraZeneca, Beigene, BMS, Boehringer Ingelheim, Celgene, Chugai, Daiichi Sankyo, GSK, Janssen Oncology, Lilly, Merck, MSD, Novartis, Pfizer, Roche, Sanofi, and Takeda. The remaining authors declare no conflicts of interest. Ethics approval and consent to participate: The trial was conducted in accordance with Good Clinical Practice and the Declaration of Helsinki. The study protocol was approved by the Ethics Committee of the Medical Faculty of the Heidelberg University. All patients provided written informed consent. Consent for publication: Not applicable.

Figures

Fig. 1
Fig. 1
CONSORT diagram of patient distribution in the FORCE trial. One patient allocated to group A received nivolumab only and was assigned to group B for safety analysis. EOS, end of study; ITT, intention-to-treat; OS, overall survival; PFS, progression-free survival; RT, radiotherapy
Fig. 2
Fig. 2
Kaplan–Meier estimates according to the two treatment groups of the FORCE trial. Group A received nivolumab + palliative radiotherapy, whereas group B was treated with only nivolumab. Analysis was performed starting from the first nivolumab infusion. (A) Progression-free survival, (B) Overall survival
Fig. 3
Fig. 3
Kaplan–Meier estimates according to PD-L1 and ECOG in ITT population. (A) PFS in ITT population stratified according to PD-L1 TPS < 1% or ≥ 1%. (B) PFS in ITT stratified according to ECOG PS 0 or 1. (C) OS in ITT population stratified according to PD-L1 TPS < 1% or ≥ 1%. (D) OS in ITT population stratified according to ECOG PS 0 or 1
See this image and copyright information in PMC

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