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Clinical Trial
. 2023 Aug 1;116(5):1091-1099.
doi: 10.1016/j.ijrobp.2023.02.030. Epub 2023 Mar 7.

Randomized Phase 2 Placebo-Controlled Trial of Nintedanib for the Treatment of Radiation Pneumonitis

Andreas Rimner  1 , Zachary R Moore  2 , Stephanie Lobaugh  3 , Alexander Geyer  4 , Daphna Y Gelblum  2 , Raja-Elie E Abdulnour  5 , Annemarie F Shepherd  2 , Narek Shaverdian  2 , Abraham J Wu  2 , John Cuaron  2 , Jamie E Chaft  4 , Marjorie G Zauderer  4 , Juliana Eng  6 , Gregory J Riely  4 , Charles M Rudin  4 , Nicholas Vander Els  4 , Mohit Chawla  4 , Megan McCune  2 , Henry Li  2 , David R Jones  7 , Dennis M Sopka  8 , Charles B Simone 2nd  2 , Raymond Mak  9 , Gerald L Weinhouse  5 , Zhongxing Liao  10 , Daniel R Gomez  2 , Zhigang Zhang  3 , Paul K Paik  4
Affiliations
Clinical Trial

Randomized Phase 2 Placebo-Controlled Trial of Nintedanib for the Treatment of Radiation Pneumonitis

Andreas Rimner et al. Int J Radiat Oncol Biol Phys. .

Abstract

Purpose: Radiation pneumonitis (RP) is the most common dose-limiting toxicity for thoracic radiation therapy. Nintedanib is used for the treatment of idiopathic pulmonary fibrosis, which shares pathophysiological pathways with the subacute phase of RP. Our goal was to investigate the efficacy and safety of nintedanib added to a prednisone taper compared with a prednisone taper alone in reducing pulmonary exacerbations in patients with grade 2 or higher (G2+) RP.

Methods and materials: In this phase 2, randomized, double-blinded, placebo-controlled trial, patients with newly diagnosed G2+ RP were randomized 1:1 to nintedanib or placebo in addition to a standard 8-week prednisone taper. The primary endpoint was freedom from pulmonary exacerbations at 1 year. Secondary endpoints included patient-reported outcomes and pulmonary function tests. Kaplan-Meier analysis was used to estimate the probability of freedom from pulmonary exacerbations. The study was closed early due to slow accrual.

Results: Thirty-four patients were enrolled between October 2015 and February 2020. Of 30 evaluable patients, 18 were randomized to the experimental Arm A (nintedanib + prednisone taper) and 12 to the control Arm B (placebo + prednisone taper). Freedom from exacerbation at 1 year was 72% (confidence interval, 54%-96%) in Arm A and 40% (confidence interval, 20%-82%) in Arm B (1-sided, P = .037). In Arm A, there were 16 G2+ adverse events possibly or probably related to treatment compared with 5 in the placebo arm. There were 3 deaths during the study period in Arm A due to cardiac failure, progressive respiratory failure, and pulmonary embolism.

Conclusions: There was an improvement in pulmonary exacerbations by the addition of nintedanib to a prednisone taper. Further investigation is warranted for the use of nintedanib for the treatment of RP.

Trial registration: ClinicalTrials.gov NCT02452463.

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Conflict of interest statement

Declaration of interests

AR previously consulted for Boehringer Ingelheim. MZ participated in a separate investigator-initiated trial of nintedanib in mesothelioma with Boehringer Ingelheim funding. JEC has served as consultant to AstraZeneca, Bristol Myers Squibb, Genentech, Merck, Flame Biosciences, Novartis, Regeneron-Sanofi, Guardant Health, Janssen, and received research funding to institution from AstraZeneca, Bristol Myers Squibb, Genentech, Merck, and Novartis. CMR has consulted regarding oncology drug development with AbbVie, Amgen, AstraZeneca, Epizyme, Genentech/Roche, Ipsen, Jazz, Lilly, and Syros, and serves on the scientific advisory boards of Bridge Medicines, Earli, and Harpoon Therapeutics. DRJ has consulted for AstraZeneca and serves on the clinical trial steering committee for Merck. RM has served on advisory board for AstraZeneca. All other authors declare no competing interest.

Figures

Figure 1.
Figure 1.
Trial Profile
Figure 2.
Figure 2.. Freedom from pulmonary exacerbations.
A. Kaplan-Meier plot of time to first acute pulmonary exacerbation beginning 2 weeks after the start of treatment with nintedanib + prednisone or placebo + prednisone. In the prespecified one-sided Z-test for significance at one year p=0.037. B. Kaplan-Meier estimate of median freedom from exacerbation (FFE) and estimated freedom from pulmonary exacerbation at 1 year. NR=not reached
Figure 3.
Figure 3.. Univariable associations with exacerbation-free survival
Cox Proportional hazards regression analysis of freedom from pulmonary exacerbations. Age in years, KPS, smoking status (former smoker versus never smoker), baseline FEV, and number of weeks of steroid treatment prior to enrollment did not have a statistically significant association with the hazard of pulmonary exacerbation. Hazard ratios (HR) are plotted with with 95% confidence intervals (CI) in panel B.
Figure 4.
Figure 4.. Patient reported outcomes
A. PRO-CTCAE scores are plotted from the following domains: cough severity, shortness of breath (SOB) severity, SOB with daily activities, and wheezing severity scores in the placebo and nintedanib arms. Triangles represent the median values at each time point. B. SGRQ spaghetti plots of total score as well as symptoms, activity, and impacts sub scores. Each line represents a single patient with triangles denoting the median scores at each time point.
See this image and copyright information in PMC

References

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