A Phase 2 Randomized, Double-Blind, Placebo-Controlled Study Evaluating Nintedanib Versus Placebo as Prophylaxis Against Radiation Pneumonitis in Patients With Unresectable NSCLC Undergoing Chemoradiation Therapy

Nintedanib is a multikinase inhibitor that is U.S. Food and Drug Administration–approved for the treatment of interstitial lung disease.1Richeldi L. Costabel U. Selman M. et al.Efficacy of a tyrosine kinase inhibitor in idiopathic pulmonary fibrosis.N Engl J Med. 2011; 365: 1079-1087Crossref PubMed Scopus (768) Google Scholar,2Richeldi L. Du Bois R. Raghu G. et al.Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis.N Engl J Med. 2014; 370 (2701–2082)Crossref Scopus (2334) Google Scholar We report the results of the first randomized, placebo-controlled, double-blind trial conducted to determine whether nintedanib will reduce the rate of symptomatic radiation pneumonitis in patients with unresectable NSCLC after completion of concurrent chemoradiation therapy. Patients with unresectable stage II/III NSCLC who received concurrent chemoradiation (54–66 Gy thoracic radiation dose) and with at least stable disease after completing the last fraction of radiation treatment were randomized in 2:1 fashion to start nintedanib 200 mg or placebo twice daily no later than 6 weeks after completing the last dose of radiation. Nintedanib or placebo was administered for 6 months. The primary end point was the rate of symptomatic Common Terminology Criteria for Adverse Events grade 2 or higher radiation pneumonitis after completion of chemoradiation. The secondary end points were to compare survival and pulmonary function. A maximum of 99 participants, stratified by chemotherapy regimen, was planned with 81% probability of detecting a clinically significant reduction in the expected rate of grade 2 or higher radiation pneumonitis from 30% to 10%, at an α significance level of 0.05. A total of eight patients (nintedanib, n = 5; placebo, n = 3) underwent randomization before the trial was closed in June 2019 owing to poor accrual and change in the standard of care with the approval of durvalumab.3Antonia S.J. Villegas A. Daniel D. et al.Overall survival with durvalumab after chemoradiotherapy in stage III NSCLC.N Engl J Med. 2018; 379: 2342-2350Crossref PubMed Scopus (1266) Google Scholar One treatment-related Common Terminology Criteria for Adverse Events grade 5 hemorrhagic fatality occurred in a nintedanib-assigned patient with squamous cell histology. The protocol was subsequently amended to only enroll patients with nonsquamous histology. None of the five nintedanib-assigned patients encountered the event of interest whereas 67% (two of three) of placebo-assigned patients had clinically significant pneumonitis deemed to be related to radiation, requiring oxygen supplementation and steroid treatment. These two placebo-treated patients received higher V5 (percent of lung volume receiving ≥5 Gy) dose to contralateral lung (63 Gy and 72 Gy, respectively) compared with the remaining placebo- or nintedanib-treated patients who did not develop symptomatic pneumonitis attributed to radiation (range = 7–25 Gy). No clinically significant differences were found otherwise with baseline demographics and other dosimetric parameters between groups (V20 [percent of lung volume receiving ≥20 Gy], mean lung dose, gross tumor volume dose). Furthermore, there were no clinically relevant differences observed in pulmonary function, progression-free survival, nor overall survival between the groups. In summary, there were more clinically significant symptomatic radiation pneumonitis events that occurred in the patients assigned to placebo versus the nintedanib group. However, because the study was terminated prematurely owing to accrual logistics and there were potential treatment imbalances in this small sample size, our study is unable to conclusively prove or disprove the role of nintedanib in mitigating radiation pneumonitis. Our study illustrates the accrual challenges posed by standard-of-care changes during the enrollment period. Nonetheless, the preliminary efficacy and safety data will provide important context in the future in the interpretation of the yet-to-be reported results of the ongoing double-blind, randomized, placebo-controlled trial evaluating the addition of nintedanib to prednisone in patients with acute radiation pneumonitis in reducing acute pulmonary exacerbations as primary outcome (NCT02496585). This study was approved and funded by the National Comprehensive Cancer Network Oncology Research Program from the general research support provided by Boehringer Ingelheim Pharmaceuticals, Inc. (BIPI). BIPI had no role in the design, analysis, or interpretation of the results in this study; BIPI was given the opportunity to review the manuscript for medical and scientific accuracy as it relates to BIPI substances and intellectual property considerations.