Severe Pulmonary Toxicity With Concurrent Anlotinib and Chemoradiotherapy in Stage III NSCLC: The ALTER-L042 Phase 1 Clinical Trial.

Introduction: Anlotinib has brought about marked progression-free survival and overall survival benefit compared with placebos as third-line or further treatment in advanced NSCLC. Nevertheless, the safety and efficacy of concurrent anlotinib and chemoradiotherapy are still unclear. Methods: Patients with histologically or cytologically confirmed stage III NSCLC suitable for concurrent chemoradiotherapy were enrolled in this study. The enrolled patients were treated with concurrent two cycles of anlotinib and chemoradiotherapy followed by anlotinib consolidation until disease progression or intolerance toxicity. The primary end point was the maximum tolerance dose of anlotinib, whereas the secondary end point was the overall response rate. Results: Seven patients were enrolled in this study. Six patients completed concurrent anlotinib and chemoradiotherapy and then entered the consolidation period. Among the patients, 28.57% (two of seven patients) developed fatal treatment-related adverse events (fatal pneumonitis and fatal hemoptysis). In addition, two other patients developed grade 3 radiation pneumonitis; one was induced by a cold, and the patient received only 18 Gy per nine fractions of radiotherapy. This study was terminated early owing to the high rate of fatal adverse events and radiation pneumonitis. Conclusions: This study presented severe pulmonary toxicity with concurrent anlotinib and chemoradiotherapy. Several previous clinical trials evaluated the safety of concurrent bevacizumab and radiotherapy or chemoradiotherapy; all were terminated owing to severe treatment-related toxicity. Results of these studies suggest that concurrent antiangiogenic and thoracic radiotherapy should be avoided until appropriate safety data are presented, at least for bevacizumab and anlotinib.