Pulmonary haemorrhage and haemoptysis associated with bevacizumab-related treatment regimens: a retrospective, pharmacovigilance study using the FAERS database

Background: Bevacizumab (BV) is widely used in routine cancer treatment and clinical therapy in combination with many other agents. This study aims to describe and analyse post-market cases of pulmonary haemorrhage and haemoptysis reported with different BV treatment regimens by mining data from the United States Food and Drug Administration Adverse Event Reporting System (FAERS) database. Methods: Data were collected from the FAERS database between 2004 Q1 and 2023 Q1. Disproportionality analysis including the reporting odds ratio (ROR) was employed to quantify the signals of disproportionate reporting of pulmonary haemorrhage and haemoptysis adverse events (AEs) associated with BV-related treatment regimens. The demographic characteristics, time to onset and outcomes were further clarified. Results: A total of 55,184 BV-associated reports were extracted from the FAERS database, of which 497 reports related to pulmonary haemorrhage and haemoptysis. Overall, the median onset time of pulmonary haemorrhage and haemoptysis AEs was 43 days (interquartile range (IQR) 15-117 days). In the subgroup analysis, BV plus targeted therapy had the longest median onset time of 90.5 days (IQR 34-178.5 days), while BV plus chemotherapy had the shortest of 40.5 days (IQR 14–90.25). BV plus chemotherapy disproportionately reported the highest percentage of death (148 deaths out of 292 cases, 50.68%). Moreover, the BV-related treatments including four subgroups in our study demonstrated the positive signals with the association of disproportionate reporting of pulmonary haemorrhage and haemoptysis. Notably, BV plus chemotherapy showed a significant higher reporting risk in pulmonary haemorrhage and haemoptysis signals of disproportionate reporting in comparison to BV monotherapy (ROR 5.35 [95% CI, 4.78–6.02] vs. ROR 4.19 [95% CI, 3.56–4.91], p = 0.0147). Conclusion: This study characterized the reporting of pulmonary haemorrhage and haemoptysis, along with the time to onset and demographic characteristics among different BV-related treatment options. It could provide valuable evidence for further studies and clinical practice of BV.

[1]  P. Catalano,et al.  Bevacizumab in Combination With Oxaliplatin, Fluorouracil, and Leucovorin (FOLFOX4) for Previously Treated Metastatic Colorectal Cancer: Results From the Eastern Cooperative Oncology Group Study E3200 , 2023, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[2]  R. Herbst,et al.  Randomized Phase II Trial Comparing Bevacizumab Plus Carboplatin and Paclitaxel With Carboplatin and Paclitaxel Alone in Previously Untreated Locally Advanced or Metastatic Non-Small-Cell Lung Cancer , 2023, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[3]  Dehua Wu,et al.  Interstitial pneumonitis associated with combined regimen of immunotherapy and conventional therapies—pharmacovigilance database analysis with real-world data validation , 2023, BMC Medicine.

[4]  Q. Cheng,et al.  Adverse reactions associated with immune checkpoint inhibitors and bevacizumab: A pharmacovigilance analysis , 2022, International journal of cancer.

[5]  Y. Kanbayashi,et al.  Evaluation of lung toxicity with bevacizumab using the spontaneous reporting database , 2022, Scientific Reports.

[6]  Junyan Wu,et al.  Stevens-Johnson syndrome/toxic epidermal necrolysis in patients treated with immune checkpoint inhibitors: A safety analysis of clinical trials and FDA pharmacovigilance database , 2021, EClinicalMedicine.

[7]  J. Pacheco,et al.  Immune-related adverse event profile of combination treatment of PD-(L)1 checkpoint inhibitors and bevacizumab in non-small cell lung cancer patients: data from the FDA adverse event reporting system , 2021, Translational lung cancer research.

[8]  Shusen Sun,et al.  Adverse event profiles of dipeptidyl peptidase-4 inhibitors: data mining of the public version of the FDA adverse event reporting system , 2020, BMC pharmacology & toxicology.

[9]  O. Chinot,et al.  Bevacizumab (Avastin®) in cancer treatment: A review of 15 years of clinical experience and future outlook. , 2020, Cancer treatment reviews.

[10]  T. Taguchi,et al.  Predictive factors for the development of proteinuria in cancer patients treated with bevacizumab, ramucirumab, and aflibercept: a single-institution retrospective analysis , 2020, Scientific Reports.

[11]  Jin-fang Xu,et al.  Endocrine toxicity of immune checkpoint inhibitors: a real-world study leveraging US Food and Drug Administration adverse events reporting system , 2019, Journal of Immunotherapy for Cancer.

[12]  R. Nishikawa,et al.  Safety and effectiveness of bevacizumab in Japanese patients with malignant glioma: a post-marketing surveillance study , 2019, Japanese journal of clinical oncology.

[13]  Marc P. Bonaca,et al.  Cardiovascular toxicities associated with immune checkpoint inhibitors: an observational, retrospective, pharmacovigilance study. , 2018, The Lancet. Oncology.

[14]  Tetsuya Tanimoto,et al.  EGFR–TKI-Associated Interstitial Pneumonitis in Nivolumab-Treated Patients With Non–Small Cell Lung Cancer , 2018, JAMA oncology.

[15]  M. Kusumoto,et al.  Bevacizumab for non‐small‐cell lung cancer: A nested case control study of risk factors for hemoptysis , 2016, Cancer science.

[16]  H. Uetake,et al.  Bevacizumab safety in Japanese patients with colorectal cancer. , 2016, Japanese journal of clinical oncology.

[17]  Kunihiko Takahashi,et al.  Effect of database profile variation on drug safety assessment: an analysis of spontaneous adverse event reports of Japanese cases , 2015, Drug design, development and therapy.

[18]  D. Shin,et al.  Bevacizumab plus capecitabine versus capecitabine alone in elderly patients with previously untreated metastatic colorectal cancer (AVEX): an open-label, randomised phase 3 trial. , 2013, The Lancet. Oncology.

[19]  L. Leibovici,et al.  The Impact of Bevacizumab (Avastin) on Survival in Metastatic Solid Tumors - A Meta-Analysis and Systematic Review , 2013, PloS one.

[20]  N. Petrelli,et al.  Bevacizumab in stage II-III colon cancer: 5-year update of the National Surgical Adjuvant Breast and Bowel Project C-08 trial. , 2013, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[21]  P. Garrido,et al.  MO19390 (SAiL): bleeding events in a phase IV study of first-line bevacizumab with chemotherapy in patients with advanced non-squamous NSCLC. , 2012, Lung cancer.

[22]  F. Zhu,et al.  A Phase II Study of Capecitabine, Oxaliplatin, and Cetuximab with or Without Bevacizumab as Frontline Therapy for Metastatic Colorectal Cancer. A Fox Chase Extramural Research Study , 2012, Journal of Gastrointestinal Cancer.

[23]  C. Henschke,et al.  Predicting and managing the risk of pulmonary haemorrhage in patients with NSCLC treated with bevacizumab: a consensus report from a panel of experts , 2011, Annals of oncology : official journal of the European Society for Medical Oncology.

[24]  Shenhong Wu,et al.  Increased Risk of Serious Hemorrhage with Bevacizumab in Cancer Patients: A Meta-Analysis , 2010, Oncology.

[25]  A. Bate,et al.  Quantitative signal detection using spontaneous ADR reporting , 2009, Pharmacoepidemiology and drug safety.

[26]  R. Ramlau,et al.  Phase III trial of cisplatin plus gemcitabine with either placebo or bevacizumab as first-line therapy for nonsquamous non-small-cell lung cancer: AVAil. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[27]  H. Verheul,et al.  Possible molecular mechanisms involved in the toxicity of angiogenesis inhibition , 2007, Nature Reviews Cancer.

[28]  D. McDonald,et al.  Mechanisms of adverse effects of anti-VEGF therapy for cancer , 2007, British Journal of Cancer.

[29]  J. Verweij,et al.  The clinical toxicity profile of vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor (VEGFR) targeting angiogenesis inhibitors; a review. , 2006, European journal of cancer.

[30]  Kenneth J. Hillan,et al.  Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer , 2004, Nature Reviews Drug Discovery.

[31]  M. Wolzt,et al.  Large amounts of vascular endothelial growth factor at the site of hemostatic plug formation in vivo. , 1999, Arteriosclerosis, thrombosis, and vascular biology.

[32]  D. Berry,et al.  Impact of the addition of carboplatin and/or bevacizumab to neoadjuvant once-per-week paclitaxel followed by dose-dense doxorubicin and cyclophosphamide on pathologic complete response rates in stage II to III triple-negative breast cancer: CALGB 40603 (Alliance). , 2015, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[33]  R. Greil,et al.  Continuation of bevacizumab after first progression in metastatic colorectal cancer (ML18147): a randomised phase 3 trial. , 2013, The Lancet. Oncology.

[34]  T. Yoshino,et al.  [Bevacizumab (Avastin)]. , 2007, Gan to kagaku ryoho. Cancer & chemotherapy.