Small Molecules Prescribed On- and Off-Label for Thoracic Cancers During Pregnancy: A Combined VigiBase and Systematic Review Analysis.
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BACKGROUND: Thoracic cancers during pregnancy are rare but increasingly encountered because of delayed childbearing and the rising incidence of cancer in younger individuals. Despite guideline recommendations, exposure to targeted small-molecule therapies occurs across all trimesters, but safety data remain limited. OBJECTIVE: To investigate the safety of targeted small-molecule therapies for thoracic cancers during pregnancy by combining VigiBase data with a systematic review. PATIENTS AND METHODS: We performed a pharmacovigilance disproportionality analysis based on the reporting odds ratio (ROR) and a systematic review. Individual case safety reports from VigiBase (January 1, 2006-February 24, 2026) were analysed. A systematic review of PubMed, EMBASE, and Scopus through June 25, 2026 included case reports and case series. RESULTS: The VigiBase analysis included 15,023 reports of anticancer exposure during pregnancy, of which 162 involved small molecules currently used on- and off-label for thoracic cancers, including 75 with approved agents for non-small-cell lung cancer (NSCLC). Compared with other anticancer agents, including cytotoxic drugs, immune checkpoint inhibitors, other immunotherapies, antibody-drug conjugates, molecularly targeted therapies (including biologics and small molecules other than those of interest), and anticancer agents not further specified, the small molecules of interest were associated with disproportionate reporting of premature labor (ROR: 2.64; 95% confidence interval [CI]: 1.21-5.75), foetal growth restriction (ROR: 2.10; 95% CI 1.15-3.84), neonatal respiratory distress syndrome (ROR: 3.78; 95% CI 1.50-9.57), and low birth weight (ROR: 2.27; 95% CI 1.18-4.37). Among approved small molecules for NSCLC, signals were observed for premature labor (ROR: 4.17; 95% CI 1.65-10.53), neonatal respiratory complications (ROR: 2.56; 95% CI 1.02-6.42), and low birth weight (ROR: 3.55; 95% CI 1.61-7.83). Of note, anaplastic lymphoma kinase (ALK) inhibitor ICSRs were fewer, and 14/18 alectinib reports described pregnancy exposure without pregnancy-related ADRs of interest, precluding alectinib-specific disproportionality analysis. The systematic review included 26 women (27 pregnancies) with oncogene-driven metastatic NSCLC. Live births occurred in 96.3% of pregnancies, with 53.8% preterm deliveries, 33.3% pregnancy complications, and 19.2% neonatal complications. Maternal outcomes were favourable (objective response rate 80.8%). There were no clinically significant pregnancy complications reported in the 10 cases involving alectinib exposure alone. CONCLUSIONS: Exposure during pregnancy to small molecules currently used on- and off-label for thoracic cancers was associated with disproportionate reporting signals for selected adverse foetal outcomes. The available clinical evidence remains limited, and although no clinically significant pregnancy complications were reported with alectinib exposure, the current data are insufficient to establish its safety. Treatment decisions should therefore be individualised and made within a multidisciplinary expert setting.