Descriptive Analysis
A total of 14,8647 cases were reported in the FAERS database. Of these, 1,459 cases were excluded due to the indication of “liver injury” indication. Consequently, 134,088 cases with VEGFR-TKIs as primary suspected drugs were included in the study. Among these cases, 10,236 cases were reported with hepatotoxicity events. The characteristics of these cases are shown in Table 1. The five drugs with the highest number of cases were sunitinib (2410 cases), sorafenib (2061 cases), pazopanib (1955 cases), cabozantinib (1168 cases), and regorafenib (946 cases). The ratio between males and females with drug-related hepatotoxicity was 1.50. Drug-induced liver injury was concentrated among patients aged 18 to 64 years. A majority of drug-related hepatotoxicity cases (71.28%) were reported by healthcare professionals. The top five drug-related hepatotoxicity reporting regions were North America (36.01%), followed by Asia (34.52%), Europe (21.66%), South America (4.45%), and Oceania (1.08%). We conducted an analysis of the outcomes of VEGFR-TKIs-associated hepatotoxicity events, revealing a fatality proportion of 23.09%. The details of the fatality proportion for VEGFR-TKIs-associated hepatotoxicity were presented in Fig. 1. In addition, VEGFR-TKIs associated hepatotoxicity events resulted in a larger proportion of hospitalization and other serious events. The proportions of hospitalizations and other serious events were 28.69% and 29.55%, respectively. Figure 2 provides the number of hepatotoxicity cases associated with VEGFR-TKIs submitted to the FAERS database from 2006 to 2022. Notably, the number of reports for sorafenib has shown a significant surge since 2009. However, it has experienced a sharp decline since 2013. On the other hand, the number of reports for axitinib, lenvatinib, and cabozantinib has steadily increased over the past five years.
Table 1
Characteristics of VEGFR-TKIs-related hepatotoxicity events and nonhepatotoxicity events submitted to the FAERS database.
| Hepatotoxicity cases | Non hepatotoxicity cases |
Characteristics | Number(n) | Proportion (%) | Number(n) | Proportion (%) |
VEGF-TKIs | | | | |
Sunitinib | 2410 | 23.54 | 32594 | 26.32 |
Sorafenib | 2061 | 20.13 | 9365 | 7.56 |
Pazopanib | 1955 | 19.10 | 21107 | 17.04 |
Cabozantinib | 1168 | 11.41 | 20316 | 16.40 |
Regorafenib | 946 | 9.24 | 6452 | 5.21 |
Apatinib | 641 | 6.26 | 11154 | 9.01 |
Lenvatinib | 505 | 4.93 | 9101 | 7.35 |
Axitinib | 482 | 4.71 | 11910 | 9.62 |
Vandetanib | 44 | 0.43 | 1151 | 0.93 |
Erdafitinib | 24 | 0.23 | 702 | 0.57 |
Sex | | | | |
Female | 3813 | 37.25 | 48481 | 39.14 |
Male | 5703 | 55.72 | 65861 | 53.18 |
Unknown | 720 | 7.03 | 9510 | 7.68 |
Age group | | | | |
<18 year | 47 | 0.46 | 606 | 0.49 |
18–64 year | 4158 | 40.62 | 42731 | 34.50 |
≥ 65 year | 3914 | 38.24 | 41470 | 33.48 |
Unknown | 2117 | 20.68 | 39045 | 31.53 |
Reporter occupation | | | | |
Health professionals | 7296 | 71.28 | 65776 | 53.11 |
Non-health professionals | 2639 | 25.78 | 54191 | 43.75 |
Unknown | 301 | 2.94 | 3885 | 3.14 |
Reporter region (Top 5) | | | | |
North America | 3686 | 36.01 | 77744 | 62.77 |
Asia | 3533 | 34.52 | 18241 | 14.73 |
Europe | 2217 | 21.66 | 17767 | 14.35 |
South America | 456 | 4.45 | 5023 | 4.06 |
Oceania | 111 | 1.08 | 1030 | 0.83 |
Outcomes | | | | |
Death | 2363 | 23.09 | 27962 | 22.58 |
Disability | 60 | 0.59 | 706 | 0.57 |
Hospitalization | 2937 | 28.69 | 29627 | 23.92 |
Life threatening | 362 | 3.54 | 2421 | 1.95 |
Other serious events | 3025 | 29.55 | 22797 | 18.41 |
Required intervention | 2 | 0.02 | 61 | 0.05 |
Unknown | 1487 | 14.53 | 40278 | 32.52 |
VEGFR-TKIs, vascular endothelial growth factor tyrosine kinase inhibitors |
Signal Values
Ten VEGFR-TKI drugs were investigated for severe hepatotoxicity cases by narrow SMQ search in the FAERS database. The strongest significant signal was detected with sorafenib (ROR = 7.86, 95% CI 7.43–8.32; IC = 2.81, 95% CI 2.62–2.99), followed by regorafenib (ROR = 3.68, 95% CI 3.34–4.05; IC = 1.81, 95% CI 1.49–2.12), pazopanib (ROR = 2.20 95% CI 2.05–2.35; IC = 1.10, 95% CI 0.87–1.33) and sunitinib (ROR = 1.79 95% CI 1.69–1.91; IC = 0.82, 95% CI 0.62–1.02). The weakest signal was detected with lenvatinib (ROR = 1.59, 95% CI 1.40–2.80; IC = 0.65, 95% CI 0.24–1.06). No significant signal was detected with cabozantinib, axitinib, apatinib, vandetanib and erdafitinib (Table 2).
Table 2
Signal values of severe hepatotoxicity cases associated with VEGFR-TKIs by SMQ narrow search in FAERS
VEGF-TKIs | Hepatotoxicity cases (N) | ROR (95% CI) | IC (95% CI) |
Sorafenib | 1365 | 7.86 (7.43, 8.32) | 2.81 (2.62, 2.99) |
Sunitinib | 1054 | 1.79 (1.69, 1.91) | 0.82 (0.62, 1.02) |
Pazopanib | 845 | 2.20 (2.05, 2.35) | 1.10 (0.87, 1.33) |
Regorafenib | 443 | 3.68 (3.34, 4.05) | 1.81(1.49, 2.12) |
Cabozantinib* | 384 | 1.05 (0.95, 1.16) | 0.07 (-0.27, 0.40) |
Axitinib* | 259 | 1.23 (1.09, 1.39) | 0.29 (-0.11, 0.70) |
Lenvatinib | 257 | 1.59 (1.40, 1.80) | 0.65 (0.24, 1.06) |
Apatinib* | 247 | 1.23 (1.09, 1.40) | 0.30 (-0.12, 0.71) |
Vandetanib* | 18 | 0.88 (0.55, 1.41) | -0.18 (-1.68, 1.34) |
Erdafitinib* | 12 | 0.97 (0.55, 1.72) | -0.04 (-1.86,1.78) |
VEGFR-TKIs, vascular endothelial growth factor tyrosine kinase inhibitors; ROR, reporting odds ratio; IC, information component; SMQ, Standardized medical dictionary for regulatory activities queries. |
*Signal was not detected |
The signal detection results of liver injury and three classifications (hepatic failure, cholestatic injury, and hepatocellular injury) were summarized in Table 3. In terms of liver injury, significant signals were detected for the other eight VEGFR-TKIs investigated in our study, except for vandetanib and erdafitinib. For hepatic failure detection, only sorafenib, sunitinib, regorafenib, pazopanib and lenvatinib were detected with significant signals. Compared with other drugs, the strongest signal was observed in sorafenib (ROR = 18.90, 95% CI 17.26–20.70; IC = 4.16, 95% CI 3.81–4.42), followed by regorafenib (ROR = 7.58, 95% CI 6.38-9.00; IC = 2.89, 95% CI 2.26–3.40). The weakest signal was detected for pazopanib (ROR = 1.89, 95% CI 1.56–2.29; IC = 0.91, 95% CI 0.26–1.54). For cholestatic injury, five drugs detected significant signals, including regorafenib (ROR = 9.48, 95% CI 8.54–10.52; IC = 3.17, 95% CI 2.80–3.49), sorafenib (ROR = 6.29, 95% CI 5.69–6.96; IC = 2.61, 95% CI 2.25–2.92), sunitinib (ROR = 5.73, 95% CI 5.39–6.08; IC = 2.47, 95% CI 2.26–2.66), apatinib (ROR = 4.20, 95% CI 3.72–4.74; IC = 2.04, 95% CI 1.63–2.42) and pazopanib (ROR = 3.82, 95% CI 3.49–4.18; IC = 1.91, 95% CI 1.60–2.20). For hepatocellular injury, significant signals were observed for eight VEGFR-TKIs (sorafenib, sunitinib, regorafenib, pazopanib, lenvatinib, cabozantinib, apatinib and axitinib).
Table 3
Signal values of liver injury and three classifications (hepatocellular injury, cholestatic injury, hepatic failure) associated with VEGFR-TKIs
VEGF-TKIs | Hepatotoxicity cases (N) | ROR (95% CI) | IC (95% CI) |
Liver injury |
Sunitinib | 2410 | 2.55 (2.44, 2.65) | 1.28 (1.14, 1.42) |
Sorafenib | 2061 | 7.58 (7.23, 7.95) | 2.67 (2.51 ,2.82) |
Pazopanib | 1955 | 3.19 (3.04, 3.34) | 1.58 (1.43, 1.73) |
Cabozantinib | 1168 | 1.98 (1.86, 2.10) | 0.94 (0.74, 1.14) |
Regorafenib | 946 | 5.04 (4.71,5.40) | 2.17 (1.94, 2.39) |
Apatinib | 641 | 1.97 (1.82, 2.14) | 0.94 (0.67, 1.20) |
Lenvatinib | 505 | 1.91 (1.74, 2.08) | 0.89 (0.59, 1.19) |
Axitinib | 482 | 1.39 (1.27, 1.52) | 0.46 (0.15, 0.76) |
Vandetanib* | 44 | 1.31 (0.97,1.77) | 0.38 (-0.62, 1.36) |
Erdafitinib* | 24 | 1.17 (0.78, 1.76) | 0.22 (-1.11, 1.54) |
Hepatic failure | | | | | | | |
Sorafenib | 491 | 18.90 (17.26, 20.70) | 4.16 (3.81, 4.42) |
Sunitinib | 179 | 2.14 (1.85, 2.48) | 1.09 (0.60, 1.57) |
Regorafenib | 132 | 7.58 (6.38, 9.00) | 2.89 (2.26, 3.40) |
Pazopanib | 104 | 1.89 (1.56, .29) | 0.91 (0.26, 1.54) |
Lenvatinib | 48 | 2.09 (1.57, 2.78) | 1.06 (0.09, 1.96) |
Apatinib | 36 | 1.27 (0.92, 1.77) | 0.35 (-0.74, 1.41) |
Cabozantinib* | 34 | 0.66 (0.47, 0.92) | -0.60 (-1.69, 0.52) |
Axitinib* | 18 | 0.60 (0.38, 0.96) | -0.72 (-2.19 ,0.80) |
Erdafitinib* | 1 | 0.57 (0.08, 4.08) | -0.80 (-5.07, 4.15) |
Vandetanib* | 1 | 0.35 (0.05, 2.47) | -1.52 (-5.56, 3.66) |
Cholestatic injury |
Sunitinib | 1087 | 5.73 (5.39, 6.08) | 2.47 (2.26, 2.66) |
Pazopanib | 486 | 3.82 (3.49, 4.18) | 1.91 (1.60, 2.20) |
Sorafenib | 391 | 6.29 (5.69, 6.96) | 2.61 (2.25, 2.92) |
Regorafenib | 375 | 9.48 (8.54, 10.52) | 3.17 (2.80, 3.49) |
Apatinib | 273 | 4.20 (3.72, 4.74) | 2.04 (1.63, 2.42) |
Cabozantinib* | 155 | 1.29 (1.10, 1.51) | 0.36 (-0.17, 0.88) |
Lenvatinib* | 73 | 1.35 (1.08, 1.71) | 0.43 (-0.33, 1.19) |
Axitinib* | 70 | 1.00 (0.79, 1.27) | 0.01 (-0.77, 0.78) |
Vandetanib* | 7 | 1.04 (0.50, 2.19) | 0.06 (-2.26, 2.36) |
Erdafitinib* | 6 | 1.47 (0.66, 3.29) | 0.56 (-2.01, 2.93) |
Hepatocellular injury |
Pazopanib | 1432 | 3.91 (3.71, 4.12) | 1.89 (1.71, 2.07) |
Sorafenib | 1066 | 6.07 (5.70, 6.47) | 2.48 (2.27, 2.68) |
Sunitinib | 1005 | 1.74 (1.64, 1.85) | 0.78 (0.57, 0.99) |
Cabozantinib | 861 | 2.46 (2.30, 2.63) | 1.26 (1.03, 1.49) |
Regorafenib | 551 | 4.74 (4.35, 5.17) | 2.16 (1.86, 2.43) |
Apatinib | 412 | 2.13 (1.93, 2.35) | 1.06 (0.73, 1.39) |
Axitinib | 328 | 1.60 (1.43, 1.79) | 0.66 (0.30, 1.02) |
Lenvatinib | 313 | 1.98 (1.77, 2.22) | 0.96 (0.58, 1.33) |
Vandetanib* | 26 | 1.31 (0.89, 1.93) | 0.38 (-0.90, 1.63) |
Erdafitinib* | 17 | 1.41(0.87, 2.28) | 0.49 (-1.10, 2.01) |
VEGFR-TKIs, vascular endothelial growth factor tyrosine kinase inhibitors |
*Signal was not detected |