The Effects of Drug Exposure and Single Nucleotide Polymorphisms on Aaptinib-Induced Severe Toxicities in Solid Tumors.

To investigate the value of drug exposure and host germline genetic factors in predicting apatinib (APA)-related toxicities. METHOD: In this prospective study, plasma APA concentrations were quantified using liquid chromatography with tandem mass spectrometry, and 57 germline mutations were genotyped in 126 advanced solid tumor patients receiving 250 mg daily APA, a vascular endothelial growth factor receptor II inhibitor. The correlation between drug exposure, genetic factors, and the toxicity profile was analyzed. RESULTS: Non-small cell lung cancer (NSCLC) was more prone to APA-related toxicities and plasma concentrations of APA, and its main metabolite M1-1 could be associated with high-grade adverse events (AEs) (P < 0.01; M1-1, P < 0.01) and high-grade antiangiogenetic toxicities (APA, P = 0.034; P < 0.05), including hypertension, proteinuria, and hand-foot syndrome, in the subgroup of NSCLC. Besides, CYP2C9 rs34532201 TT carriers tended to have higher levels of APA (P < 0.001) and M1-1 (P < 0.01), whereas CYP2C9 rs1936968 GG carriers were predisposed to higher levels of M1-1 (P < 0.01). CONCLUSION: Plasma APA and M1-1 exposures were able to predict severe AEs in NSCLC patients. Dose optimization and drug exposure monitoring might need consideration in NSCLC patients with CYP2C9 rs34532201 TT and rs1936968 GG. SIGNIFICANCE STATEMENT: Apatinib is an anti-VEGFR2 inhibitor for the treatment of multiple cancers. Though substantial in response, apatinib-induced toxicity has been a critical issue that is worth clinical surveillance. Few data on the role of drug exposure and genetic factors in apatinib-induced toxicity are available. Our study demonstrated a distinct drug-exposure relationship in NSCLC but not other tumors and provided invaluable evidence of drug exposure levels and single nucleotide polymorphisms as predictive biomarkers in apatinib-induced severe toxicities.

Efficacy of apatinib in advanced hepatocellular carcinoma with lung metastasis: a retrospective, multicenter study.

PURPOSE: Lung is the most common extrahepatic metastatic site for patients with advanced hepatocellular carcinoma (HCC) and has a worse prognosis than intrahepatic metastasis. Apatinib is a receptor tyrosine kinase inhibitor that is promising for HCC treatment. We investigated whether apatinib is particularly effective for advanced HCC with lung metastasis. METHODS: Sixty-one study patients with advanced HCC treated with apatinib seen at three different institutions between 2015 and 2018 were identified by retrospective review. Forty-one had lung metastasis (13 multi-organ metastasis and 28 lung metastasis only). Twenty had non-lung metastasis. Treatment consisted of oral apatinib 500 mg once daily. Response was assessed by imaging. The primary endpoint was metastasis-specific (m) progression-free survival (mPFS), for which only progression of metastatic lesions was assessed. RESULTS: Median PFS was 3.37 months (range, 0.6-16.1) for all 61 patients. Objective response (OR) was achieved in 7/61 (11.6%) patients. For the 41 patients with lung metastasis, the median mPFS was 5 months (range, 0.9-21.9), with a mOR rate (mORR) of 22.0% (9/41). The mPFS of the 28 patients with only lung metastasis was better (hazard ratio/HR=0.316; 95% confidence interval/CI=0.144-0.696; log-rank p<0.001) than for the 20 with non-lung metastasis; comparison of the mORR showed similar results (21.4 vs. 5%; p=0.019). For the 13 patients with multi-organ metastasis, the mORR of lung lesions was marginally higher than that of other metastatic lesions (23.1 vs. 0%; p=0.096). CONCLUSIONS: Apatinib showed promising therapeutic effects on advanced HCC with lung metastasis, highlighting a population that could benefit preferentially from this treatment.