Phase I study of nintedanib in Japanese patients with advanced hepatocellular carcinoma and liver impairment

Abstract

This phase I, dose‐escalation study evaluated the safety, preliminary efficacy and pharmacokinetics of nintedanib, a triple angiokinase inhibitor, in Japanese patients with advanced hepatocellular carcinoma and mild/moderate liver impairment. Thirty patients with unresectable hepatocellular carcinoma were enrolled to groups, depending on whether liver impairment was mild (group I, aspartate aminotransferase and alanine aminotransferase ≤2× upper limit of normal and Child–Pugh score 5 [n = 14] or 6 [n = 2]) or moderate (group II, Child–Pugh score 5–6 and aspartate aminotransferase or alanine aminotransferase >2× to ≤5× upper limit of normal [n = 7] or Child–Pugh score 7 [n = 7]); 22 patients had prior sorafenib treatment. Nintedanib was given twice daily in 28‐day cycles until disease progression or unacceptable adverse events, starting at 150 mg (group I) or 100 mg (group II) and escalating to 200 mg. The primary objective was to define the maximum tolerated dose based on occurrence of dose‐limiting toxicities during cycle 1 (grade ≥3 non‐hematological and grade 4 hematological adverse events). No dose‐limiting toxicities were reported during cycle 1 and the maximum tolerated dose for both groups was 200 mg twice daily. The most frequent adverse events were gastrointestinal (diarrhea, nausea, vomiting, and decreased appetite). No patients discontinued nintedanib due to adverse events; 31% of group I and 21% of group II had dose reductions. Median time to progression was 2.8 months (95% confidence interval, 1.05–5.52) for group I and 3.2 months (95% confidence interval, 0.95–6.70) for group II. Nintedanib showed a manageable safety profile and efficacy signals, including in patients previously treated with sorafenib. Clinical trial registration NCT01594125; 1199.120 (ClinicalTrials.gov).

Inhibition of FGF‐FGFR and VEGF‐VEGFR signalling in cancer treatment

“…In patients with metastatic RCC who progressed after or were intolerant to sorafenib or sunitinib, dual FGFR and VEGFR inhibitors, including anlotinib, dovitinib and lenvatinib with promising results in phase I or II clinical trials bring them another chance to overcome resistance 132‐134 . Lenvatinib and nintedanib also offer opportunities for patients with HCC who progressed on sorafenib treatment 135,136 …”

“…[132][133][134] Lenvatinib and nintedanib also offer opportunities for patients with HCC who progressed on sorafenib treatment. 135,136 The roles of VEGF-VEGFR signalling in suppressing tumour immunity have been discussed above. Coincidentally, FGF-FGFR signalling has similar effects on immune evasion.…”

“…[166][167][168] Based on these results, nintedanib has been or is being tried in various tumour types in clinical trials. Most phase I studies have shown nintedanib to be safe and efficacious at 200mg bid, 42,136,169,170 but it frequently showed limited efficacy in most phase II and III studies. [171][172][173][174][175] Fortunately, nintedanib was approved by EMA for its second-line use in combination with docetaxel in patients with lung adenocarcinoma based on the results of the phase III LUME-Lung 1 study in November 2014.…”

Nintedanib inhibits growth of human prostate carcinoma cells by modulating both cell cycle and angiogenesis regulators

“…Nintedanib has shown interesting preliminary results in the treatment of non-small cell lung 19 , salivary gland 20 , ovarian 21 and hepatocellular carcinomas 22 . Furthermore, Nintedanib has no reported drug-drug interactions when administered along with other chemotherapeutic agents 23 .…”