Median Ang-1 and Ang-2 levels at 1 month after initiation of lenvatinib therapy for 36 patients were significantly lower than those pre-therapy (Ang-1: 5750 pg/mL from 6459 pg/mL, P < 0.001; Ang-2: 967 pg/mL from 1590 pg/mL, P < 0.001). The median rates of change of Ang-1 and Ang-2 levels at 1 month from baseline in 36 patients were − 15.3% and − 48.4%, respectively. However, the rates of change of Ang-1 and Ang-2 levels at 1 month relative to baseline did not correlate with the C0 for lenvatinib at 1 month after initiation of treatment (Fig. 1). On the other hand, there were no significant differences in Ang-1 or Ang-2 levels between 1 month and 1 year time points (P = 0.267 and 0.248, respectively).
Partial response (PR), stable disease (SD) and progressive disease (PD) were observed as best responses to lenvatinib treatment in 23, 8 and 5 patients, respectively (Table 1). Among groups with these best responses, there were no significant differences in Ang-1 plasma levels at baseline or at 1 month and 1 year after initiation of lenvatinib therapy, and there were no significant differences in the rate of change of Ang-1 at 1 month and 1 year from baseline (Table 1). However, in patients with PR to lenvatinib, Ang-1 levels 1 month after treatment initiation were significantly lower than Ang-1 levels at baseline (P < 0.01, Table 1).
Similar to the Ang-1 levels, there were no significant differences in Ang-2 levels at baseline or at 1 month and 1 year after initiation of lenvatinib therapy among patients with PR, SD and PD; however, in patients with PR to lenvatinib, Ang-2 levels at 1 month and 1 year after treatment initiation were significantly lower than Ang-2 levels at baseline (P < 0.001 and P < 0.01, respectively, Table 1).
There were no significant differences in lenvatinib C0 1 month after treatment initiation among patients with PR, SD and PD (Table 1); however, in patients with PR, lenvatinib C0 at 1 year after treatment initiation was significantly lower than at 1 month (P < 0.01).
A waterfall plot of rate of change of Ang-2 levels 1 month after initiation of lenvatinib therapy relative to baseline is shown in Fig. 2. The rate of change of Ang-2 levels in 2 patients (1 patient with papillary thyroid cancer and 1 patient with follicular thyroid cancer) increased after lenvatinib therapy, and these 2 patients showed an overall response of PD for lenvatinib therapy.
A receiver operating characteristic (ROC) analysis showed the discrimination potential of the rate of change of Ang-2 levels for prediction of PR to lenvatinib (Fig. 3). The area under the ROC was 0.667 (95% confidence interval (CI), 0.478–0.873), giving the best sensitivity (69.2%) and specificity (73.9%) at a threshold of
Patients were divided into two groups depending on their exhibited rates of change of Ang-2 levels: those with rates of change of at least − 49.83% and those with rates of change of less than − 49.83%. The overall survival (OS) rates of patients in the group with changes of at least − 49.83% tend to be longer than those with changes less than − 49.83%, but these differences were not statistically significant (median OS: 676 day and 273 day, respectively, Fig. 4). The median 1 year OS for patients having rates of change of levels of Ang-2 of at least − 49.83% and less than − 49.83% were 62.5% and 45%, respectively.
Furthermore, the 18 patients that continued treatment with lenvatinib for 1 year were compared with 18 patients who discontinued treatment at less than 1 year (Table 2). There were no significant differences between Ang-1 and Ang-2 levels at baseline or at 1 month after initiation of lenvatinib therapy. The rates of change of Ang-1 and Ang-2 levels at 1 month relative to baseline between these 2 groups were also not significantly different. In addition, there was no significant difference in lenvatinib C0 at 1 month after initiation of treatment between these 2 groups (Table 2).
However, in patients who continued lenvatinib treatment beyond 1 year, Ang-2 levels and the Ang-2/Ang-1 ratio at 1 month and 1 year after treatment initiation were significantly lower than those at baseline (each P < 0.001, Table 2). In addition, lenvatinib C0 at 1 year after treatment initiation was significantly lower than that at 1 month (P < 0.01). On the other hand, in patients who discontinued lenvatinib therapy prior to 1 year, both Ang-1 and Ang-2 levels 1 month after treatment were significantly lower than those at baseline (P < 0.01 and P < 0.05, respectively).
None of the 10 patients with anaplastic thyroid cancer continued treatment with lenvatinib for more than 1 year (P = 0.002 in Table 2). Therefore, subgroup analyses were performed only on the 21 patients with papillary thyroid cancer (PTC) or follicular thyroid cancer (FTC) (Table 2, lower berth). Similar to the results from the 36 patients of five different histological types of thyroid cancer, there were no significant differences in Ang-1 and Ang-2 levels at baseline or at 1 month after initiation of lenvatinib therapy. Similarly, there were no significant differences in the rates of change at 1 month relative to baseline between these 2 groups. However, Ang-2 levels at 1 month after treatment initiation were significantly lower than Ang-2 at baseline (P < 0.001).