Abstract
Background:
Treatment for patients with radioactive iodine (RAI)-refractory differentiated thyroid carcinoma (DTC) is challenging. Recently, two tyrosine kinase inhibitors (sorafenib and lenvatinib) have been approved and showed benefits for progression-free survival with tolerable adverse events.
Methods:
This is an extension study of a previous multicenter, retrospective cohort study of real-world experience in treating 98 patients with progressive RAI-refractory DTC with sorafenib. The primary endpoint was overall survival (OS). The efficacy of lenvatinib as salvage therapy after disease progression on first-line sorafenib was evaluated by comparing outcomes in 32 patients who were treated with lenvatinib with 41 patients who were not and therefore served as a no salvage treatment group.
Results:
The median OS of all 98 patients treated with sorafenib was 41.5 months, and the median progression-free survival was 13.5 months. Patients without disease-related symptoms before sorafenib treatment had better OS than those with symptoms (hazard ratio [HR] = 0.56 [95% confidence interval, CI 0.31–0.99], p = 0.048). Larger tumor size was associated with a minimally increased risk of death (HR = 1.02 [CI 1.00–1.03], p = 0.049). Best tumor response was not associated with OS (p = 0.490). Lenvatinib salvage treatment significantly improved OS in patients receiving it compared with those who did not (HR = 0.28 [CI 0.15–0.53], p < 0.001). The median OS from the time of disease progression after first-line sorafenib treatment was 4.9 months in no salvage treatment group, whereas it was not reached in the lenvatinib salvage group.
Conclusions:
The absence of disease-related symptoms and smaller tumor burden was associated with survival benefits of first-line sorafenib treatment in patients with progressive RAI-refractory DTC. Lenvatinib salvage therapy was effective in improving OS in patients with disease progression after first-line sorafenib.
Introduction
Distant metastases occur in less than 10% of patients with differentiated thyroid carcinoma (DTC) (1,2). For those with distant metastases, radioactive iodine (RAI) therapy is the mainstay of treatment (3 –5). However, in two-thirds of patients, the disease eventually becomes RAI-refractory, and long-term survival drops to less than 10% (6,7). Treatment options for RAI-refractory DTC are challenging because it is unresponsive to traditional chemotherapy (5,8). So far, two oral multikinase inhibitors, sorafenib and lenvatinib, have been approved for the treatment of RAI-refractory DTC by the U.S. Food and Drug administration (FDA) and the European Medicines Agency (EMA). Sorafenib was the first approved drug (in 2013) and it showed improved progression-free survival (PFS) compared with placebo in the DECISION trial (phase 3 study of sorafenib in DTC) (9). Previously, we reported the efficacy and safety profiles of sorafenib in real-world clinical practice (10). However, there have been no real-world data focusing on overall survival (OS) in patients whose RAI-refractory DTC progressed after sorafenib therapy.
Lenvatinib, a second approved drug (in 2015), also showed a significantly improved PFS with tolerable adverse effect (AE) profiles in the SELECT trial (phase 3 study of Lenvatinib in DTC) (11). In that trial, 25% of patients in the lenvatinib group had one prior course of treatment with a tyrosine kinase inhibitor (TKI) (11). This suggests that lenvatinib can be used as salvage treatment for patients in whom sorafenib has been unsuccessful (12). Although some studies have investigated effects of other TKIs after failure of first-line TKI therapy, the efficacy and benefits of a second-line TKI are unclear (11,13,14). Korea has approved and will reimburse for sorafenib or lenvatinib as first-line treatment for RAI-refractory DTC. Only lenvatinib has been approved for clinical second-line therapy, but without reimbursement.
In this study, we extended our observation of survival in patients with progressive RAI-refractory DTC treated with sorafenib. We also evaluated the efficacy of lenvatinib as salvage therapy in patients with confirmed disease progression after sorafenib treatment.
Materials and Methods
Patients and study design
This is an analysis of extended observation of patients in our previous multicenter, retrospective cohort study of Korean Thyroid Cancer Study Group of real-world experience with sorafenib for progressive RAI-refractory DTC (10). Six centers participated in the study, and the protocol was reviewed and approved by the institutional review board of each participating institution. The inclusion and exclusion criteria of study patients have been previously described (10). A total of 98 patients in Korea with progressive RAI-refractory DTC were treated with sorafenib beginning April 1, 2011. The extended observation reported in this study continued to October 31, 2018.
The primary outcome was OS, defined as the time from sorafenib administration to the time of death from any cause. PFS, disease control rate (complete response [CR] plus partial response [PR] plus stable disease [SD] for six months or more), and disease control duration (i.e., duration of CR, PR, or SD) were also evaluated. PFS was defined as the time from sorafenib administration to the first documentation of disease progression according to Response Evaluation Criteria in Solid Tumors (RECIST) v 1.1 (15). Progression and objective response were assessed every two to three months by repeated axial images obtained from computed tomography or magnetic resonance imaging of the neck, chest, abdomen, pelvis, spine, and all other known sites of disease according to RECIST.
Of 73 patients who had disease progression with sorafenib treatment by the time of data cutoff (October 31, 2018), 32 (33% of the total study sample of 98 patients) were given lenvatinib as salvage treatment. They were compared with the 41 patients with progressive disease after sorafenib who were not treated with lenvatinib and thus served as a no salvage treatment group. These patients were not treated with second-line lenvatinib due to the following reasons: poor performance status (n = 21), economic problem (n = 4), refusal of systemic treatment (n = 8), and lenvatinib not available in Korea (n = 8). In these patients, other local therapies were performed as follows: external beam-radiation therapy (n = 9), radiofrequency ablation (n = 3), and surgical excision for local lesion (n = 2). The OS was defined as the time from documentation of progression after sorafenib treatment to death from any cause. The OS was analyzed in all patients with disease progression and in the subgroup of patients with good performance status, that is, 1 or 2 on the Eastern Cooperative Oncology Group Performance Status (ECOG PS) scale. In Korea, lenvatinib was approved for RAI-refractory DTC from October 2015, but reimbursement was available only for its use as first-line treatment beginning October 2017. The decision to use lenvatinib as salvage therapy was thus decided based on the availability of lenvatinib, ECOG PS, the physician's opinion, the patient's preferences, and economic conditions. Before initiating lenvatinib treatment, baseline routine laboratory test, including renal, hepatic, complete blood count test, and urine analysis evaluating the baseline proteinuria status, and electrocardiography were performed.
Safety and AEs
Safety and tolerability were monitored every one to two weeks for one month after starting sorafenib or lenvatinib and then monthly when the patients were clinically stable. The severity of AEs was graded according to the National Cancer Institute's Common Terminology Criteria for Adverse Events v 4.0. If a causal relationship between an AE and sorafenib or lenvatinib could not be ruled out, the event was classified as a treatment-related AE.
Thyroglobulin and antithyroglobulin antibody measurement
Thyroglobulin (Tg) and antithyroglobulin antibody (TgAb) levels were measured by the same methods as previously described (10). The best change of serum Tg level ≥60% was analyzed only in the 72 patients whose TgAb levels were negative.
Statistical analysis
R version 3.4.0 was used for statistical analysis (R Foundation for Statistical Computing). Graphs were produced using GraphPad Prism version 5.0 (GraphPad Software, Inc., San Diego, CA). Continuous variables are reported as means with standard deviations or medians with interquartile range and categorical variables as frequencies with percentages. The chi-square test was used to investigate associations between categorical variables. Survival curves were plotted using the Kaplan–Meier method, and the log-rank test was used to determine their significance. A Cox proportional hazards model was used to evaluate prognostic factors associated with OS. The relative risk for OS is reported as a hazard ratio (HR) with 95% confidence interval [CI]. A p-value <0.05 was considered statistically significant.
Results
Baseline characteristics of patients with progressive RAI-refractory DTC
The baseline characteristics of the 98 patients with progressive RAI-refractory DTC have previously been reported (10) and are also listed in Supplementary Table S1. Briefly, the median age was 66 years (58–72 years), and 30 (31%) patients were men. The most common pathology type was papillary carcinoma (68%), followed by follicular carcinoma (18%) and poorly differentiated carcinoma (12%). The median time from diagnosis of thyroid cancer to initiation of sorafenib was 9 years (5–14 years). Fifty-three (54%) patients were symptomatic at the time of sorafenib administration. All patients had distant metastases, including to the lung (98%), lymph nodes (55%), bones (38%), pleura (14%), liver (2%), head and neck (24%), or other organs, including adrenals, kidney, pancreas, or soft tissue (7%). The lung was the only site of metastases in 24% of patients.
Efficacy of sorafenib treatment
In this extended study, the median OS with sorafenib was 41.5 months, and the 36-month OS rate was 54.7% (Fig. 1A). In this cohort, 32 patients started lenvatinib salvage treatment after progression with sorafenib treatment. The median OS of patients who were treated with sorafenib only was 33 months, and the median OS of patients who received sorafenib followed by lenvatinib salvage therapy was 61 months. During follow-up, 73 (74%) patients had disease progression on sorafenib, and 49 (50%) died due to disease progression. The median PFS with sorafenib was 13.7 months, and the 12-month PFS was 56.5% (Fig. 1B). PR or SD (i.e., disease control) was achieved in 66 (67%) patients.
Therapeutic response to first-line sorafenib treatment in patients with progressive radioactive iodine-refractory differentiated thyroid carcinoma. Kaplan–Meier estimates of (
The duration of disease control is summarized in Supplementary Table S2. During sorafenib treatment, 27 patients (28%) had disease progression within 6 months, while 34 (35%) had disease control for at least 24 months. Clinical characteristics of patients according to disease control duration (progressive disease [PD] <6 months vs. disease control duration ≥24 months) were compared (Supplementary Table S3). Significantly more patients were symptomatic at the time of sorafenib initiation in patients with PD <6 months than in disease control for ≥24 months (p = 0.044).
Clinicopathologic factors associated with survival benefit of sorafenib treatment
We evaluated prognostic factors associated with longer OS in patients treated with sorafenib (Supplementary Fig. S1 and Table 1). OS was not associated with age, sex, and pathologic subtypes. OS was not related with the best response to sorafenib treatment (Supplementary Fig. S1A, p = 0.490). Patients without disease-related symptoms before administration of sorafenib had a better OS than those with symptoms (Supplementary Fig. S1B, HR = 0.56 [CI 0.31–0.99], p = 0.048) on univariate analysis. However, the statistical significance of this factor disappeared on multivariate analysis (p = 0.082). The presence of lung metastases alone or of bone metastases was not associated with survival (p = 0.241 and p = 0.686). A greater sum of the largest diameters of target lesions was significantly associated with a minimally increased risk of death (HR = 1.02 per centimeter increase [CI 1.00–1.03], p = 0.049). The daily maintenance dose and a reduction in serum Tg level ≥60% were not associated with OS.
Univariate and Multivariate Cox Regression Analysis of Prognostic Factors Associated with Overall Survival in Progressive Radioactive Iodine-Refractory Differentiated Thyroid Carcinoma
CI, 95% confidence interval; FTC, follicular thyroid carcinoma; HR, hazard ratio; PDTC, poorly differentiated thyroid carcinoma; PR, partial response; PTC, papillary thyroid carcinoma; SD, stable disease; Tg, thyroglobulin.
Efficacy of lenvatinib as salvage treatment
The efficacy of lenvatinib was analyzed in the 73 patients who had disease progression after sorafenib. Baseline characteristics did not differ significantly between the 32 patients treated with lenvatinib and the 41 in the no salvage treatment group (Table 2) with the exception of ECOG PS. Significantly more patients in the no salvage treatment group had poor ECOG PS than in the lenvatinib salvage group (p < 0.001). In 29 of the 32 (91%) patients treated with lenvatinib, the disease could be evaluated at a median of 10.0 months (4.1–14.9 months) of treatment. PR was achieved in 8 (20%) and SD in 18 (56%), while 3 (9%) had progression of disease. Patients in the lenvatinib salvage group had a significantly better OS than the no salvage treatment group (Fig. 2A, HR = 0.28 [CI 0.15–0.53], p < 0.001). This advantage with lenvatinib was also true when analyzing only patients with ECOG PS 1–2 (Fig. 2B, HR = 0.30 [CI 0.10–0.81], p = 0.018). The median OS after progression in the no salvage treatment group was 4.9 months, while the median OS had not been reached at data cutoff in the lenvatinib salvage group.
Comparison of Kaplan–Meier estimates of OS after disease progression with first-line sorafenib treatment with or without lenvatinib salvage therapy in (
Clinical Features of 73 Patients with Disease Progression After First-Line Sorafenib Treatment
ECOG PS, Eastern Cooperative Oncology Group Performance Status; FTC, follicular thyroid carcinoma; PDTC, poorly differentiated thyroid carcinoma; PTC, papillary thyroid carcinoma.
AEs with sorafenib and lenvatinib
During the median 12 months (5–28 months) of sorafenib treatment, the daily mean maintenance dose of sorafenib was 670 ± 136 mg. AEs occurred in 94 of 98 patients (96%), of whom 40 (41% of the total 98) had grade 3 or 4 AEs (Supplementary Table S4). Drug interruptions, reductions, and withdrawals due to AEs occurred in 19 (19%), 52 (53%), and 21 patients (21%), respectively.
The mean starting dose of lenvatinib was 17 ± 4.9 mg, and the daily median maintenance dose was 10 mg (10.0–11.0 mg). AEs occurred in 29 (91%) of the 32 patients, of whom 13 (41%) had grade 3 or 4 AEs (Supplementary Table S5). Drug interruptions, reductions, and withdrawals due to AEs occurred in 4 (13%), 10 (31.3%), and 6 patients (19%).
Discussion
This extended Korean multicenter study in a real-world clinical setting reports survival with sorafenib as well as the role of lenvatinib as salvage treatment in patients with progressive RAI-refractory DTC. The median OS after beginning sorafenib was 41.5 months. Lenvatinib salvage therapy conferred further significant survival benefits in patients whose disease progressed after first-line sorafenib treatment.
Our study suggests that sorafenib is a clinically effective treatment option for progressive RAI-refractory DTC. In this extended study, the median PFS with first-line sorafenib treatment was 13.7 months, longer than the median of 10.8 months in the DECISION trial (9). In that trial, the median OS was not reached in the study period, and it did not differ significantly between the sorafenib and placebo groups (9). The median OS with sorafenib in our extended study was 41.5 months. Considering that median OS of progressive RAI-refractory DTC is around 2.5 to 3.5 years (6,16,17), it is thus difficult to conclude from our results whether sorafenib indeed confers a survival benefit. Longer observations in real-world clinical settings are needed to conclusively demonstrate better survival with sorafenib.
To our knowledge, this is the first study to demonstrate survival benefits with lenvatinib salvage therapy following first-line sorafenib treatment in the clinical setting. Lenvatinib is a TKI with multiple targets, including VEGFRs 1–3, FGFRs 1–3, RET, and cKIT (18). It is approved for treatment of locally recurrent or metastatic progressive RAI-refractory DTC by the U.S. FDA and the EMA. The SELECT trial proved the efficacy of lenvatinib in progressive RAI-refractory DTC by demonstrating a 15-month median PFS, and 25% of patients in the lenvatinib group had prior treatment regimen with a TKI therapy (11). This indicated the possibility that lenvatinib could be used as second-line therapy for patients in whom sorafenib has been unsuccessful (12). In Korea, second-line lenvatinib therapy is the only approved option for patients with progressive disease after sorafenib. Because there was a window period before lenvatinib's approval and reimbursement were confirmed, we could not start second-line lenvatinib in all patients in our study after progression with sorafenib was documented. Lenvatinib as salvage therapy produced a 72% reduction in the risk of death during follow-up, a risk reduction that remained when analyzing only patients with good performance (ECOG PS1–2). Although our study did not reach the median OS due to relatively short follow-up, our findings did suggest a true clinical survival benefit with lenvatinib salvage therapy. Further studies are needed to confirm the benefits of sequential TKI therapy in patients with progressive RAI-refractory DTC. Our study suggests there indeed is a benefit, although questions on the order of sequential therapies (sorafenib to lenvatinib or lenvatinib to sorafenib) and the optimal timing of a second agent remain to be resolved. As some tumors have accelerated tumor progression or “flare-up” when a TKI is discontinued, a subsequent TKI should be considered without hesitation (19,20).
Deciding the optimal timing to initiate TKI therapy in progressive RAI-refractory DTC is very difficult because of the risk of AEs and the high cost of the drugs (21). Several guidelines and expert consensus generally agree that a TKI should be given to patients with metastatic, rapidly progressive, symptomatic, or life-threatening disease (5,7,12). In our study, disease-related symptoms and larger tumor size at the time sorafenib was begun were associated with poor survival. There is a possibility of length-time bias, that is, an overestimation of survival duration due to the relative excess of cases detected that are slowly progressing. However, these findings support the need to begin TKI therapy before the onset of disease-related symptoms or the tumor grows larger. Therefore, regular monitoring every six months to evaluate symptoms and tumor size is essential for patients with watchful waiting before starting a TKI (10). The recent concept of tumor volume doubling time might be helpful in deciding the optimal time to initiate a TKI (22,23). Further clinical research is needed to define individualized approaches to starting TKI therapy in patients with RAI-refractory DTC.
In the first report of our sorafenib study, factors associated with a better PFS were the absence of disease-related symptoms, lung-only metastases, a daily maintenance dose ≥600 mg, and a Tg reduction ≥60% (10). However, in this extended sorafenib study, patterns of metastasis, the sorafenib maintenance dose, and the best change in the serum Tg level were not associated with OS. The response to TKI therapy may vary according to metastases (24,25). Previous studies have reported that pulmonary metastases respond well to TKIs (10,25). The degree of reduction in serum Tg levels with TKI therapy seems to be related to the overall response to the drug (9,10). However, factors predictive of PFS might be different than those associated with OS, and the best response could not be correlated with improved survival.
The AEs of sorafenib and lenvatinib in our study were generally consistent with the previously known safety profiles of each TKI (5,7,10 –12). The most common AEs were hand/foot skin reaction (76%) with sorafenib and hypertension (56%) with lenvatinib, consistent with previous trials (9,11). Discontinuation of drugs due to AEs occurred more frequently in the real-world clinical setting compared with clinical trials (sorafenib: 21% vs. 18.8% and lenvatinib: 19% vs. 14.2%) (9,11). The proportion of patients with severe AEs (grades 3–4) in our study was similar between sorafenib (41%) and lenvatinib (41%). Most were mild and manageable with standard clinical intervention or dose modification.
The starting dose of lenvatinib was lower than in the clinical trials (17 vs. 24 mg) (11). In the subgroup analysis of the SELECT trial, Japanese patients showed more dose reductions due to adverse events; however, no difference in lenvatinib exposure was found between Japanese patients and the overall SELECT population after adjusting for body weight (26). These findings suggest that starting doses can be recommended based on the patient's body weight, sex, or performance status. Due to concerns about AEs, an international phase 2 clinical trial is underway to compare the starting dose of lenvatinib at 24 mg and 18 mg (27).
This study has several limitations. First, there is a possibility of selection bias due to its retrospective design. Second, due to the relatively short period of follow-up for lenvatinib salvage treatment, the median OS was not reached. Third, some patients were not included in the analysis of the lenvatinib salvage therapy, again introducing the possibility of selection bias. Future large, well-designed cohort studies are needed to confirm the efficacy of lenvatinib as salvage therapy. Finally, molecular profiles were available for only 16 patients so that we could not evaluate treatment outcomes according to mutational status. Given that certain molecular profiles are associated with prognosis in thyroid cancer, the response to and outcome of molecular-targeted therapy may differ depending on mutational status (28,29). Despite these limitations, this study has some strengths. We demonstrate the median OS with sorafenib treatment in the real-world clinical setting. In addition, we show preliminary findings suggesting the benefits of lenvatinib as salvage treatment after progression on sorafenib.
In conclusion, the median OS of patients with progressive RAI-refractory DTC treated with sorafenib was 41.5 months. The absence of disease-related symptoms and a smaller tumor burden at the time of sorafenib administration were associated with a better OS. Lenvatinib salvage treatment was associated with improved survival in patients with disease progression after first-line sorafenib treatment in a real-world clinical setting.
Footnotes
Author Disclosure Statement
Y.K.S. and W.B.K. have received consultation fees and honoraria from Bayer and Eisai. For all other authors, no competing financial interests exist.
Funding Information
No funding was received for this article.
Supplementary Material
Supplementary Figure S1
Supplementary Table S1
Supplementary Table S2
Supplementary Table S3
Supplementary Table S4
Supplementary Table S5