Lenvatinib for Anaplastic Thyroid Cancer

Background Lenvatinib has been approved by regulatory agencies in Japan, the United States, and the European Union for treatment of radioiodine-refractory differentiated thyroid cancer (RR-DTC). Thyroid cancer, however, is a clinically diverse disease that includes anaplastic thyroid cancer (ATC), the subtype associated with the highest lethality. Effective therapy for ATC is an unmet need. Patients and methods This phase 2, single-arm, open-label study in patients with thyroid cancer, including ATC, RR-DTC, and medullary thyroid cancer was conducted from 3 September 2012 to 9 July 2015. Patients received lenvatinib 24 mg daily until disease progression or development of unacceptable toxicity. The primary endpoint was safety, and the secondary endpoint was efficacy, as assessed by progression-free survival (PFS), overall survival (OS), and objective response rate. Results At data cutoff, 17 patients with ATC were enrolled. All experienced ≥1 treatment-emergent adverse event (TEAE). The most frequent TEAEs were decreased appetite (82%), hypertension (82%), fatigue (59%), nausea (59%), and proteinuria (59%). Of note, only one patient required lenvatinib withdrawal because of a TEAE, and this TEAE was considered unrelated to lenvatinib. The median PFS was 7.4 months [95% confidence interval (CI): 1.7–12.9], the median OS was 10.6 months (95% CI: 3.8–19.8), and the objective response rate was 24%. Conclusion In this study, lenvatinib demonstrated manageable toxicities with dose adjustments and clinical activity in patients with ATC. This clinical activity of lenvatinib warrants further investigation in ATC. ClinicalTrials.gov NCT01728623.

Patients and methods: This phase 2, single-arm, open-label study in patients with thyroid cancer, including ATC, RR-DTC, and medullary thyroid cancer was conducted from 3 September 2012 to 9 July 2015. Patients received lenvatinib 24 mg daily until disease progression or development of unacceptable toxicity. The primary endpoint was safety, and the secondary endpoint was efficacy, as assessed by progression-free survival (PFS), overall survival (OS), and objective response rate.
conclusion: In this study, lenvatinib demonstrated manageable toxicities with dose adjustments and clinical activity in patients with ATC. This clinical activity of lenvatinib warrants further investigation in ATC.

clinicalTrials.gov: NCT01728623.
Keywords: lenvatinib, anaplastic thyroid cancer, tyrosine kinase inhibitor, phase 2, clinical trial inTrODUcTiOn Thyroid cancer is a clinically diverse disease that can be classified into differentiated, medullary, and anaplastic thyroid cancer (ATC) subtypes. ATC is an undifferentiated tumor from the follicular epithelium and typically presents with a rapidly enlarging mass as well as dysphagia, neck pain, vocal cord paralysis, and dyspnea (1). Nearly half of all patients with ATC have metastatic disease at initial diagnosis (1). According to the American Joint Committee on Cancer, all patients diagnosed with ATC are classified with stage IV disease (2,3). Although the incidence is rare among thyroid cancers (1-2%), ATC represents an unmet medical need and is difficult to treat, with an associated mortality rate over 90% (4).
Current therapies for ATC have limited efficacy. Historically, doxorubicin has been considered the most effective treatment, with a response rate of ~20% (5,6). When combined with other chemotherapies, a higher response rate (50%) can be achieved, but the duration of response is often short (2-5 months) (7,8). A phase 2 trial of paclitaxel in patients with ATC reported an overall response rate (ORR) of 53%; another trial of carboplatin and paclitaxel in combination with fosbretabulin reported a non-significant increase in overall survival (OS) (9,10). Combination therapies have also been associated with substantial toxicities, including leukocytopenia, neutropenia, anemia, diarrhea, and vomiting (11).
This phase 2 study examines the safety and efficacy of lenvatinib in advanced thyroid cancer, including ATC. Although efficacy was not a primary objective, we highlight the efficacy outcome of patients with ATC in this report because encouraging preliminary evidence of antitumor activity was observed in this first trial of lenvatinib treatment for this disease.

Patients
Eligible patients were aged ≥20 years, had an Eastern Cooperative Oncology Group performance status of ≤2, systolic blood pressure ≤140 mmHg, diastolic blood pressure ≤90 mmHg and had histologically confirmed diagnosis of any of the specified advanced thyroid cancer subtypes (anaplastic, radioiodinerefractory differentiated, or medullary). Patients with ATC must have had evaluable target lesions per the Response Evaluation Criteria in Solid Tumors version 1.1, agreed to hospitalization in cycle 1, and were expected to live for ≥8 weeks after the first dose of study drug. Tumor samples from these patients were subjected to independent pathological review, where possible.
Exclusion criteria included concomitant brain metastases (unless previously treated and clinically stable for ≥1 month prior to screening), bleeding or thrombotic disorders, use of anticoagulants (e.g., warfarin), and proteinuria (urine protein levels of ≥1 g/24 h).

study Oversight
This study was sponsored by Eisai Co., Ltd., designed according to the Guidelines for Clinical Evaluation of Anticancer Drugs in Japan and conducted in accordance with the Declaration of Helsinki and local laws. All patients provided written informed consent.
The study and protocol were approved by the Institutional Review Board of each medical institution (National Cancer Center Hospital East, Kashiwa, Japan; The Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan; and the Kobe University Hospital, Kobe, Japan). The study is registered at http://clinicaltrials.gov (NCT01728623).
Statistical analyses were performed by Eisai Co., Ltd., and Takumi Information Technology Inc., statisticians.

study Design
This was a single-arm, open-label, multicenter, phase 2 study to evaluate the safety and efficacy of lenvatinib in patients with advanced thyroid cancer at three study sites in Japan from 3 September 2012 to 9 July 2015. Patients received treatment until progressive disease according to Response Evaluation Criteria in Solid Tumors version 1.1 or development of unacceptable toxicity. Lenvatinib was administered orally at 24 mg once daily on a 28-day continuous cycle. For patients with ATC, tumor assessments were performed at 4, 8, 12, and 16 weeks after the first dose, and every 8 weeks thereafter. Tumor responses were evaluated based on investigator assessment.
Because of historically poor OS, patients with ATC were followed every 4 weeks after treatment discontinuation. Enrollment for this study continued until lenvatinib was approved for unresectable thyroid cancer in Japan, and after approval continued as a post-marketing study until lenvatinib was commercially available at each site. The protocol was amended to include the post-marketing study, but the endpoints and analysis were not changed.

safety and efficacy analyses
The primary endpoint was the safety of lenvatinib in patients with advanced thyroid cancer, including adverse events (AEs), clinical laboratory results (including urinalysis, hematology, and blood chemistry), vital signs, weight, electrocardiography, and Eastern Cooperative Oncology Group performance status. The assessment of AEs were completed using the Medical Dictionary for Regulatory Activities, and AEs were graded using Common Terminology Criteria for AEs version 4.0.
The secondary endpoints included: PFS (defined as time from the date of first dose to first documentation of disease progression

Patients
Of the 60 patients screened, nine failed to meet inclusion or met exclusion criteria and 51 were enrolled [ Figure 1 (CONSORT diagram)]. There were 17 patients with ATC and results for this patient group are reported here. Tumor samples were available for 10 of these patients and all were retrospectively confirmed to be anaplastic by an independent pathologist. All 17 patients with ATC were included in efficacy and safety analyses. At data cutoff, four (17%) were on treatment, 12 (46%) discontinued because of disease progression, and one (6%) discontinued because of an AE that was deemed unrelated to lenvatinib treatment by the investigator (suicide attempt).
Patient baseline characteristics are summarized in Table 1. All patients were Asian (Japanese) with baseline Eastern Cooperative Oncology Group performance status of 0 or 1, except for two patients with a score of 2. The majority of patients were females (65%) and the median age was 65 years. Most patients (82%) had previous thyroid cancer surgery. Of these patients, seven (41%) had received previous chemotherapy, nine (53%) had received prior external radiotherapy, and two (12%) had not received any prior treatment.

safety
The median duration of lenvatinib treatment was 5.5 months (range: 0.7-33.1). All patients experienced ≥1 treatment-    Table 2. The most common grade 3 or 4 TEAE were hypertension (n = 5; 29%), decreased appetite (n = 3; 18%), and thrombocytopenia (n = 3; 18%). Serious AEs were reported in 13 patients. There were four fatal serious AEs that occurred within 30 days of the last dose of lenvatinib for this study, three of which occurred in patients with ATC. These three patients died of primary disease progression. All deaths were reported as unrelated to lenvatinib.
Clinical activity was observed in the majority of patients (Figure 2). Patients with ATC demonstrated a durable response to lenvatinib therapy throughout the course of the study (Figure 3). Further, the observed tumor shrinkage in these patients was continuous throughout treatment (Figure 4). These results are illustrated by computed tomography scans of a representative patient with ATC, which revealed remarkable tumor reduction at 24 and 72 weeks post-lenvatinib treatment compared with a baseline scan (Figure 5).

DiscUssiOn
In this phase 2 study, lenvatinib demonstrated a manageable safety profile and meaningful antitumor activity in patients with ATC. The safety profile reported here was comparable to that observed in the phase 2 trial of lenvatinib in medullary thyroid cancer, the phase 3 SELECT trial of lenvatinib in RR-DTC (15,21), and the Japanese subgroup analysis of the SELECT trial (22). Fatigue, decreased appetite, proteinuria, and hypertension were among the most frequent AEs observed, which are known class effects of vascular endothelial growth factor-targeted treatments (23). Toxicities were effectively managed with dose interruptions and reductions, as demonstrated by having only one patient  discontinue treatment because of an AE, which was considered unrelated to lenvatinib.
Responses were observed in all subtypes studied, and most patients experienced tumor shrinkage. We especially note the encouraging responses in patients with ATC, an aggressive form of thyroid cancer with no effective treatment options. This study and the SELECT trial (15) supported regulatory approval of lenvatinib for unresectable thyroid cancer in Japan, and lenvatinib is now commercially available there for the treatment of ATC (24).
As lenvatinib demonstrated striking efficacy in RR-DTC (15), we hypothesized that the ATC subtype may be sensitive to lenvatinib based on evidence that ATC tumors evolved from a background of differentiated thyroid cancer (25). Preclinical studies have also shown that lenvatinib reduced tumor growth in human ATC xenograft mouse models (19). The high vascularity of ATC tumors may also make them more responsive to angiogenesis inhibition by lenvatinib (26).
The ORR in patients with ATC on lenvatinib was noteworthy, with four (24%) patients achieving a partial response, 12 (71%) achieving stable disease, and eight (47%) with durable stable disease. In the context of other investigative or approved agents for the treatment of ATC, which have shown response durations from 2 to 27 months, lenvatinib demonstrated durable response and disease stabilization throughout the course of the study (8,27). Median OS in patients with ATC who received lenvatinib was 10.6 months, a particularly important finding given that previous studies have reported median OS of <8 months with the use of cytotoxic agents (4,28,29). AEs previously reported for paclitaxel included grade 1 stomatitis, alopecia, nausea, diarrhea, and fatigue, grade 2 nausea, gastritis, fever and netropenia, and grades 2−3 neuropathy (9). Doxorubicin is the only approved agent for ATC. Toxicities reported with doxorubicin treatment for advanced thyroid cancer included vomiting and hematologic toxicity (6). Because of the risk of developing cardiotoxicity with increasing total cumulative doxorubicin doses in excess of 400 mg/m 2 , prolonged doxorubicin treatment is problematic (30).
Although there were no bleeding events in the current study, post-marketing surveillance in Japan recently reported some cases of carotid artery and tumor hemorrhage due to rapid tumor shrinkage in patients with ATC treated with lenvatinib. This is further evidence of the antitumor activity of lenvatinib in patients with ATC, although careful administration is especially warranted for patients with tumor invasion of the carotid arteries.
This study has several limitations. First, it is a non-randomized study with a relatively small patient population. Second, there was no biomarker evaluation of tumor samples. Finally, the results for the ATC subgroup represent only one cohort of the study that was not designed to evaluate efficacy of lenvatinib for this subtype as a primary endpoint. In addition, association of biomarkers with efficacy of lenvatinib in ATC was not evaluated in this study, but this will be examined as an exploratory endpoint in ongoing phase 2 trials of lenvatinib in patients with ATC (NCT02657369, NCT02726503). Despite these limitations, the encouraging results observed in this study indicate potentially important improvements in the treatment of advanced thyroid cancer.
In conclusion, lenvatinib therapy demonstrated manageable toxicities, with meaningful and promising antitumor activity in patients with ATC. The results warrant further investigation into the clinical value of lenvatinib for this rare and aggressive malignancy.