The Efficacy and Safety of Anlotinib in Neoadjuvant Treatment of Locally Advanced Thyroid Cancer: A Single-Arm Phase II Clinical Trial

Abstract

Background:

Surgery is the primary treatment for locally advanced thyroid cancer. For some cases, R0/R1 resection could not be achieved at initial diagnosis and neoadjuvant treatment would be an option. Anlotinib is a multitarget tyrosine kinase inhibitor, which demonstrated antitumor activity in radioiodine-refractory differentiated thyroid cancer and medullary thyroid cancer. We aimed to evaluate the efficacy and safety of anlotinib in locally advanced thyroid cancer in the neoadjuvant setting.

Methods:

This single-arm phase II study investigated the efficacy and safety of anlotinib (12 mg orally daily, 2 weeks on/1 week off) for 2–6 cycles in patients with locally advanced thyroid cancer in the neoadjuvant setting. The key eligibility criteria included age 14–80 years old; locally advanced thyroid cancer that would benefit from surgery, and at least one measurable lesion. Operable patients received surgery after neoadjuvant treatment. The primary endpoint was objective response rate (ORR).

Results:

A total of 13 patients were enrolled and received an average of 3.5 cycles of anlotinib treatment. The ORR of anlotinib was 76.9% (95% confidence interval: 46.2–95.0%). The R0/R1 resection rate in the intent-to-treat population was 61.5% and in the per-protocol population was 72.7%. The median time to response was 61.5 days, and the disease control rate at 18 weeks was 92.3%. No patients had blood transfusion or tracheotomy. Most adverse events (AEs) were grade 1 or 2 and tended to discontinue when neoadjuvant treatment ceased. Common AEs of all grades were hypertension (76.9%), hypertriglyceridemia (69.2%), proteinuria (53.8%), thyrotropin increase (53.8%), cholesterol elevation (53.8%), and hand–foot syndrome (38.5%).

Conclusions:

Anlotinib demonstrated antitumor activity in the neoadjuvant treatment and the majority of patients achieved R0/R1 resection. AEs were consistent with the known anlotinib AE profile. These results suggest that anlotinib neoadjuvant treatment represents a new option for locally advanced thyroid cancer.

Clinical Trial Registration Number: NCT04309136.

Introduction

Thyroid cancer is one of the most commonly seen endocrine malignancies, and the primary treatment of thyroid cancer is surgery. Although early-stage thyroid cancer has excellent prognosis after surgical resection, there are still ∼5% locally advanced cases that require extensive surgery and have high risk of recurrence (1). Local-regional failure of these patients may cause hemorrhage, airway obstruction, infection, and other fatal conditions (2,3). Therefore, complete surgical resection would improve survival in locally advanced thyroid cancer patients (4). As thyroid cancer is not sensitive to chemotherapy nor radiotherapy, there is limited evidence of neoadjuvant treatment in locally advanced thyroid cancer (5,6). Although rising numbers of targeted regimens are used to treat locally advanced and metastatic thyroid cancer, the neoadjuvant targeted treatment is confined to case reports and case series (7).

The most important genetic alternations identified in thyroid cancer include BRAF^V600E point mutations in papillary thyroid carcinoma, RET mutations in medullary thyroid carcinoma, and RAS point mutations in follicular and poorly differentiated thyroid carcinoma (8,9). Besides, angiogenesis is a common carcinogenic pathway in the development of thyroid cancer. Vascular endothelial growth factor (VEGF) and its receptors (VEGFR) are frequently overexpressed in thyroid cancer cells (10,11). Hence, multitarget tyrosine kinase inhibitors (mTKIs) are the clinical targeted treatment for locally advanced and metastatic thyroid cancers (12 –14). Anlotinib is an mTKI, targeting VEGFR, fibroblast growth factor receptor, and c-Kit (15,16). It demonstrated broad antitumor activity against a variety of xenograft models in preclinical data (17,18). In medullary thyroid carcinoma, anlotinib showed an objective response rate (ORR) of 48.4%, and prolonged progression-free survival (PFS) compared with placebo (20.7 months vs. 11.1 months, p = 0.029) (19). In radioiodine-refractory differentiated thyroid carcinoma, anlotinib also showed an ORR of 59.21%, and prolonged PFS compared with placebo (40.5 months vs. 8.4 months, p < 0.001) (20). In the current study, we aimed to evaluate the efficacy and safety of anlotinib in locally advanced thyroid cancer in the neoadjuvant setting.

Materials and Methods

Study design and patients

This was a single-center, single-arm, phase II clinical trial. Key eligibility criteria included: age 14–80 years old; locally advanced thyroid cancer that would benefit from surgery; differentiated, medullary, poorly differentiated, and anaplastic thyroid cancer confirmed by core-needle biopsy, surgical biopsy, or prior surgery; Eastern Cooperative Oncology Group (ECOG) performance status 0–1; at least one measurable lesion by computed tomography (CT) scan according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1; and adequate bone marrow, renal, hepatic, and cardiac function checked within seven days before the start of the neoadjuvant treatment. Locally advanced thyroid cancer was defined as (i) unresectable thyroid cancer with extensive disease and multiple-organ invasion; or (ii) thyroid cancer and/or local-regional metastatic lymph node invaded at least one of the structures (trachea, esophagus, larynx, anterior vertebral fascia, brachial plexus) or encased at least one of the vessels (common carotid artery, mediastinal vessels), and R0/R1 resection might not be achieved based on CT assessment. The eligibility of locally advanced thyroid cancer patients was determined by a panel consisting of 5 high-volume surgeons from the Department of Head and Neck Surgery, Fudan University Shanghai Cancer Center, who performed more than 400 thyroid cancer surgeries per year.

Key exclusion criteria were as follows: patients who had received prior antiangiogenic agents; external radiation therapy or ¹³¹I therapy within the past 3 months; other uncontrolled/under treatment malignancies; any severe and/or uncontrolled illness; received major surgical treatment or traumatic injury within 28 days before enrollment; CT assessment indicated that tumor had invaded into important blood vessels that might cause fatal bleeding; patients with any signs or history of bleeding regardless of severity; and bleeding event ≥ CTCAE level 3 within 4 weeks before enrollment.

The trial was approved by the Fudan University Shanghai Cancer Center Institutional Review Board and conducted in accordance with guidelines for Good Clinical Practice and the Declaration of Helsinki. All patients provided written informed consent.

Procedures

Enrolled patients received oral anlotinib 12 mg once daily, 2 weeks on/1 week off (3 weeks as a cycle) until surgery, disease progression, death, unacceptable toxicity, noncompliance, or withdrawal of consent. CT assessment was performed every two cycles, and surgery was performed in operable patients. Adverse events (AEs) were graded according to the National Cancer Institute's CTCAE v4.0. Patients were followed up for safety for 30 days following the last study treatment and then every 3 months for overall survival (OS).

The primary endpoint was ORR according to RECIST v1.1. However, we did not perform confirmatory imaging since operable patients received surgery after 2–6 cycles of neoadjuvant treatment. The secondary endpoints were R0/R1 resection rate, disease control rate (DCR) at 18 weeks, OS, and safety.

Statistical analyses

Assuming the minimum ORR of 5% and anticipated ORR of 30%, the Simon two-stage testing procedure was applied with type I error of 10% and type II error of 20% (α = 0.1, β = 0.2). Five patients were enrolled in the first stage. If at least 1 patient had complete response (CR) or partial response (PR), 7 patients were further enrolled in the second stage. If 2/12 patients had CR or PR, the result would be positive. A surplus recruitment of one patient was allowed.

The ORR was defined as proportion of patients who had a CR or PR. R0/R1 resection rate was defined as the proportion of patients who had complete resection of all tumor cells or only microscopic residue was present. The DCR was defined as the proportion of patients who had achieved CR, PR, or stable disease (SD) at 18 weeks. The OS was measured from the date of treatment initiation to the date of death from any cause. The ORR, DCR and R0/R1 resection rate were reported with 95% confident intervals (CIs). Summary statistics were provided for safety outcomes in all patients who received at least one dose of study medication.

Results

Baseline features

From September 2019 to July 2020, 13 eligible patients were recruited to this study. Baseline characteristics are listed in Table 1. The median age was 60.0 years (range: 50–77 years). A total of 7 (53.8%) cases were newly diagnosed thyroid cancer, 6 (46.2%) had previous surgery, and 2 (15.4%) had radioactive iodine treatment. None of the patients had chemotherapy or radiotherapy.

Table 1.

Baseline Features of Enrolled Patients

Characteristic	n	%
Age, median (range), years	60.0 (50–77)
Sex
Female	10	76.9
Male	3	23.1
ECOG PS
0	11	84.6
1	2	15.4
Pathology
Papillary thyroid cancer	11	84.6
Papillary+poorly differentiated thyroid cancer	1	7.7
Follicular thyroid cancer	1	7.7
Structure involved on initial CT evaluation
Recurrent laryngeal nerve	6	46.2
Trachea	6	46.2
Esophagus	10	76.9
Common carotid artery	8	61.5
Mediastinal vessels	3	23.1
Pyriform fossa	2	15.4
Parapharyngeal tissue	2	15.4
Prevertebral fascia	1	7.7
cT stage
X	1	7.7
I	2	15.4
IVA	8	61.5
IVB	2	15.4
cN stage
0	1	7.7
IA	1	7.7
IB	11	84.6
cM stage
0	8	61.5
I	5	38.5
AJCC 8th cTNM stage
I	2	15.4
II	4	30.8
III	3	23.1
IV	4	30.8
Distant metastatic site
Lymph nodes	3	23.1
Lung	2	15.4

CT, computed tomography; ECOG, Eastern Cooperative Oncology Group; PS, performance status.

All patients started treatment according to the protocol. The average neoadjuvant treatment cycle was 3.5 (range: 2–6 cycles). Two (15.4%) patients were not operable after neoadjuvant treatment, 2 (15.4%) patients withdrew the consent, and the rest 9 (69.2%) patients received surgery (Fig. 1). In 9 patients who had surgery, 6 received ¹³¹I treatment and 3 were planning to receive ¹³¹I treatment at the time of the last follow-up.

FIG. 1.

Swimmer's plot of patients' treatment course. FTC, follicular thyroid cancer; PDTC, poorly differentiated thyroid cancer; PTC, papillary thyroid cancer.

Efficacy

The study met its primary endpoint, showing an ORR of 76.9% (CI 46.2–95.0), with 10 patients had PR, 2 had SD, and 1 had progressive disease (PD) (Fig. 2). The median best percentage change in the sum of the target lesion diameter was 33.1% (range: 30.9–45.5%) in PR patients. The median time to response was 61.5 days (range: 35–111 days). The DCR at 18 weeks was 92.3% (CI 64.0–99.8), and the OS was 100% with a median follow-up time of 203 days (range: 178–477 days).

FIG. 2.

Waterfall plot showing best percentage change from baseline in the sum of the longest diameters of target lesions.

Toxicity

All patients had at least one AE of any grade. AEs were predominantly grade 1 or 2 (Table 2) and tended to discontinue when neoadjuvant treatment deceased. The most common AEs of all grades were hypertension (76.9%), hypertriglyceridemia (69.2%), proteinuria (53.8%), thyrotropin increase (53.8%), cholesterol elevation (46.2%), and hand–foot syndrome (38.5%). The most common grade 3 AEs included hypertension (53.8%), hypertriglyceridemia (7.7%), and lung infection (7.7%). No grade 4 or 5 AEs were recorded. Dose reduction occurred in 1 (7.7%) patient.

Table 2.

Adverse Events Occurring in ≥15% Patients

Adverse event	Any grade^a		Grade 1/2		Grade 3
Adverse event	N	%	N	%	N	%
Hypertension	10	76.9	3	23.1	7	53.8
Hypertriglyceridemia	9	69.2	8	61.5	1	7.7
Proteinuria	7	53.8	7	53.8	0	0.0
TSH increased	7	53.8	7	53.8	0	0.0
Cholesterol high	6	46.2	6	46.2	0	0.0
Hand–foot syndrome	5	38.5	5	38.5	0	0.0
Hyperuricemia	5	38.5	5	38.5	0	0.0
AST increase	5	38.5	5	38.5	0	0.0
Blood bilirubin increased	4	30.8	4	30.8	0	0.0
Mucositis oral	3	23.1	3	23.1	0	0.0
PLT decreased	3	23.1	3	23.1	0	0.0
Cough	2	15.4	2	15.4	0	0.0
Hyperglycemia	2	15.4	2	15.4	0	0.0
Creatinine increased	2	15.4	2	15.4	0	0.0
Voice alternation	2	15.4	2	15.4	0	0.0

No grade 4 or 5 adverse events were observed.

AST, aspartate transaminase; PLT, platelet; TSH, thyrotropin.

Surgery

Eight PR patients and 1 SD patient received surgery, of whom 8 had R0/R1 resections and 1 had R2 resection. Two PR patients refused to have surgery. And the rest 1 SD patient and 1 PD patient were not operable after neoadjuvant treatment. The R0/R1 resection rate in intent-to-treat (ITT) population was 61.5% (CI: 31.6–86.1%) and in per-protocol (PP) population was 72.7% (CI 39.0–94.0%) (Fig. 3).

FIG. 3.

Typical CT scans of patients before and after neoadjuvant treatment. Patient A: a 56-year-old PTC patient who had 4 previous surgeries and 3 radioactive iodine treatments, presented with right upper mediastinum metastasis, encasing mediastinal vessels. The PR was achieved after six cycles of neoadjuvant treatment. Patient B: a 61-year-old patient who had 1 previous surgery, presented with left thyroid PTC, superior vena cava tumor thrombus, and lung metastasis. The PR was achieved after two cycles of neoadjuvant treatment. And the tumor thrombus decreased from 2.4 to 0.8 cm. Patient C: a 58-year-old patient was newly diagnosed with locally advanced PTC. The target lesions decreased 37.7% after 6 cycles of neoadjuvant treatment. CT, computed tomography; PR, partial response.

In patients treated with surgery, total thyroidectomy and central neck dissection were performed in 8 (88.9%) patients and lateral neck dissection was performed in 8 (88.9%) patients. Two patients had open-chest surgery to resect right upper mediastinum metastasis and superior vena cava tumor thrombus, respectively. Three (33.3%) patients had recurrent laryngeal nerve resection, 2 (22.2%) had esophagus repair, 1 (11.1%) had pyriform fossa repair, 1 (11.1%) had superior vena cava repair, and 1 (11.1%) had both sympathetic nerve and prevertebral fascia resection due to tumor invasion. All the repair procedures were attributed by the disease instead of drug toxicity. No patients had blood transfusion or tracheotomy. The median time from last dose of treatment to surgery was 17 days (range: 7–29 days). The median postoperative hospitalization time was 6 days (range: 3–13 days), and 4 patients were transferred to intensive care unit (ICU) with a median of 2 days (range: 1–7 days) of ICU stay.

Discussion

To the best of our knowledge, this is the first clinical trial to evaluate the efficacy and safety of targeted therapy in the neoadjuvant setting for locally advanced thyroid cancer. While other clinical trials focused on the targeted therapy for inoperable thyroid cancer, we integrated targeted therapy with surgery and offered a new insight into the treatment of locally advanced thyroid cancer.

In our study, anlotinib showed an ORR of 76.9% (CI 46.2–95.0%) in the neoadjuvant setting, while in previous series, the ORR was 59.2% and 48.4% in radioiodine-refractory differentiated thyroid cancer and medullary thyroid cancer, respectively (19,20). Compared with their series, patients in our study were more likely to be treatment-naive, having better ECOG scores, less distant metastasis, and less dose reduction. These features may contribute to a potentially better response of anlotinib treatment. The overall R0/R1 resection rate was 61.5% in ITT population and 72.7% in PP population, representing a high R0/R1 resection rate in locally advanced thyroid cancer.

The safety profile of neoadjuvant treatment was similar to previous reports (19 –21). The majority of AEs were manageable, and most of which were asymptomatic and reversible. However, hypertension was the most commonly seen AE of all grades and grade 3. Careful blood pressure control is required during treatment and in the perioperative period. Interestingly, although anlotinib was an mTKI targeting angiogenesis pathway, we did not observe increased bleeding during surgeries.

The first report of neoadjuvant targeted treatment of locally advanced thyroid cancer was published in 2010 (22). The patient who had unresectable medullary thyroid cancer was treated with sunitinib for 19 months before surgical resection. Other regimens used for medullary thyroid cancer included lenvatinib and selpercatinib, the RET-specific inhibitor, and resulted in complete surgical resection and decrease in calcitonin (23,24). Lenvatinib and sorafenib were used in neoadjuvant treatment of locally advanced papillary thyroid cancer in several case reports (25 –29). The duration of neoadjuvant treatment varied from 4 to 14 months, and the reduction of tumor size varied from 56% to 84.3%, followed by complete surgical resection. In BRAF-mutated anaplastic thyroid cancer, dabrafenib plus trametinib was a neoadjuvant option and offered 100% local-regional control in short-time follow-up (7,30). Nevertheless, these case reports and case series were highly selected and may overestimate the effect of neoadjuvant treatment.

There is no standard therapy for potentially operable locally advanced thyroid cancer. Based on the results from the current clinical trial and previous studies, we proposed that neoadjuvant treatment should be considered under the following scenario: (i) For inoperable patients, neoadjuvant therapy offers chance of surgery; (ii) For patients who are expected to have R2 resection, complete resection is possible after neoadjuvant surgery; (iii) Tumor shrinkage enables the preservation of vital organ functions and improvement of quality of life; (iv) For differentiated thyroid cancer with both locally advanced and metastatic diseases, thyroidectomy after neoadjuvant treatment makes radioactive iodine treatment possible.

There are several limitations of our study: (i) Although we aimed to recruit all pathological types of thyroid cancer, we were only able to recruit differentiated thyroid cancer in the study. As a result, we could not evaluate the efficacy of neoadjuvant treatment in medullary or anaplastic thyroid cancer; (ii) It is difficult to evaluate whether R0/R1 resection would be achieved based on CT. The evaluation is subject to surgeon's experience as well as surgical technique; (iii) In this single-arm study, we were not able to directly determine the benefit of neoadjuvant treatment since we did not have a control group who did not receive neoadjuvant treatment; (iv) Another limitation is the short follow-up time in these patients. We were unable to determine the long-term outcome in patients treated with neoadjuvant therapy based on current data. Future studies in larger sample size are warranted to specify these questions.

Conclusions

In conclusion, anlotinib demonstrated antitumor activity in the neoadjuvant treatment in locally advanced thyroid cancer and the majority of patients achieved R0/R1 resection. AEs were consistent with the known anlotinib AE profile. These results suggest that anlotinib neoadjuvant treatment represents a new option for locally advanced thyroid cancer.

Footnotes

Acknowledgment

The result of this trial was presented on the 2021 ASCO meeting.

Authors' Contributions

Conception and design: N.-s.H. and Y.W. Administrative support: Q.-h.J. and Y.W. Provision of study materials or patients: J.X., W.-j.W., Q.G., Z.-w.L., G.-h.S., and Y.-l.W. Collection and assembly of data: N.-s.H., J.X., W.-j.W., and J.-y.C. Data analysis and interpretation: N.-s.H., J.X., and W.-j.W. Article writing: all authors. Final approval of article: all authors.

Author Disclosure Statement

No competing financial interests exist.

Funding Information

This work was supported by the National Natural Science Foundation of China (81902721 to N.-s.H., 82072951 to Y.W.), Shanghai Sailing Program (19YF1409300 to N.-s.H.), and Science and Technology commission of Shanghai Municipality (19411966600 to Y.W.).

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