Novel Multikinase Inhibitor Demonstrates Efficacy in Unresectable MTC

Promising efficacy was seen with anlotinib therapy in patients with unresectable locally advanced or metastatic medullary thyroid cancer (MTC) in the form of durable antitumor responses, according to the results of a Chinese phase II study recently published in the journalThyroid.

After a median follow-up of 9.8 months, the median progression-free survival (PFS) had not yet been reached, and the PFS rate was 85.5% at 48 weeks in the per-protocol assessment.

The investigators, led by Yongkun Sun, MD, of the Chinese National Cancer Center, noted that although vandetanib (Caprelsa) and cabozantinib (Cabometyx) have both been approved for the treatment of patients with MTC in the United States, neither have been approved for use in China due to a lack of clinical evidence in Chinese patients.

Anlotinib was selected for investigation as it inhibits VEGF/VEGFR signaling and suppresses PDGFRA/B, c-Kit, and RET activity. Additionally, promising efficacy was seen in a phase I trial of the novel multikinase inhibitor.

The single-arm phase II study of anlotinib was conducted in patients with unresectable locally advanced or metastatic MTC. Patients needed to have ECOG performance status of 0 to 2, calcitonin serum levels ≥500 pg/mL, and adequate organ function for enrollment, and no prior antiangiogenic treatment use was allowed.

The primary endpoint of the trial was PFS, and secondary endpoints included objective response rate (ORR), disease control rate (DCR) at 24 weeks, overall survival (OS), biochemical response, and safety.

Fifty-eight patients were enrolled at 8 sites in China and treated with once daily oral anlotinib at 12 mg with a schedule of 2 weeks on and 1 week off until disease progression, death, unacceptable toxicity, or withdrawal of consent.

The median age of all enrolled patients was 46.9 years (range, 22-71), 58.6% were male, and the majority had an ECOG score of 0 or 1. A total of 89.7% patients had metastatic disease with the lymph nodes being the most common metastatic site, followed by the lungs. Most patients (93.1%) had undergone surgery, but the majority had not received additional treatment; 25.9% had received prior radiation therapy, 12.1% had prior chemotherapy, and 15.5% had received another form of antitumor therapy.

“It is notable that approximately 80% of the patients included in this anlotinib study were naive to any systemic treatment, and they reflect a patient population with relatively indolent disease compared to those with progressive disease after one or more systematic treatment(s),” the investigators wrote in their report.

Only 55 patients were included in the per-protocol assessment as 2 lacked target lesions and 1 withdrew from the study within a week, but all 58 were treated and included in the full analysis and safety assessment.

The ORR in the full analysis population was 56.9%, consisting of all partial responses, and the DCR was 93.1%.

The PFS rate at 24 weeks was 92.2%; at 36 weeks, 87.8%; and at 48 weeks, 84.5%. The OS rate at 12 months was 89.7%; at 24 months, 78.6%; and at 36 months, 76.4%. Both the median PFS and median OS had not yet been reached as of the data cutoff.

The median duration of treatment was 12 months (range, 0.75-22.5).

Calcitonin response was evaluable in 51 patients at 12 weeks, and significant decreases from baseline were noted in 45 of these patients. Twenty-two of the 33 patients who had a partial response had significant calcitonin decreases.

Ten percent of patients discontinued treatment due to an adverse event (AE). The most common AEs were hand-foot syndrome in 79.3% of patients, hypertriglyceridemia in 46.6%, cholesterol elevation in 43.1%, fatigue in 41.4%, proteinuria in 39.7%, hypertension in 39.7%, sore throat in 37.9%, diarrhea in 34.5%, and anorexia in 34.5%.

“The high frequency of lipid metabolism dysfunction including hypertriglyceridemia and cholesterol elevations was consistent with safety data in the phase I study of anlotinib, most of which were asymptomatic and reversible. However, careful monitoring of lipids is required,” the study authors wrote.

The most common grade 3 AEs were hand-foot syndrome (8.62%), hypertension (5.17%), hypertriglyceridemia (3.45%), elevated cholesterol levels (3.45%), and an increased direct bilirubin (3.45%). Dose reductions were required in 20.7% of patients.

Asymptomatic grade 1/2 QTc prolongation was observed in 2 patients but normalized. Additionally, of 7 serious AEs observed, only 1 case of lacunar infarction was considered possibly related to anlotinib treatment. No grade 4/5 AEs were noted.

Reference:

Sun Y, Du F, Gao M, et al. Anlotinib for the treatment of patients with locally advanced or metastatic medullary thyroid cancer.Thyroid.2018;28(11):1455-1461. doi: 10.1089/thy.2018.0022.