Treatment of RET-Positive Advanced Medullary Thyroid Cancer with Multi-Tyrosine Kinase Inhibitors—A Retrospective Multi-Center Registry Analysis

Abstract

Background: RET (rearranged during transfection) variants are the most prevalent oncogenic events in medullary thyroid cancer (MTC). In advanced disease, multi-tyrosine kinase inhibitors (MKIs) cabozantinib and vandetanib are the approved standard treatment irrespective of RET status. The actual outcome of patients with RET-positive MTC treated with MKIs is ill described. Methods: We here retrospectively determined the RET oncogene variant status with a targeted DNA Custom Panel in a prospectively collected cohort of 48 patients with advanced MTC treated with vandetanib and/or cabozantinib at four German referral centers. Progression-free survival (PFS) and overall survival (OS) probabilities were estimated using the Kaplan-Meier method. Results: In total, 44/48 (92%) patients had germline or somatic RET variants. The M918T variant was found in 29/44 (66%) cases. In total, 2/32 (6%) patients with a somatic RET variant had further somatic variants, while in 1/32 (3%) patient with a germline RET variant, additional variants were found. Only 1/48 (2%) patient had a pathogenic HRAS variant, and no variants were found in 3 cases. In first-line treatment, the median OS was 53 (95% CI (95% confidence interval), 32–NR (not reached); n = 36), and the median PFS was 21 months (12–39; n = 33) in RET-positive MTC patients. In second-line treatment, the median OS was 18 (13–79; n = 22), and the median PFS was 3.5 months (2–14; n = 22) in RET-positive cases. Conclusions: RET variants were highly prevalent in patients with advanced MTC. The treatment results in RET-positive cases were similar to those reported in unselected cohorts.

Efficacy and safety of tyrosine kinase inhibitors for advanced metastatic thyroid cancer: A systematic review and network meta-analysis of randomized controlled trials

“…Cabozantinib is currently being studied in clinical trials for a variety of tumor types, including medullary and differentiated thyroid cancer, prostate cancer, hepatocellular carcinoma, renal cell carcinoma, and other diseases. [38][39][40][41][42] It is generally well tolerated, does not easily develop drug resistance, and has good effects in many different types of tumors. [38][39][40][41][42] At the same time, cabozantinib has better safety in clinical use because of the lower probability of SAEs.…”

“…[38][39][40][41][42] It is generally well tolerated, does not easily develop drug resistance, and has good effects in many different types of tumors. [38][39][40][41][42] At the same time, cabozantinib has better safety in clinical use because of the lower probability of SAEs. The effectiveness and safety of comprehensive drugs make cabozantinib a better choice than other drugs for the treatment of RR-TC.…”

Use of Neoadjuvant Vandetanib in Aggressive Pediatric Medullary Thyroid Carcinoma

“…Studies have shown its efficacy in slowing disease progression and improving mortality. [12][13][14] It is currently generally reserved for a postoperative treatment, especially in the case of persistent or recurring MTC. 15 With our goal of reducing tumor size before surgery, a multityrosine kinase inhibitor was opined to be the preferred option over RET-specific kinase inhibitors given the more robust previous experience with similar regimens at our institution.…”

Spontaneous and Treatment-Related Changes of Serum Calcitonin in Medullary Thyroid Cancer: Long-Term Experience in a Patient With Multiple Endocrine Neoplasia Type 2B

“…Multikinase inhibitors (sorafenib, sunitinib, vandetanib, and cabozantinib) have achieved moderate efficacy in MTC treatment, as reflected by increased PFS. [12][13][14][15][16][17] However, evaluating radiological response using RECIST 1.1 criteria might be extremely difficult in advanced MTC since radiological improvement may become apparent only after several years. [17][18][19][20] Our patient's long disease course represents typical difficulties in the real-life management of MTC in MEN2 patients.…”