Selpercatinib Prompts Dramatic Response in RET Fusion-Positive Anaplastic Thyroid Carcinoma

The highly selective RET inhibitor selpercatinib (LOXO-292) achieved an objective response rate (ORR) of 69% in patients with RET-mutant medullary thyroid cancer and those with other RET fusion-positive thyroid cancers in the phase I/II LIBRETTO-001 trial (NCT03157128), which was considered both substantial and durable anti-tumor activity. A case study of a LIBRETTO-001 patient with CCDC6-RET gene fusion-positive anaplastic thyroid carcinoma (ATC) and biopsied tumor metastasis who responded dramatically to selpercatinib was recently published in Thyroid.^1,2

“The optimal diagnostic strategy to identify tumors harboring RET gene fusions, RET point mutations, or other actionable driver mutations in malignancies, including ATC, is a broad-based next-generation sequencing (NGS) approach combining analysis of both tumor DNA and RNA,” the authors wrote, led by Dora Dias-Santagata, PhD, of Massachusetts General Hospital. “[In this case] the detection of an expressed CCDC6-RET gene fusion in a tumor metastasis by RNA-based NGS suggested that RET inhibition might be an effective treatment option.²”

In June 2017, a 73-year-old man received surgery and iodine-131 for locally advanced papillary thyroid carcinoma (PTC) containing a “minor component” of ATC. He later developed biopsy-confirmed ATC distant metastases that progressed on cytotoxic chemotherapy.

When the patient was referred to Massachusetts General Hospital the following year, the authors conducted immunohistochemistry staining, which was positive for TTF-1, keratin AE1/3/CAM5.2, and CK19, weakly positive for PAX8, present in the ATC component, and negative for BRAFV600E.

The authors then conducted molecular testing consisting of both DNA-based and RNA-based NGS of a mediastinal lymph node metastasis that had been resected along with the primary tumor. They reported that the tumor in this metastasis had features of a tall cell variant of PTC and also included scattered cells with atypical features comprising 10-15% of the total tumor.

According to the NGS analysis, the tumor was negative for a BRAF mutation, but harbored putatively pathogenic variants in TP53, the TERT promoter, and variants of uncertain clinical significance in PTCH1. “The variants detected in this lymph node met (composed primarily of PTC with rare, scattered atypical cells) had allelic frequencies of 10-15%, consistent with subclonality,” they wrote. “These results suggest that the mutations typically associated with a more aggressive tumor phenotype (i.e., TP53 and TERT) were present in a small fraction of tumor cells, possibly in the rare population of atypical cells with high-grade features.”

Immunohistochemical staining suggested that TP53 inactivation was associated with the ATC component as the papillary-rich areas of this lymph node metastasis were largely positive for p53 expression (consistent with wild-type TP53), with occasional negative cells. However, a local metastasis collected 8 months after surgery consisted almost entirely of anaplastic carcinoma cells and was negative for p53 IHC, which was consistent with the mutant TP53 gene. “Of particular note, the RNA-based NGS fusion assay showed that the PTC-rich lymph node metastasis expressed fusion transcripts derived from a CCDC6-RET gene fusion,” Dias-Santagata et al wrote.

The authors used FISH analysis with break-apart RET probes to confirm the presence of the RET gene rearrangement in the PTC component of the lymph node metastasis. They also confirmed the same in the ATC cells of the neck metastasis detected at the time of disease progression to the brain and lungs.

The authors noted that, although RET gene fusions were previously reported in ATC with mixed PTC components, it was not clear whether the ATC, PTC, or both components harbored the fusion, and RET fusions have not been identified in more recent ATC analyses. Dias-Santagata et al wrote, “The presence of a concomitant TP53 mutation predominantly in the ATC component is consistent with TP53 gene inactivation commonly observed in ATC but rarely in PTC.”

In May 2018, CT imaging of the patients’ tumor showed disease progression after one cycle of chemotherapy. The patient was offered and accepted participation in the LIBRETTO-001 trial. He received the recommended phase 2 dose of 160 mg by mouth twice daily. He tolerated selpercatinib well and experienced only grade 1 treatment-related adverse events (AEs).

After only 8 weeks of treatment, the patient’s measurable lung nodules had decreased by 40%, according to restaging CTs. Additionally, brain MRI showed a decrease in the size of the two previously treated brain lesions. After 19 months of treatment, the most recent restaging revealed ongoing shrinkage in the measurable lesions (-56.19% from baseline) and brain MRI showed a continued slight interval decrease in the size of the two treated metastases. He remains on treatment with no plans to discontinue it barring disease progression or worsening toxicity.

“Our molecular data together with a confirmed tumor response to the selective RET inhibitor LOXO-292, suggest that this patient’s ATC was driven by the identified CCDC6-RET gene fusion,” concluded Dias-Santagata et al. “This and the promising results from the ongoing phase I/II study of this agent highlight the importance of establishing diagnostic procedures to facilitate the routine clinical detection of somatic RET alterations in patients with thyroid cancer.”

According to a study update presented during the 2020 American Society of Clinical Oncology (ASCO) Virtual Scientific Program, the 73-year-old was still continued treatment with selpercatinib at 19 weeks.¹

_References:

_{1. Shah M, Sherman EJ, Robinson B, et al. Selpercatinib (LOXO-292) in patients with RET-mutant medullary thyroid cancer. J Clin Oncol 38: 2020 (suppl; abstr 3594). doi: 10.1200/JCO.2020.38.15_suppl.3594}

_{2. Dias-Santagata D, Lennerz JK, Sadow PM, et al. Response to RET-Specific Therapy in RET Fusion-Positive Anaplastic Thyroid Carcinoma. Thyroid. 2020. doi: 10.1089/thy.2019.0477.}