Last year the Food and Drug Administration approved two selective RET inhibitors for treatment of solid tumours with altered RET gene.

RET (REarranged during Transfection) gene encodes a transmembrane glycoprotein receptor with tyrosine kinase activity, which plays a fundamental role in many physiological functions like early embryogenesis, development of the enteric nervous system, kidney morphogenesis, spermatogenesis, hematopoiesis and potentially immunomodulation.
In recent years, increasing evidences show that aberrantly activated RET is a critical driver of tumor growth and proliferation across a broad spectrum of tumors.
Oncogenic activation of RET occurs mainly in two different ways: 1) chromosomal rearrangement giving rise to chimeric fusion genes and 2) somatic or germline mutations. These gain-of-function alterations lead to the constitutive activation of RET, either via ligand-independent dimerization or by aberrant expression or activation of monomeric receptors.

Somatic RET rearrangements consist of in-frame fusions of 5?-end of partner genes with the 3?-end of RET containing its kinase domain.
RET rearrangements are reported to occur in 5%-10% of sporadic Papillary Thyroid Cancers (PTC), of which >90% of cases harbour the CCDC6-RET or NCOA4-RET fusion genes, and in 1%-2% of Non-Small Cell Lung Cancer (NSCLC), where the most frequent fusion partner is KIF5B. In NSCLC RET rearrangements tend to be mutually exclusive with other major lung cancer driver alterations such as KRAS and EGFR mutations, ALK and ROS1 fusions and usually associate with low tumour mutation burden and low PD-L1 expression.
RET rearrangement has also been described in other tumours such as colorectal cancer, breast cancer, Spitz tumours, ovarian and salivary gland cancers, where they account for <1% of the total cases of each of these cancer types.

Germline RET mutations are a pathognomonic hallmark of Multiple Endocrine Neoplasia Type 2 (MEN2), an autosomal dominant multitumour syndrome that is further subdivided into MEN2A (>90% of cases), MEN2B and familial medullary thyroid cancer (FMTC).
Extracellular domain mutations are more commonly observed in MEN2A and FMTC, with p.C634R being the most frequent variation (85% of MEN2A patients), whereas those in the kinase domain are pathognomonic of MEN2B, with p.M918T being the most common mutation (95% of cases).
Somatic RET mutations are observed in >65% of sporadic Medullary Thyroid Cancers (MTCs) and correlate with an aggressive phenotype. Somatic RET mutations have been also identified in several other malignancies, such as anaplastic thyroid carcinoma (4.3%), melanoma (6.6%), desmoplastic melanoma (20%), cutaneous squamous cell carcinoma (10%), colorectal cancer (3.6%-6.9%), paraganglioma, breast cancer and ureter urothelial carcinoma.

A variety of multikinase inhibitors (MKIs), which show anti-RET activities, have been tested in RET+ solid tumors, in particular in NSCLC (cabozantinib, vandetanib, lenvatinib) and thyroid cancers (cabozantinib, vandetanib, sorafenib, lenvatinib, sunitinib, dovitinib, motesanib).
Overall, MKIs, likely due to the lack of target specificity, show modest clinical benefit and increased toxicity, that often leads to drug dose reduction or treatment discontinuation.

Two new selective RET inhibitors, selpercatinib and pralsetinib, have been FDA approved in 2020 for the treatment of patients with metastatic RET fusion-positive NSCLC, advanced or metastatic RET fusion-positive thyroid cancer who require systemic therapy and who are radioactive iodine-refractory, advanced or metastatic RET-mutant MTC who require systemic therapy.
These approvals are based on preliminary efficacy data of ongoing fase I/II clinical trials on RET altered locally advanced or metastatic solid tumours: LIBRETTO-001 for selpercatinib, ARROW for pralsetinib.

In RET fusion-positive NSCLC patients treated with selpercatinib the overall response rate (ORR) was 64% or 85%, depending on whether the patients were or not prior treated with platinum-based chemotherapy. Moreover, in the first group the median duration of response (DoR) was 17.5 months and the progression free survival (PFS) was 16.5 months; whereas in treatment naïve patients median DoR and PFS were not reached. Similar results were gained with pralsetinib for the same type of tumour: ORR was 61% in patients previously treated with platinum-based chemotherapy and 73% in treatment naïve patients, whereas the median DoR was not reached in any of the two groups.

In RET fusion-positive thyroid cancer patients ORR goes from 79% in those treated with selpercatinib (trial LIBRETTO-001) to 91% in those treated with pralsetinib (trial ARROW).

In RET-mutant MTC patients treated with selpercatinib ORR was 69% or 73%, depending on whether they were or not previously treated with cabozantinib and/or vandetanib. Moreover, in treatment naïve patients the DoR was 22 months and the PFS was 23.6 months, whereas in the first group median DoR and PFS were not reached. Similar results were obtained with pralsetinib for the same type of tumour: ORR was 60% in patients previously treated with cabozantinib and/or vandetanib and 74% in patients who did not received previously any systemic therapy; whereas median DoR and PFS were not reached in any of the two groups.

Likely on the basis of the optimal preliminary efficacy data of LIBRETTO-001 trial, on December 2020, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) recommended the granting of a conditional marketing authorisation for selpercatinib, intended for the treatment of cancers that display rearranged during transfection (RET) gene alterations: RET-fusion positive non-small cell lung cancer (NSCLC), RET-fusion positive thyroid cancer and RET-mutant medullary-thyroid cancer (MTC).

The detection of RET alterations can be done with different methods: immunohistochemistry (IHC), break-apart fluorescence in situ hybridization (FISH), Real Time RT-PCR and Next Generation Sequencing (NGS). The European Society of Medical Oncology (ESMO), in specific recommendations on methods to detect RET fusions and mutations published last month on Annal of Oncology, advises against using IHC, because of its unreliability, whereas, the choice of the other assays should be guided by the context.

Diatech Pharmacogenetics offers complete solutions for the detection of RET variants (fusions and mutations) based on Real Time RT-PCR and NGS.
More information at www.diatechpharmacogenetics.com

References

  1. Belli C, Anand S, Gainor JF, Penault-Llorca F, Subbiah V, Drilon A, Andrè F, Curigliano G. Progresses Toward Precision Medicine in RET-altered Sol