Method for Targeting RET in Thyroid Cancers and Other RET+ Advanced Cancers

RET-targeted therapy with the highly selective RET inhibitor selpercatinib (formerly known as LOXO-292; Retevmo) has been an FDA approved treatment strategy for patients with advanced or metastatic RET-mutant medullary thyroid cancer (MTC) who require systemic therapy, and those with advanced or metastatic RET fusion-positive thyroid cancer who require systemic therapy and who are radioactive iodine (RAI)–refractory (if RAI was appropriate) since May of 2020. Since the FDA’s accelerated approval, multiple analyses have been conducted to solidify its clinical benefit in these RET-altered patient populations.

There are characteristics about MTC that seclude the disease from other thyroid histologies, and according to expert, Vivek Subbiah, MD, the prevalence of RET fusions in MTC is one of the key differences between the disease and papillary and differentiated thyroid cancers. The percentages underscore the importance of somatic and germline testing. Identifying patients who may benefit from RET inhibition also might address outcomes in patients who develop resistance to multikinase inhibitors.

The phase 1/2 LIBRETTO-001 study, which supported the FDA’s decision to approve selpercatinib, showed durable efficacy in RET-altered thyroid tumors and intracranially in both heavily pretreated and treatment-naïve patients. The study is being followed by LIBRETTO-201 (NCT03906331), expanding the access of selpercatinib to patients ineligible for ongoing clinical trials that are utilizing the drug.

In addition to studying the efficacy and safety of selpercatinib in patients with MTC and papillary thyroid cancer, LIBRETTO-201 also includes patients with non­–small cell lung (NSCLC), colon, breast, pancreatic, and other RET-altered advanced cancers.

In an interview with Targeted Oncology, Subbiah, an associate professor in the Investigational Cancer Therapeutics department, and medical director of the Clinical Center for Targeted Therapy, Cancer Medicine division at The University of Texas MD Anderson Cancer Center, reviewed the data supporting selpercatinib as treatment of RET fusion-positive thyroid cancers, as well as the exploration of this agent in other RET-altered cancers. Subbiah also expressed the importance of genomic testing to identify patients who may derive benefit from RET inhibition.

TARGETED ONCOLOGY: Can you explain how the treatment of MTC sets it apart from other thyroid histologies?

Subbiah: The RET protooncogene encodes a transmembrane receptor tyrosine kinase that is constantly activated by 2 distinct mechanisms. One is mutations involving the system glitch or kinase domains, and structural rearrangements that lead to fusion of RET to a prime partner. Collectively, these alterations result in ligand dependent signaling and oncogenesis.

Specifically, for MTC, RET is activated by RET mutations. Overall, more than 60% of patients with metastatic MTC harbor that mutation and in germline patients who are also identified as multiple endocrine neoplasia (MEN) type 1/2, almost 100% have this lead mutation. The germline mutations result in hereditary MEN, type 2A, and type 2B. Collectively these hereditary cancer syndromes account for 25% of all diagnosed cases of MTC of the remaining 75% of sporadic MTC, and as I said, over 60% harbored the RET somatic mutations. RET mutations are associated with more aggressive disease in MTC, and thus, tumors in a majority of patients need a RET-targeted inhibitor.

In non MTC that primarily arise from follicular cells, including papillary, poorly differentiated, anaplastic thyroid cancer, or even Hurthle cell thyroid cancer, RET fusions are seen as a driver mechanism. The RET fusions are, therefore, higher in patients that have non MTC than in MTC. Previous to the entry of selective RET targeted therapy, we had multikinase inhibitors that were approved for MTC that included drugs like vandetanib (Calpresa) and cabozantinib (Cabometyx), as well as other drugs like sorafenib (Nexavar) and lenvatinib (Lenvima) that also have activity. These multi-targeted kinase inhibitors simultaneously target RET in addition to a lot of other kinases, like VEGFR2. Although the percentage of patients who had a response to these multikinase inhibitors were anywhere from 12% to 65%, the safety and durability of the responses to the agents were partially limited by the off-target adverse events (AEs) specifically from VEGFR2. These AEs like rash, diarrhea, and hypertension, lead to dose reductions in these patients. Also, these AEs are primarily attributed to more potent inhibition of non-RET kinases.

Prior to the entry of selective RET inhibitors, no selective RET inhibitor was approved for treating patients with RET-altered disease. Selpercatinib is a novel ADP competitive, highly selective small-molecule RET kinase inhibitor. In preclinical models, it showed that nanomolar potency against diverse RET alterations that included an acquired gatekeeper resistant mutation as well as anti-tumor activity in the brain. This acquired gatekeeper mutation is interesting because this can develop as a resistance mechanism to multikinase inhibitors, or it is also seen in rare cases ingermline patients with MTC.

Can you provide background on the LIBRETTO-001 study?

The LIBRETTO-001 study was conducted in 2 parts, which included a phase 1 dose-escalation part and a phase 2 dose-expansion part across 16 countries and 89 sites. The recommended phase 2 dose was 160 mg orally twice daily. This trial included multiple cohorts, one with RET fusion-positive lung cancer, another with RET-mutant thyroid cancer, specifically MTC, another cohort with RET fusion-positive thyroid cancers, and a basket cohort that included patients with RET-positive uterine cancers.

What results have been reported to date?

The LIBRETTO-001 study is a phase 1/2 clinical trial involving adolescents, young adults. and other patients with any solid tumor type, harboring and activating RET alteration. This study specifically reported that in the first 55 consecutively enrolled patients with MTC who harbored a RET mutation and who have previously received a multikinase inhibitor, like vandetanib, or cabozantinib, had a response was 69%. Also, the 1-year PFS w rate was 82%. In 88 patients with RET-mutant MTC, who had not previously received vandetanib or cabozantinib, had a response was 73%. In fact, the 1-year PFS rate was 92%. In 19 patients who previously had RET fusion-positive thyroid cancer and were previously treated, the percentage who had a response was 79%, and the 1-year PFS rate was 64%.

These data were recently updated, and what we saw was that patients with RET fusion-positive thyroid cancer received the clinical benefit across a variety of histologies in thyroid cancer with an objective response rate of 79% in patients who are previously treated, and 100% in those who were treatment naïve. Based on this compelling data, selpercatinib, has received approval in multiple countries, including the United States and Europe for the treatment of RET-driven thyroid cancers that include MTC. Also, RET fusion-positive thyroid cancer activity has been seen in all fusion partners across all RET alterations.

What are you hopes for the future of selpercatinib as treatment of MTC?

The implementation of effective molecular screening strategies for patients with either germline or somatic RET mutations in non-familial MTC will be essential in identifying these patients who may benefit from selective inhibition. the key message here with these targeted therapies is, although these are uncommon, these are potentially actionable. It is important to do broad-based genomic profiling to identify actionable oncogenic drivers that included mutations and RET fusions.

During the AACR Annual Meeting 2021, you presented further LIBRETTO-001 data. What was the focus of your analysis?

I presented the efficacy and safety of selpercatinib in patients with RET fusion-positive cancers other than lung or thyroid cancers. A total of 441 patients with RET fusion-positive cancers were enrolled on the study as of the data cutoff Of March 19, 2021. In this specific presentation, I discussed the 38 patients who have RET fusion-positive cancer, excluding those with lung or thyroid as data from these patients have been previously published. The efficacy evaluable population included 32 patients who enrolled on or before September 19, 2020, long enough to allow a 6-month follow-up after the first dose of selpercatinib. The patients were required to be at least 12 years of age with a diagnosis of an advanced or metastatic solid tumor and an equal performance status of 0 to 2.

The primary endpoint was ORR, and secondary end points included duration of response, PFS, safety, and others. RET fusions occur predominantly in 1% to 2% of lung cancers, and 10% to 20% of thyroid cancers. They have a very low frequency in an increasing number of diverse cancers like pancreatic cancer, salivary gland cancer, and colorectal cancer. The therapeutic relevance of RET fusions occurring outside lung and thyroid has not been well established, and that was the purpose of this analysis.

What were the differences between these rare RET-mutated histologies?

RET tumor models specifically in all other tumor models beyond lung and thyroid cancer have demonstrated potent anti-tumor activity against diverse types of RET alterations, including various fusion partners and mutation types. To provide an overview of the baseline characteristics of all patients, over 62 patients enrolled on the basket cohort. The non-lung and non-thyroid RET fusion-positive cohort had treatment-refractory gastrointestinal (GI) cancers with limited therapy options. The vast majority of patients had an equal performance status of 0 to 1, the patients had a median of 2 prior therapies, and a third of patients had received 3 or more lines of therapy. A majority of patients received prior chemotherapy. A few patients had received prior multikinase inhibitors and/or PD-1 or PD-L1 therapy. The majority of the patients received surgery, and prior radiation therapy was received by less than a third of patients. Interestingly, the most common fusion partner identified in this sub-population was the NCOA4 fusion.

What were the findings from this subgroup analysis?

The ORR by investigator assessment was 47%. That included 2 complete responses. The waterfall plot showed patients only with measurable disease. Three patients, including a patient with xanthogranuloma, who achieved a CR, were not included because they had only non-target lesions or did not have a post-baseline target lesion measurement. We showed that tumor response was observed regardless of tumor type, and tumor response was observed regardless of the spectrum of red fusion passive cancers.

What is the key takeaway from this presentation?

RET fusions in tumors other than NSCLC and thyroid cancer are uncommon but potentially actionable. Selpercatinb demonstrated promising activity across a wide variety of non-lung and non-thyroid RET fusion-positive advanced tumors that include treatment-refractory GI malignancies, like pancreatic cancer and colorectal cancer. Selpercatinib was overall well tolerated with a safety profile consistent with what has been previously reported. The important point about this analysis is that it reiterates the importance of broad-based genomic profiling to identify actionable oncogenic drivers that include RET fusions. The safety and tolerability and efficacy of selpercatnib will continue to be explored in the LIBRETTO-201 trial, which is continuing to enroll patients with RET fusion-positive cancers.

_References:

_{Drilon A, Oxnard GR, Tan D, et al. Efficacy of selpercatinib in RET fusion–positive non–small-cell lung cancer. N Engl J Med. 2020; 383(9):813-824. doi:10.1056/NEJMoa2005653}