Emerging Role of Selective RET Inhibitors in RET-Dependent Cancers

Vivek Subbiah, MD, is an associate professor in the Department of Investigational Cancer Therapeutics, Division of Investigational Cancer Therapeutics, and is the Center Clinical Medical Director of the Clinical Center for Targeted Therapy, Cancer Medicine division, at The University of Texas MD Anderson Cancer Center, in Houston, Texas. Dr Subbiah’s work includes translational cancer research and the design and conduct of early-phase, biomarker-driven clinical trials, with a specialist interest in antibody drug conjugates, radiopharmaceuticals, immunoconjugates, and basket trials.

Explain the mechanism of action of selective RET kinase inhibitors in RET-dependent cancers.

The RET gene is activated by 3 mechanisms:


●  RET fusions;
●  RET mutations; and
●  Aberrant overexpression of RET.

Pralsetinib and selpercatinib are selective and highly potent RET inhibitors. Previously, patients with RET-altered cancer were treated with multikinase drugs, such as vandetanib and cabozantinib that have some RET-inhibitory activity; however, those drugs were limited by off-target adverse effects. Selpercatinib and pralsetinib showed RET-specific activity in preclinical models. The first-in-human trials demonstrated favorable pharmacokinetic properties, including predictable exposure, high bioavailability, and minimal potential for drug–drug interactions.¹

How many selective RET inhibitors have been approved? On what trial data were those approvals based, and for which indications?

In May 2020, accelerated FDA approval was granted to selpercatinib [Retevmo™, Eli Lilly and Company] for the treatment of:

● Adult patients with metastatic RET fusion-positive, non–small cell lung cancer (NSCLC);
●  Adult and pediatric patients 12 years and older who require systemic therapy for advanced or metastatic RET-mutant medullary thyroid cancer (MTC); and
●  Patients with RET fusion-positive thyroid cancer who are radioactive iodine-refractory (if radioactive iodine is appropriate).²

In September 2020, the FDA also granted accelerated approval to pralsetinib [Gavreto™, Blueprint Medicines Corporation and Genentech, Inc.] for the treatment of adult patients with metastatic RET fusion-positive NSCLC whose cancer has been detected by an FDA-approved test.³

In December 2020, the FDA approved pralsetinib for the treatment of adult and pediatric patients 12 years and older who require systemic therapy and who have (1) advanced or metastatic RET-mutant MTC or (2) RET fusion-positive thyroid cancer and are radioactive iodine-refractory (if radioactive iodine is appropriate).⁴

In which RET-driven cancers, other than NSCLC and metastatic thyroid cancer, are selpercatinib and pralsetinib being investigated?

Selpercatinib continues to be explored in the phase 1/2 LIBRETTO-001 study (ClinicalTrials.gov Identifier: NCT03157128), which is still enrolling patients with RET fusion-positive nonlung cancers and nonthyroid cancers. We’ve enrolled 32 patients—an efficacy population. Gastrointestinal tumors, such as colon and pancreatic cancer, accounted for more than 52% of cancers in the patient population. Beyond that, we’ve enrolled patients with breast cancer, salivary cancer, sarcoma, ovarian cancer, and xanthogranuloma, an extremely rare skin cancer.

This is a histology-independent study; we are not talking about tumor type based on the location of origin of the tumor but, rather, on the tumor’s genetic origin. The objective response rate (ORR) was 47%, including 2 complete responses and 13 partial responses.⁵ We also saw durable response across the spectrum of fusion partners.

Pralsetinib continues to be explored in the ARROW study (ClinicalTrials.gov Identifier: NCT03037385), which is still enrolling patients with various RET fusion-positive solid cancers beyond lung and thyroid cancers. The results of ARROW were presented at the ASCO20 Virtual Scientific Program.⁶ We included 27 patients in this group: 13 with thyroid cancer and 14 with other solid tumor types, beyond thyroid cancer. Among the RET fusion-positive thyroid cancer patients, mean age was 63 years; 92% of patients had received prior systemic therapy. The most common fusion partner in the thyroid cohort was CCDC6, followed by NCOA4. Among patients with all other tumor types (colon, 3; pancreatic, 3; cholangiocarcinoma, 2; mixed-histology lung, 3; neuroendocrine, 1; ovarian, 1; and thymus, 1), median age was 54 years; 43% were men; and all but 1 had metastatic disease at enrollment, including 14 % who had brain metastases. All patients received chemotherapy; 50% received additional anticancer therapy; and 1 received a multikinase inhibitor. The most common fusion partner in that data set was CCDC6 (29%), followed by KIF5B (21%) and NCOA4 (14%).

Interestingly, ORR in the thyroid cancer cohort was 91%. In the RET fusion-positive cohort among the 12 evaluable patients, ORR was 50%, all of which were partial responses. Beyond partial responses, we also saw stable disease and a disease-control rate of 92%. Responses were seen regardless of fusion partner and in heavily pretreated patients. The 3 patients with pancreatic cancer and both patients with cholangiocarcinoma achieved a partial response.

What is the long-term potential for selective RET inhibitors to influence outcomes in patients with RET-driven cancer?

Rapid clinical development and FDA approval of RET inhibitors has altered the precision oncology landscape of RET-dependent cancers, including RET fusion-positive NSCLC, RET fusion-positive thyroid cancer, and RET-mutant MTC. The fewer off-target adverse effects, compared with multikinase inhibitors cabozantinib and vandetanib, means that treatment with these RET inhibitors is poised to improve the quality of life of these patients.

Continued implementation of molecular screening strategies and broad-based genomic profiling that includes the ability to detect RET fusions will be critical for identifying patients who might benefit from a selective RET inhibitor beyond lung and thyroid cancers. The key message is that we need to genetically test all patients with cancer and look for these alterations, to see if patients can, potentially, benefit from these drugs. If we do comprehensive genomic sequencing for multiple alterations, we will pick up these patients with RET fusions as well.