Posted: Wednesday, November 4, 2020
The recent emergence of highly potent selective rearranged during transfection (RET) inhibitors—selpercatinib and pralsetinib—is changing the treatment landscape for RET-dependent cancers. In May 2020, selpercatinib was approved for the treatment of patients with advanced or metastatic RET-mutant medullary thyroid cancer who require systemic therapy, as well as for patients with advanced or metastatic RET fusion–positive thyroid cancer who require systemic therapy and who are radioactive iodine–refractory.1
RET-Altered Thyroid Cancer and Therapeutic Options
Although the majority of patients with thyroid cancer fare well—the overall 5-year relative survival is among the highest of all malignancies at 98.3%—the survival rate decreases dramatically in patients with metastatic disease (54.9%)2 and in those with more aggressive, less differentiated subtypes. For example, the 5-year relative survival rates for patients with regional and metastatic medullary thyroid cancers are 90% and 39%, respectively.3
Because advanced medullary thyroid cancer is often insensitive to conventional therapy, patients had few treatment options prior to the approval of two tyrosine kinase inhibitors, vandetanib and cabozantinib, almost a decade ago. The addition of these targeted therapies changed the therapeutic landscape for patients with advanced medullary thyroid cancer, improving progression-free survival. However, responses to tyrosine kinase inhibitors are not usually durable, and toxicities often limit their efficacy.4 Additionally, RET mutations, strongly associated with medullary thyroid cancer, are associated with a poor prognosis.5
The RET proto-oncogene encodes a transmembrane receptor and member of the tyrosine protein kinase family of proteins. RET is classified as a proto-oncogene because a single activating RET mutation of one allele can lead to neoplastic transformation.6 Binding of ligands to the encoded receptor activates downstream signaling pathways, which play essential roles in cell differentiation, growth, migration, and survival.7
Somatic and germline point mutations of the RET gene play an important role in the development of medullary thyroid cancer, a rare neuroendocrine tumor that originates from parafollicular C cells and accounts for 2% to 8% of all thyroid malignancies.8,9 Germline mutations in RET—almost always a result of the hereditary condition, multiple endocrine neoplasia type 2 (MEN2) syndrome—are responsible for one-quarter of medullary thyroid cancers, and the remaining 75% are considered sporadic cancers.10
Although medullary thyroid cancer can harbor alterations in various genes, such as HRAS, KRAS, and KMT2D, RET is the most common alteration in patients with medullary thyroid cancer.11 “RET mutation is a critical component in the pathogenesis of medullary thyroid cancer,” said Manisha H. Shah, MD, a medical oncologist at The Ohio State University Comprehensive Cancer Center. Activating RET germline point mutations have been found in almost all cases of hereditary medullary thyroid cancer—only about 2% of families affected by MEN2 have no detectable germline mutations.5 Approximately half of sporadic medullary thyroid cancers harbor a RET mutation; of them, a single mutation (M918T) accounts for most (70%) somatic RET mutations.12
Beyond Medullary Thyroid Cancer
“In addition to pathogenic point mutations triggering RET-altered thyroid cancer, deletions, translocations, and fusions can also drive change in the RET transmembrane protein complex to include an oncogenic feature,” explained Jennifer L. Zadlo, PharmD, BCOP, a clinical pharmacy specialist at The University of Texas MD Anderson Cancer Center, Houston. Although less common, RET alterations are also present in other types of thyroid cancer. Known as a RET fusion, this type of alteration occurs when the RET gene combines with a partner gene to form a fusion gene, activating the RET tyrosine kinase and leading to evasion of regulation by ligands.11,13 “RET fusion can occur in papillary thyroid cancer and, rarely, in anaplastic thyroid cancer,” Dr. Shah told JNCCN 360. “This type of alteration is very different from the RET point mutations seen in medullary thyroid cancer.”
About 20% of papillary thyroid cancer cases contain RET fusion genes known as RET/PTC rearrangements.14 The most common genetic alteration identified in this type of thyroid cancer, RET/PTC rearrangements are associated with the most aggressive histologic variant of papillary thyroid carcinoma.5,15
Role of Genetic Testing
Genetic testing has an important role in differentiating sporadic from hereditary medullary thyroid cancers, and according to Dr. Shah, it should be performed in all patients diagnosed with medullary thyroid cancer. “The RET gene is long and can be mutated at several locations along the gene,” Dr. Shah told JNCCN 360. “Based on the site of the mutation, we can predict the likelihood that someone will develop medullary thyroid carcinoma and how aggressive the disease will be.” In addition to patients with medullary thyroid cancer, Dr. Zadlo said that anyone with differentiated thyroid cancer who is eligible for systemic treatment should undergo genetic testing. “These patients are generally refractory to radioactive iodine,” she said.
Treatment of Advanced RET-Altered Thyroid Cancer
The primary treatment of medullary thyroid carcinoma is extensive and meticulous surgical resection. Because neuroendocrine-derived medullary thyroid carcinoma does not respond to either radioiodine or thyroid-stimulating hormone (TSH) suppression, these options are not available for treatment of progressive metastatic medullary thyroid carcinoma.
Targeted Therapy With Tyrosine Kinase Inhibitors
The approval of the oral tyrosine kinase inhibitors vandetanib and cabozantinib, in 2011 and 2012, respectively, expanded treatment options for patients with advanced RET-altered thyroid cancer. In the ZETA trial, a double-blind phase III trial of vandetanib compared with placebo, median progression-free survival was significantly longer for patients with locally advanced or metastatic medullary thyroid carcinoma who were treated with vandetanib (30.5 vs. 19.3 months).16 Similarly, cabozantinib also significantly increased progression-free survival in patients with progressive or metastatic medullary thyroid carcinoma compared with patients who received placebo (11.2 vs. 4.0 months) in the double-blind phase III EXAM trial.17
Off-Target Effects Limit Use of Tyrosine Kinase Inhibitors
Both cabozantinib and vandetanib selectively target multiple tyrosine kinase–mediated pathways, including RET, MET, and VEGF2 and RET, VEGF, and EGFR, respectively.4 Due to their nonselective nature, the multikinase inhibitors are often associated with off-target adverse effects, such as hypertension, rash, and diarrhea. These toxicities limit the ability to dose for clinically effective RET inhibition because of the narrow therapeutic index.18
Next-Generation Highly Selective RET Inhibitors
With the recent introduction of highly potent selective RET inhibitors—pralsetinib and selpercatinib—the treatment landscape of RET-dependent cancers has evolved again. Both agents are also demonstrating success in the treatment of metastatic RET fusion–positive non–small cell lung cancer (NSCLC).19 The RET fusion genetic alteration is present in 1% to 2% of patients with NSCLC. [Editor’s Note: Pralsetinib is currently awaiting approval for treatment of RET fusion–positive thyroid cancer. A new drug application was submitted to the U.S. Food and Drug Administration for pralsetinib on the basis of responses reported in the phase I/II ARROW trial.20]
In May 2020, selpercatinib was approved for treatment of patients with advanced or metastatic RET-mutant medullary thyroid carcinoma who require systemic therapy, as well as patients with advanced or metastatic RET fusion–positive thyroid cancer who require systemic therapy and who are radioactive iodine–refractory.1
The approval was based on the results of the LIBRETTO-001 study, a phase I/II trial that enrolled patients in one of six cohorts based on tumor type, RET alteration, and prior therapy.21 Selpercatinib showed durable efficacy, with mainly low-grade toxic effects, in patients with medullary thyroid carcinoma, some of whom had been previously treated with vandetanib or cabozantinib. In patients with advanced or metastatic RET-mutant medullary thyroid carcinoma, the overall response rate for previously treated patients was 69%, and 1-year progression free survival was 82%. For those who were not previously treated, the overall response rate was 73%; of those patients, 91% had an ongoing response at 1 year.22
In patients with RET fusion–positive thyroid cancer, the overall response rate in 19 patients who were radioactive iodine–refractory and had received another prior systemic treatment was 79%. Activity was seen across multiple histologic types of thyroid cancer, including an 18-month response in a patient with anaplastic thyroid cancer (response still ongoing).
Because selpercatinib is very selective for RET, we do not see the ‘off-target’ side effects common with earlier agents that target both RET and VEGF.
In a review of data from 531 patients, selpercatinib appears to be well tolerated. Most reported adverse events were grade 1 or 2, and few patients (2%) discontinued therapy for treatment-related adverse events.21 “Because selpercatinib is very selective for RET, we do not see the ‘off-target’ side effects common with earlier agents that target both RET and VEGF,” Dr. Shah observed. “Overall, selpercatinib has a more favorable toxicity profile.”
Neelam K. Patel, PharmD, BCOP, a clinical pharmacy specialist at The University of Texas MD Anderson Cancer Center, recommends regular monitoring of patients who are on selpercatinib for potential toxicities, including hypertension, cytopenias, hepatotoxicity, and QT prolongation. “We perform an electrocardiogram at baseline and then periodically thereafter,” she explained to JNCCN 360. “QT prolongation is a real possibility with this medication.” Dr. Zadlo added: “It can be tricky in this population because many of these patients have been on cabozantinib and vandetanib, which can also prolong the QT interval. We monitor closely but have yet to make any dose reductions or interruptions at our institution due to QT prolongation.”
Monitoring renal function and serum creatinine is also recommended, said Dr. Zadlo. “Even in healthy patients, an increase in serum creatinine in the first 10 to 14 days of starting selpercatinib is common. It appears that this may be related to a downstream effect of blocking the RET pathway and is not necessarily due to nephrotoxicity,” she explained. “Before jumping to conclusions, we use alternative means of measuring renal function such as urine output or 24-hour urine collection.”
When this reaction [hypersensitivity reaction] occurs, we will stop selpercatinib, give steroids, and resume treatment at a lower dose.
Hypersensitivity reaction has been reported in 4.3% of patients receiving selpercatinib, including grade 3 hypersensitivity in 1.6%. It is most common in the first few weeks of treatment.23 “This is similar to cytokine-release syndrome and includes a drop in blood pressure, fever, rash, and thrombocytopenia,” explained Dr. Shah. “When this reaction occurs, we will stop selpercatinib, give steroids, and resume treatment at a lower dose.”
Other common adverse events with selpercatinib include diarrhea, dry mouth, and fatigue. “Patients often assume that fatigue is part of the disease and treatment because it is frequently associated with other treatments such as chemotherapy,” said Dr. Shah. “However, extreme fatigue is not normal with selpercatinib, and we want patients to report this.”
Serum calcitonin and carcinoembryonic antigen (CEA) are established tumor markers measured during both initial diagnosis of medullary thyroid carcinoma and for long-term monitoring for disease recurrence. Calcitonin is useful for surveillance because this hormone is produced only in the parafollicular cells. Although calcitonin and CEA levels fail to differentiate between locoregional and metastatic disease, conflicting changes in values should trigger further investigation such as additional imaging.24
In a study of patients treated with vandetanib, calcitonin levels decreased suddenly, which did not directly correlate with changes to tumor volume.25 Thus, calcitonin may not be a reliable marker of tumor response in patients receiving RET inhibitor therapy; the decreases in serum CEA may serve as a more reliable marker of tumor response.25 Dr. Shah has observed this in patients treated with selpercatinib as well: “Calcitonin may drop dramatically, but CEA can drop off and then rise again. We don’t know why, but it is helpful to be aware of.”
Tips for Patients and Families
Patients and caregivers should be counseled regarding the use of acid-reducing medications during treatment with selpercatinib. “H2 antagonists or proton pump inhibitors can decrease the gastrointestinal absorption of selpercatinib if they are taken simultaneously,” explained Dr. Patel. “Selpercatinib should be taken with food if the patient is concurrently using a proton pump inhibitor and separated from administration with H2 antagonists to avoid this interaction. We should also ask patients about the use of over-the-counter acid-reducers, because they often forget to report them to us.” Dr. Zadlo added, “many patients with medullary thyroid carcinoma may take something for calcium supplementation (eg, Tums Because it neutralizes acid in the stomach, it should be separated from selpercatinib as well.”
Unexpected side effects are another factor to consider in patients receiving selpercatinib. “We were very surprised by how frequently dry mouth was reported during clinical trials,” Dr. Zadlo told JNCCN 360. “It is worth educating both patients and clinicians because it is not a side effect we would anticipate.”
Selpercatinib was effective even in patients who had exhausted other treatment options and would otherwise have been offered hospice.
In conclusion, Dr. Shah has witnessed “amazing transformations” in some patients treated with selpercatinib. “Very sick patients who have run out of other options begin taking this medication and have a quick and dramatic change in how they feel,” she said. “Because it is so well tolerated and can have impressive results, selpercatinib was effective even in patients who had exhausted other treatment options and would otherwise have been offered hospice.”
Manisha H. Shah, MD, received institutional grant support and consulting fees from Eli Lilly.
Jennifer L. Zadlo, PharmD, BCOP, reported no conflicts of interest.
Neelam K. Patel, PharmD, BCOP, reported no conflicts of interest.
- Research C for DE and. FDA approves selpercatinib for lung and thyroid cancers with RET gene mutations or fusions. FDA. Published online May 11, 2020. Available at https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-selpercatinib-lung-and-thyroid-cancers-ret-gene-mutations-or-fusions. Accessed October 26, 2020.
- National Cancer Institute: Cancer of the Thyroid – Cancer Stat Facts. SEER. June 29, 2020. Available at https://seer.cancer.gov/statfacts/html/thyro.html. Accessed October 26, 2020.
- ASCO Cancer.Net: Thyroid Cancer – Statistics. Cancer.Net. June 25, 2012. Available at https://www.cancer.net/cancer-types/thyroid-cancer/statistics. Accessed October 26, 2020.
- Milling RV, Grimm D, Krüger M, et al. Pazopanib, cabozantinib, and vandetanib in the treatment of progressive medullary thyroid cancer with a special focus on the adverse effects on hypertension. Int J Mol Sci 2018;19:3258.
- Romei C, Ciampi R, Elisei R. A comprehensive overview of the role of the RET proto-oncogene in thyroid carcinoma. Nat Rev Endocrinol 2016;12:192–202.
- Priya SR, Dravid CS, Digumarti R, et al. Targeted therapy for medullary thyroid cancer: A review. Front Oncol 2017;7:238.
- NCBI. RET ret proto-oncogene [Homo sapiens (human)]. Gene. Available at https://www.ncbi.nlm.nih.gov/gene/5979. Accessed October 26, 2020.
- Lim H, Devesa SS, Sosa JA, et al. Trends in thyroid cancer incidence and mortality in the United States, 1974–2013. JAMA 2017;317:1338–1348.
- Taccaliti A, Silvetti F, Palmonella G, et al. Genetic alterations in medullary thyroid cancer: Diagnostic and prognostic markers. Curr Genomics 2011;12:618–625.
- Raue F, Frank-Raue K. Epidemiology and clinical presentation of medullary thyroid carcinoma. Recent Results Cancer Res 2015;204:61–90.
- AACR Project GENIE Consortium. AACR Project GENIE: Powering precision medicine through an international consortium. Cancer Discov 2017;7:818–831.
- Cote GJ, Evers C, Hu MI, et al. Prognostic significance of circulating RET M918T mutated tumor DNA in patients with advanced medullary thyroid carcinoma. J Clin Endocrinol Metab 2017;102:3591–3599.
- Dias-Santagata D, Lennerz JK, Sadow PM, et al. Response to RET-specific therapy in RET fusion-positive anaplastic thyroid carcinoma. Thyroid 2020;30:1384–1389.
- Nikiforov YE. Molecular diagnostics of thyroid tumors. Arch Pathol Lab Med 2011;135:569–577.
- Nikiforov YE. RET/PTC rearrangement in thyroid tumors. Endocr Pathol 2002;13:3–16.
- Wells SA Jr, Robinson BG, Gagel RF, et al. Vandetanib in patients with locally advanced or metastatic medullary thyroid cancer: a randomized, double-blind phase III trial. J Clin Oncol 2012;30:134–141.
- Elisei R, Schlumberger MJ, Müller SP, et al. Cabozantinib in progressive medullary thyroid cancer. J Clin Oncol 2013;31:3639–3646.
- Subbiah V, Yang D, Velcheti V, et al. State-of-the-art strategies for targeting RET-dependent cancers. J Clin Oncol 2020;38:1209–1221.
- Kohno T, Ichikawa H, Totoki Y, et al. KIF5B-RET fusions in lung adenocarcinoma. Nat Med 2012;18:375–377.
- Blueprint Medicines. Blueprint Medicines Announces Submission of New Drug Application to FDA for Pralsetinib for the Treatment of Advanced RET Mutant and RET Fusion-Positive Thyroid Cancers | Blueprint Medicines Corp. Available at http://ir.blueprintmedicines.com/news-releases/news-release-details/blueprint-medicines-announces-submission-new-drug-application. Accessed October 26, 2020.
- Wirth LJ, Sherman E, Drilon A, et al. Registrational results of LOXO-292 in patients with RET-altered thyroid cancers. ESMO 2019 Congress. Abstract 2402.
- Wirth LJ, Sherman E, Robinson B, et al. Efficacy of selpercatinib in RET-altered thyroid cancers. N Engl J Med 2020;383:825–835.
- Retevmo (selpercatinib) capsules, for oral use. Lilly USA, May 2020. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/213246s000lbl.pdf. Accessed October 26, 2020.
- Zheng-Pywell R, Cherian AJ, Enman M, et al. Carcinoembryonic antigen should be concurrently checked with calcitonin to identify distant metastases in medullary thyroid cancer. Int J Endocrine Oncol 2020;7:IJE27.
- Wells SA Jr, Gosnell JE, Gagel RF, et al. Vandetanib for the treatment of patients with locally advanced or metastatic hereditary medullary thyroid cancer. J Clin Oncol 2010;28:767–772.