In this interview, Lori Wirth, MD, speaks with i3 Health about selpercatinib (RetevmoTM, Eli Lilly), which was recently approved by the FDA for the treatment of patients with metastatic RET fusion-positive non-small cell lung cancer (NSCLC), advanced/metastatic RET-mutant medullary thyroid cancer (MTC), and advanced/metastatic RET fusion-positive thyroid cancer. Dr. Wirth, Medical Director of the Center for Head and Neck Cancers at Massachusetts General Hospital and first author of the phase 1/2 LIBRETTO-001 trial, on which the approval was based, discusses selpercatinib's significance for patients with advanced/metastatic RET-mutant MTC and RET fusion-positive thyroid cancer and shares her advice for optimizing the treatment of these conditions.
What are some of the most challenging aspects of treating patients with advanced/metastatic RET-mutant MTC and RET fusion-positive thyroid cancer?
Lori Wirth, MD: There are a number of challenges when treating patients with RET-altered thyroid cancer. First, it's not a one-size-fits-all entity. There is a great deal of diversity in thyroid cancers in general. Even within the various histologic types of thyroid cancer, there is a wide spread in the natural history of the disease.
For example, MTC can arise in the setting of germline mutations in the familial MEN2A or 2B syndromes, or it can arise sporadically. Essentially all patients with familial MTC will harbor a driver mutation in the RET gene. There are a number of RET mutations that give rise to MEN2A, whereas RET M918T is the predominant mutation in MEN2B. In addition, a majority of the sporadic MTCs harbor somatic RET mutations. Thus, knowing who to test for RET mutations and how to do so in patients with MTC is not entirely straightforward.
Beyond the complexity of driver RET mutations in MTC, we also see a fair amount of diversity in the natural history of the disease. In MEN2A and 2B, there are distinct genotype-phenotype correlations seen. For example, some RET mutations give rise to a higher risk of earlier onset MTC, as well as the risk of other neoplasia, such as pheochromocytoma, compared with other less high-risk RET mutations. Other thyroid cancers, mainly differentiated thyroid cancers, can harbor driver RET fusions. Overall, these are seen in approximately 10% of papillary thyroid cancers, but it is important to know that thyroid cancers arising in children and young adults are enriched for RET fusions. We can even occasionally find RET fusions in anaplastic thyroid cancers.
Lastly, regarding the complexity of MTC, some patients with metastatic MTC will have indolent disease that grows slowly over years and may not necessarily require immediate systemic therapy, whereas other patients have more aggressive disease that needs effective therapy right away.
Can you comment on the significance of the approval of selpercatinib for patients with advanced/metastatic RET-mutant MTC and RET fusion-positive thyroid cancer?
Dr. Wirth: The approval of selpercatinib does not just give patients with advanced/metastatic RET-mutant MTC and advanced/metastatic RET fusion-positive thyroid cancer another therapeutic option. Selpercatinib provides a highly specific and targeted treatment option designed to block the pathway driving these cancers as effectively as possible, while limiting the off-target side effects that can impact the tolerability of treatment.
How do you foresee the treatment of patients with advanced/metastatic RET-mutant MTC and RET fusion-positive thyroid cancer evolving in the coming years?
Dr. Wirth: Selpercatinib offers these patients who need systemic therapy a new, first-of-its-kind targeted therapy option. Over the last decade, we have sometimes struggled with the decision of when to start systemic therapy in thyroid cancer patients because of the need to balance the efficacy of therapy and its side effect profile, especially in patients with low-burden rather than slow-growing disease. With a RET-specific inhibitor designed to minimize off-target side effects, that formulation should become easier to figure out.
Do you have any words of advice for community oncologists and other members of the cancer care team treating patients with advanced/metastatic RET-mutant MTC and RET fusion-positive thyroid cancer?
Dr. Wirth: First and foremost, because of the frequency of the actionable driver mutations that can be found in patients with advanced thyroid cancer, genotyping is a critical aspect of treatment decision making. For MTC patients, we need to rule out germline RET mutations, which has important implications not just for the patient but also for family members. For patients with sporadic MTC in need of systemic therapy, a majority of tumors will harbor a driver RET mutation. Genotyping may also be important for patients with progressive radioiodine-refractory thyroid cancer, given the frequency of RET fusions seen, as well as other gene alterations that may be targeted.
About Dr. Wirth
Lori Wirth, MD, is the Medical Director of the Center for Head and Neck Cancers at Massachusetts General Hospital (MGH) and is the Elizabeth and Michael Ruane Endowed Chair of Medical Oncology and Associate Professor of Medicine at Harvard Medical School in Boston, Massachusetts. She is also the Oncology Director of the Endocrine Tumor Center and Chief of Head and Neck Oncology at MGH's Advanced Thyroid Cancer Center. Dr. Wirth specializes in the treatment of head and neck cancers, including thyroid cancer, Merkel cell carcinoma, and endocrine tumors, with particular expertise in combined modality therapy for these diseases. Her research focuses on the development of novel therapeutics for the treatment of head and neck cancers. She is a member of several national and international committees that have published cancer treatment guidelines, including the National Comprehensive Cancer Network (NCCN) Thyroid Committee and the American Board of Internal Medicine (ABIM) Medical Oncology Exam Committee.
For More Information
Wirth LJ, Sherman E, Drilon A, et al (2019). Registrational results of LOXO-292 in patients with RET-altered thyroid cancers. Ann Oncol (ESMO Congress Abstracts, 30(suppl_5):v851-v934. Abstract LBA93. DOI:10.1093/annonc/mdz394
Transcript edited for clarity. Any views expressed above are the speaker's own and do not necessarily reflect those of i3 Health.