Precision medicine in aggressive thyroid cancer: Moving beyond multitargeted tyrosine kinase inhibitors

Abstract

Thyroid cancer is a diverse group of malignancies that encompass a wide range of biological behaviors. Although most cases are curable with surgery, which is often followed by radioactive iodine (RAI), a few cases of differentiated thyroid cancer (DTC) along with its subtypes papillary thyroid cancer and follicular thyroid cancer become refractory to RAI and ultimately require systemic therapy. Poorly differentiated thyroid cancer and especially anaplastic thyroid cancer (ATC) are typically very aggressive. Because thyroid cancer is considered resistant to traditional chemotherapy, the advent of targeted therapy has changed the outlook for these patients. Several Food and Drug Administration (FDA)–approved treatments have become available, and thyroid cancer remains a disease of intense research with more treatments on the horizon. The genomic landscape of thyroid cancer is characterized by a paucity of genetic abnormalities in comparison with other cancer types, and this has limited the use of personalized treatment strategies. The first class of drugs to emerge for the treatment of aggressive thyroid cancers was multitargeted tyrosine kinase inhibitors (TKI), which primarily target vascular endothelial growth factor receptors (VEGFRs) 1 to 3 but also numerous other targets such as Raf serine/threonine kinases (RAF-1, wild-type B-RAF, and oncogenic B-RAFV600E), platelet-derived growth factor receptor β (PDGFR-β), Flt-3, and c-Kit. Sorafenib was the first TKI that was FDA-approved for DTC refractory to RAI on the basis of results from a phase 3, placebo-controlled trial (DECISION).1 Among 417 patients who were randomized to sorafenib or a placebo, the median progression-free survival (PFS) was 10.8 months with sorafenib and 5.8 months with the placebo. Lenvatinib, a similar multi-TKI, was tested in a similarly designed, randomized phase 3 study of patients with progressive, RAI-refractory DTC (SELECT); the study demonstrated improved PFS (median PFS, 18.3 vs 3.6 months) and high overall response rates (ORRs) in comparison with a placebo, including 3 complete responses (Table 1).2 Toxicity remains a problem with these drugs: 64.3% of subjects on sorafenib require a dose reduction, and 75.9% of treated patients suffer from grade 3 or higher treatment-related adverse events (TRAEs), including death (Table 1). Activating point mutations of v-raf murine sarcoma viral oncogene homolog B1 (BRAF) occur in approximately 60% of DTC cases and 40% of ATC cases, and they most commonly consist of the BRAF V600E mutation. The BRAF-specific TKI inhibitor vemurafenib was tested in a phase 2 study, and good tumor control was observed both in TKI-naive patients and in cases that had previously been treated with TKIs; however, it resulted in modest response rates (Table 1).3 In ATC, BRAF V600 mutations are detected in approximately 20% to 50% of cases, and despite its aggressiveness, it appears to respond surprisingly well to dual BRAF and MAPK/ERK kinase (MEK) inhibition with dabrafenib and trametinib. This combination has received FDA approval on the basis of data from 16 patients who were part of a larger basket study for patients with BRAF-mutant tumors. In this cohort, the ORR was 69% with 80% alive at 12 months.4 Could the response rate be improved in cases of BRAF-mutant DTC with the BRAF/MEK inhibitor combination as opposed to a BRAF inhibitor such as vemurafenib alone? An ongoing, randomized phase 2 study comparing dabrafenib with dabrafenib plus trametinib in RAI-refractory thyroid cancer is addressing this question. However, preliminary results presented as an abstract suggest that the combination may not be more effective than dabrafenib alone (Table 1).5 The rearranged during transfection (RET) proto-oncogene plays a dominant role in medullary thyroid cancer (MTC), which originates from calcitonin-producing parafollicular C cells and constitutes approximately 2% of thyroid cancer cases. Similarly to DTC, metastatic MTC frequently remains stable for prolonged time periods during which it may not require treatment. However, most patients with MTC eventually enter an accelerated phase with more rapid disease progression necessitating systemic therapy. RET activation in MTC is usually through point mutations while in DTC, RET activation is due to rearrangements with a number of possible fusion partners, which lead to dimerization of the RET molecule and thus to RET activation. The advent of RET-specific TKIs such as selpercatinib and pralsetinib represents a significant advance in the treatment of RET-altered thyroid cancer. LIBRETTO-001 was a phase 1 basket trial using selpercatinib in patients with advanced and/or metastatic MTC and DTC harboring RET mutations and fusions of RET genes, respectively.6 Most patients, including those who had previously been treated with other TKIs, achieved a treatment response in the RET-mutant MTC cohort (Table 1), and the 1-year PFS rate was 86% (95% CI, 67%-95%). This also included patients harboring an RET V804M gatekeeper mutation, which typically conveys resistance to traditional TKIs. Treatment responses could occur very rapidly, and cases of tumor lysis syndrome were observed in some instances. TRAEs were generally mild and occurred among 30% of the study subjects; this compared favorably with the older multi-TKIs. Pralsetinib, a similar RET-specific TKI, was tested in the ARROW basket trial and was evaluated in a similar group of patients with RET-altered thyroid cancer; it yielded similar results with a favorable side-effect profile (Table 1).7 On the basis of these data, selpercatinib and pralsetinib received FDA approval for RET-mutant MTC and RET fusion–positive DTC, and they are recommended for first-line use. Follow-up studies comparing the RET inhibitor with older VEGF TKIs, as required by the FDA, are under way for both drugs. Neurotrophic tropomyosin receptor kinases (NTRKs) 1 to 3 are therapeutic targets where fusions in NTRK genes involve fusions with specific binding partners, and they are found in 5% to 25% of thyroid cancers.11 Larotrectinib is a selective inhibitor of TRK that has been evaluated in DTC and ATC subjects harboring NTRK1 and NTRK3 gene fusions. After initial reports for NTRK-fusion thyroid carcinoma (n = 5) demonstrating partial responses in all patients,12 results from a larger data set showed an ORR of 90% in the DTC cohort (n = 21) and a perhaps slightly disappointing ORR of 29% in the ATC cohort, but this was limited by the small size of the cohort (n = 7).8 The median overall survival was not reached for the DTC cohort. Larotrectinib was well tolerated with only 7% of the participants experienced grade 3 or higher TRAEs (Table 1), and none discontinued protocol therapy because of toxicity. Entrectinib, another similar selective inhibitor of TRK, showed similar efficacy and a favorable safety profile, and both drugs were granted FDA approval. Findings recently presented at the American Society of Clinical Oncology conference in 2020 demonstrated an ORR of 43% (all partial responses), albeit in a limited patient population of thyroid cancer subjects (n = 7).9 Mammalian target of rapamycin (mTOR) inhibition has long been available through rapamycin and its analogues, which are highly specific allosteric inhibitors binding to the rapamycin-binding pocket of the mTOR molecule. Everolimus, an oral rapamycin analogue, has been tested with demonstrated activity in RAI-refractory DTC, MTC, and ATC in a phase 2 study (Table 1).10 Patients with progressive DTC and MTC had median PFS of 12.9 and 13.1 months, respectively. Two additional similar trials showed comparable results.13-15 The median overall survival was not reached for the DTC group but was observed to be 21.4 months for the MTC cohort; the chief complaints (grade 3 or higher) were reported among 44% of the patients receiving protocol therapy (Table 1).10 In ATC, evidence from patients treated at our institution showed PFS up to 27.9 months, particularly in patients with activation along the PI3K/mTOR pathway: TSC2, PIK3CA, and PTEN deletions may indicate sensitivity in ATC.16, 17 However, immunosuppression and the risk for developing pneumonitis are significant side effects. Second-generation mTOR inhibitors such as MLN0128 appear to lack these side effects. Results from a phase 2 study in ATC and DTC have not been published (NCT02244463). In conclusion, the development of specific drugs targeting BRAF, NTRK, RET, and mTOR has expanded the treatment landscape for aggressive thyroid cancer significantly. Incorporating advanced molecular diagnostic testing into routine practice is necessary to match patients with their optimal treatment. Open questions such as optimal sequencing of lines of treatment will need to be addressed in ongoing clinical trials. No specific funding was disclosed. Jochen H. Lorch reports institutional research support from Novartis, Bayer, Takeda, and BMS and consulting fees from Bayer and Lilly. The other author made no disclosures. Umair Mahmood, MSc, is a clinical researcher at the Center for Head and Neck Oncology and the Department of Radiation Oncology at the Dana-Farber Cancer Institute. He pursued additional research training in radiation biology at the University of Oxford. High-impact literature originating from his scholarly work on advanced head and neck malignancies has been published in multiple peer-reviewed journals and presented at national meetings, including those of the American Society of Clinical Oncology and the American Society for Radiation Oncology. His academic interests lie in clinical trials using targeted agents and immune checkpoint inhibitors for head and neck cancers, in exploring the interplay between radiotherapy and the tumor microenvironment, and in clinical bioinformatics. Jochen H. Lorch, MD, MSc, is an associate professor at Harvard Medical School, an associate physician at Brigham and Women's Hospital and Faulkner Hospital, and a senior physician at the Dana-Farber Cancer Institute. His principal effort is as a medical oncologist within the Head and Neck Cancer Program, where he serves as the clinical trials leader and director of the Thyroid Center. He is a national expert in the management of thyroid cancer and routinely sees direct referrals of challenging cases.