A Decade of Thyroid Cancer Research Brings Precision Medicine to the Forefront of Care

The rising prevalence of thyroid cancer and thyroid nodules, especially for differentiated thyroid cancer (DTC), has brought into question the management of disease as it is known today. Literature has examined the most up-to-date recommendations for DTC management to provide guidelines on risk stratification and individualized care of patients with the disease.

Targeted therapy can offer optimal outcomes for patients with DTC, but in order for oncologists to recommend targeted therapy, there must understanding of disease risk and other factors in patients. It is also important to understand sequencing, as there are many other treatment types in the landscape aside from targeted agents.

Guidelines from the American Thyroid Association (ATA) now include consideration of surveillance with imaging and serum thyroglobulin use before treatment for patients with recurrent disease, hormone therapy, how to consider patients for clinical trials, which patients should receive targeted therapy, and new recommendations for managing patients with recurrent and metastatic disease. For thyroid nodules, the ATA provides guidance on initial evaluation and molecular testing. The new guidelines also state that in all cases of DTC with thyroid nodules, patients should undergo a neck ultrasonography for purposes of risk stratification.^1,2

Risk/Benefit Measurement in DTC With Thyroid Nodules

A 2016 study determined that several characteristics observed through neck ultrasonography can be utilized to determine risk for patients with DTC and thyroid nodules. Advancing age was the key characteristic identified in patients with a higher risk histologic phenotype and higher risk papillary thyroid cancer (PTC) variants, poorly differentiated cancer, or anaplastic carcinoma.²

Despite the utility of neck ultrasonography, the study made clear that this diagnostic tool is only intended to identify patients who are at high risk for thyroid nodules, it does not have the sensitivity and specificity to identify patients who have cancer. Instead, diagnosing patients with malignant thyroid tumors is left up to using molecular genetics.

“Most oncologists are embracing the use of next-generation sequencing to look for potentially actionable mutations. While the majority of these mutations are rare in number, the therapies that act on these targets often are more tolerable than tyrosine kinase inhibitors that target primarily VEGFR and are likely to produce more durable responses. This provides patients with more treatment options and, perhaps, improvements in quality of life,” said Frank P. Worden, MD, oncologist and professor, University of Michigan Rogel Cancer Center, in an interview with Targeted Oncology.

Molecular Markers in Thyroid Cancer

Molecular markers help identify both diagnostic and prognostic information that can help in making treatment decisions. In some cases, the targeted therapies needed to treat a patient’s unique condition are already available, but many targeted therapies for thyroid cancer are still in development. Of the agents being tested for the treatment of thyroid cancers, tyrosine kinase inhibitors (TKIs) are ahead of other classes of agents.

Worden explained that certain TKIs are showing more promise than others, stating, “entrectinib (Rozlytrek) and larotrectinib (Vitrakvi) target NTRK fusions and pralsetinib (Gavreto) and selpercatinib (Retevmo) target RET mutations in medullary thyroid cancer and RET fusions in radioactive iodine (RAI)–refractory differentiated thyroid cancers and anaplastic thyroid cancers (ATCs). Dabrafenib (Tafinlar) and vemurafenib (Zelboraf) show promise, too, in RAI-refractory papillary thyroid cancers and the combination of dabrafenib and trametinib (Mekinist) have been FDA approved.”

Pralsetinib is now FDA approved for the treatment of adult and pediatric patients who are 12 years old or older with advanced or metastatic RET-mutant medullary thyroid cancer and require systemic therapy.

Entrectinib

Patients with NTRK fusion–positive solid tumors, including thyroid cancers, demonstrated clinically meaningful responses to entrectinib in multiple clinical trials, according to pooled data from phase 1 ALKA-372-001, the phase 1 STARTRK-1, and the phase 2 STARTRK-2 studies. The patient population consisted of 54 patients total, with 52 patients from the STARTRK-2 study and 1 patient each from the STARTRK-1 and ALKA-372-001 studies.³

At a median duration of follow-up of 12.9 months, the objective response rate (ORR) in the population was 57% (95% CI, 43.2%-70.8%), which included complete responses (CRs) in 7% and partial responses (PRs) in 50%. There were also 9 patients from the pooled population who achieved stable disease (SD). The median duration of response (DOR), a secondary end point of the trials, was 10.4 months (range, 7.1-not estimable).

Survival was also assessed as a secondary end point, and the median PFS observed was 11 months (95% CI, 8.0-14.9). At the time of data cutoff, 29 patients either demonstrated disease progression or died. Based on these data, the estimated median overall survival (OS) was 21 months (95% CI, 14.9-not estimable).

Patients with central nervous system (CNS) involvement were included in the pooled analysis and in the CNS population, the ORR was 50% and all responses were PRs. Four patients had SD in this subgroup. The median DOR was not estimable.

In terms of survival in the CNS subgroup, the median PFS was 7.7 months (95% CI, 4.7-not estimable); studies of entrectinib remain ongoing.

Entrectinib was considered to be a safe treatment option. In the study, the most common grade 3/4 treatment-related adverse events were increased weight and anemia. Also, nervous system disorders were the most common serious TRAEs. No treatment-related deaths were observed.

Larotrectinib

Phase 1 and 2 studies of larotrectinib as treatment of patients with TRK fusion–positive thyroid cancer, namely DTC (NCT02122913 & NCT02576431) have revealed the promise of the agent in inducing disease control and high response rates.⁴

Together the study populations included 28 patients who had either PTC (n =19), follicular thyroid cancers (n = 2), and ATCs (n = 3). The remainder of the patients had DTC. Four individuals with CNS involvement were also included.

In the overall population from both clinical trials, the ORR was 75% (95% CI, 55%-89%), which included 2 CRs, 19 PRs, and SD in 3 patients. There were also 3 patients in the overall population who had progressive disease (PD).

After a median follow-up of 10.2 months, the median DOR was not estimable (NE; 95% CI, 14.8-NE), but the 12-month median DOR was estimated to be 95% (95% CI, 85%-100%).

At a median follow-up of 12.8 months, the overall population had a median PFS of NE (95% CI, 16.6-NE), the PFS rate at 12 months was estimated to be 81% (95% CI, 67%-96%) and 70% at 18 months (95% CI, 45%-94%). The median OS was 27.8 months (95% CI, 16.7-NE), and it was estimated that at 12 months the OS rate would be 92% (95% CI, 82%-100%).

In the subgroup populations, treatment with larotrectinib led to an ORR of 90% in the patients with DTC and 29% in patients with ATC. The 18-month PFS rate was 86% in patients with DTC (95% CI, 60%-100%). The median OS was not reached in the DTC cohort and was 14.1 months (95% CI, 2.6-NE) in the ATC cohort.

Larotrectinib also demonstrated tolerable safety in the clinical trial setting with the most common adverse events (AEs) being mostly grades 1 or 2 in severity, and grade 3 AEs occurred in 32% of patients. Grade 3 treatment-related AEs occurred in 7% of the patients and no patients experienced grade 4 events.

Based on these findings for larotrectinib, routine testing for NTRK gene fusions was recommended by the study investigators for patients with non-medullary advanced thyroid cancer.

Selpercatinib

Findings from the thyroid cancer cohorts of the phase 1/2 LIBRETTO-001 clinical trial (NCT03157128) show that selpercatinib may be an effective and safe treatment for adult and adolescent patients with RET-mutated medullary thyroid cancer (MTC) regardless of prior receipt of vandetanib (Caprelsa) or cabozantinib (Cabometyx).⁵

The ORR observed in the MTC cohort of 55 patients was ORR was 69% (95% CI, 55%-81%), according to an independent review. Responses included CRs in 9% of patients and PRs in 60%. At 1 year, responses remained ongoing in 86% of patients (95% CI, 67%-95%). In addition, biochemical responses were observed in 91% of patients (95% CI, 80%-97%). The median DOR was NE (95% CI, 19.1-NE) after a median follow-up of 14.1 months.

The median PFS per independent review was NE (95% CI, 24.4-NE) after a median follow-up of 16.7 months. The 1-year PFS rate was 82% (95% CI, 69%-90%).

Among patients previously treated with vandetanib or cabozantinib, the ORR achieved was 73% (95% CI, 62%-82%), which included CRs in 11% of patients and PRs in 61% of patients. Responses were still ongoing in 91% of patients (95% CI, 72%-97%) at 1 year. Additionally, 2% of patients were progression free (95% CI, 82%-97%) at 1 year. The median DOR in this subgroup was 22.0 months after a median follow-up of 7.8 months.

After a median follow-up of 11.1 months, patients who were previously treated with vandetanib or cabozantinib had a median PFS of 23.6 months (95% CI, NE-NE). The 1-year PFS rate in this population was 92% (95% CI, 82%-97%).

The results of this study show that testing all patients with thyroid cancer for potential RET mutations or fusions is an important step for oncologists to take.

Vemurafenib

In a phase 2 clinical trial, vemurafenib demonstrated antitumor activity in patients with progressive, BRAF V600E–positive PTC who are refractory to RAI and who had never been treated with a multikinase inhibitor.⁶

The study included 51 patients who were divided into 2 cohorts based on whether or not they had received prior VEGFR multikinase inhibitor therapy. Twenty-six patients have no prior treatment with a VEGFR multikinase inhibitor (cohort 1), and 25 did (cohort 2). Patients in cohort 1 were followed for a median duration of 18.8 months (interquartile range [IQR], 14.2-26.0) and patients in cohort 2 were followed for a median of 12.0 months (IQR, 6.7-20.3).

A best overall response of 38.5% (95% CI, 20.2%-59.4%) was observed in cohort 1, which were all PRs. Cohort 2 was excluded from the pre-protocol analysis but it was shown that 27.3% of patients (95% CI, 10.7-50.2) achieved a PR as a best overall response to therapy and 6 had SD lasting for at least 6 months.

The safety analysis showed grade 3 or 4 AEs were observed in 65% of cohort 1 and 68% of the patients in cohort 2. The most common grade 3 and 4 AEs in cohorts 1 and 2 were squamous cell carcinoma of the skin (27% and 20%, respectively), lymphopenia (8% each), and increased γ-glutamyltransferase (4% and 12%).

Investigators led by Marcia S. Brose, MD, PhD, of Penn Medicine, stated in the published study that screening for BRAF V600E mutations in the setting of disease refractory to RAI is vital for the identification of patients who may benefit from treatment with vemurafenib.

Dabrafenib Plus Trametinib

The efficacy and safety of the combination of dabrafenib plus trametinib was investigated in a phase 2 open-label study of 100 patients, 16 of whom had BRAF V600–mutated ATC.⁷

The combination led to a confirmed ORR of 69% (95% CI, 41%-89%). One patient had a CR and 10 achieved PRs. Ongoing responses were noted in 7 patients at the time of the analysis. The median DOR was not reached in the study. The 12-month Kaplan-Meier estimate for DOR was 90%.

Survival was also assessed as secondary end points in the study, but both median PFS and OS were not reached by the time of data cutoff. It was estimated that at 12 months the PFS rate would be 79% and the OS rate would be 80%.

In terms of safety in the overall population, 93% of patients in the study experienced an AE of any grade and 42% had grade 3 or 4 AEs. AEs leading to dose reduction were seen in 30 patients, 38 patients required dose interruption or delay, and 8 of them discontinued treatment.

The most common any-grade AEs in the ATC cohort included fatigue (44%), pyrexia (31%), and nausea (31%). The most common grade 3/4 AE was anemia (13%).

In regard to these clinical trial data, study investigators led by Vivek Subbiah, MD, of The University of Texas MD Anderson Cancer Center stated: “These data indicate that tumor mutation screening should be performed for patients with ATC as it has the potential to transform outcomes for these patients.”

Unmet Needs With Precision Medicine in Thyroid Cancer

Data from clinical trials of targeted therapies for the treatment of thyroid cancers led to the FDA approval of selpercatinib as treatment of for RET fusion–positive disease, entrectinib for NTRK fusion–positive disease, and the combination of dabrafenib plus trametinib as treatment of patients with BRAF V600–mutated disease. But some targets have yet to be drugged in thyroid cancers.

“Follicular thyroid cancers are associated with RAS mutations. Currently, there are no agents that act on these biomarkers meaningfully,” Worden stated, in an interview.

In thyroid cancer, RAS mutations are unique because they can be activated in 2 different pathways, MAPK and the phosphoinositide-3-(PI3K/AKT) pathways. RAS mutations are found in about 17% of RET-negative thyroid tumors, underscoring a need to develop an agent that can target the mutation. Thyroid cancers with ALK rearrangement represent another unmet need in the field.

The key message from clinical trial research on actionable targets is that “next-generation sequencing should be done on all thyroid cancers to look for potentially actionable mutations. Although we do not have sequencing data, most would consider treating a driver mutation first and saving a pankinase inhibitor for patients who progress on such targeted therapies,” Worden explained.

_References:

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_{6. Brose MS, Cabanillas ME, Cohen EW, et al. Vemurafenib in patients with BRAFV600E-positive metastatic or unresectable papillary thyroid cancer refractory to radioactive iodine: a non-randomised, multicentre, open-label, phase 2 trial. Lancet Oncol. 2016;17(9):1272-1282. doi:10.1016/S1470-2045(16)30166-8}

_{7. Subbiah V, Kreitman RJ, Wainberg ZV, et al. Dabrafenib and trametinib treatment in patients with locally advanced or metastatic BRAF V600–mutant anaplastic thyroid cancer. J Clin Oncol. 2017;36(1):7-13. doi:10.1200/JCO.2017.73.6785}

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