Emerging Single-Target Approaches to Treating Thyroid Cancer Subtypes

Lori J. Wirth, MD

There may be systemic targeted therapies available for patients with advanced thyroid cancer, yet they do not last forever and the side effects of these current therapies are limiting, according to Lori J. Wirth, MD.

However, during her keynote address at the 3rd World Congress on Thyroid Cancer in Boston, Massachusetts, she stated that the era of precision genotype targeted therapy is upon us in advanced thyroid cancer, focusing on individual targets in subtypes of thyroid cancer.

Sorafenib (Nexavar) and lenvatinib (Lenvima) are both FDA approved for patients with radioactive iodine (RAI)—refractory differentiated thyroid cancer (DTC). Lenvatinib, for example, showed a 65% objective response rate (ORR) in the SELECT trial that led to its approval and a median progression-free survival (PFS) of 18.3 months compared with 3.6 months with placebo.¹For medullary thyroid cancer (MTC), both vandetanib (Caprelsa) and cabozantinib (Cometriq) are FDA approved in the setting of progressive disease, each showing a significant improvement over placebo in these patients.

These agents are multikinase inhibitors and are involved in the downstream inhibition of the RAS/RAF/ERK and PI3K/AKT/ mTOR pathways. However, Wirth, associate professor of medicine, Harvard Medical School, and medical director, Center for Head and Neck Cancers, Massachusetts General Hospital Cancer Center, noted that adverse events (AEs) seen with these multikinase inhibitors could often impact patients’ quality of life. AEs, including hypertension, diarrhea, fatigue, weight loss, nausea, stomatitis, and hand-foot syndrome, could usually be managed by dose holds or reductions and supportive care. She noted, though, that “patients will eventually progress or discontinue treatment due to toxicity.”

Fortunately, new targeted treatments are emerging to directly target driver mutations of the disease, potentially causing fewer or more manageable AEs. Somatic RET mutations occur in 40% to 65% of sporadic MTCs and germline mutations of RET are found in all familial cases of MTC.²RET fusions have been found in 6% of papillary thyroid cancers (PTCs).³

As such, a new focus has been placed on targeting RET for patients with MTC or PTC. “Efficacy of other multikinase inhibitors may in fact be limited by insufficient RET inhibition,” Wirth said.

She mentioned that there are 2 new highly potent and specific RET inhibitors that are now involved in first-in-human trials: BLU-667 and LOXO-292, which are both design to inhibit oncogenic RET mutations for MTC and RET fusions for PTC with little activity against KDR/VEGFR-2. “And, the V804L/M gatekepper mutation should prevent the emergence of acquired resistance,” she added.

A 2-part phase I study is open and enrolling to study BLU-667 in patients with thyroid cancer and other solid tumors with RET alterations (NCT03037385). A phase I study is also ongoing for LOXO-292 in patients with RET fusion-positive lung cancer, MTC, and other solid tumors (NCT03157128).

BRAF mutations are among the most frequently identified mutations in patients with PTC, found in 60% of 496 samples of PTC tumors.³In a nonrandomized, open-label phase II study, of vemurafenib (Zelboraf), a BRAF kinase inhibitor that has been approved for the treatment of patients with BRAF-positive melanoma, showed antitumor activity in patients with progressive BRAF V600E-positive PTC who were RAI-refractory and had no prior multikinase inhibitor treatments (n = 26).⁴Ten patients achieved a partial response (38.5%), and 15 patients achieved stable disease (57.5%). Sixty-five percent of patients in the cohort had a grade 3/4 AE, most commonly including squamous cell carcinoma of the skin, lymphopenia, and increased gamma-glutamyltransferase.

In a randomized phase II study looking at the combination of the BRAF inhibitor dabrafenib (Tafinlar) and the MEK inhibitor trametinib (Mekinist) in patients with BRAF-mutant PTC, 9 patients achieved a partial response to the combination and 4 patients achieved a minor response for an ORR of 54% compared with an ORR of 50% for those treated with dabrafenib alone (P = .78).5 The median PFS with the combination was 15.1 months versus 11.4 with dabrafenib monotherapy (P = .27). Wirth noted that the treatments were well tolerated in both arms and that responses were durable.

In another study of the combination in patients with BRAF V600E-mutant anaplastic thyroid cancer (ATC), dabrafenib and trametinib demonstrated robust and durable responses with a favorable safety profile.6 The ORR was 69% with 7 of 11 responses ongoing at the time of data cutoff. Kaplan-Meier estimates of PFS and overall survival at 1 year were 79% and 80%, respectively. Common grade 3/4 AEs included hyponatremia (19%), pneumonia (13%), and anemia (13%).

NTRK1 and NTRK3 fusions are present in about 2% of PTCs, and patients with NTRK1/3-mutant PTC are being included in basket trials with TRK inhibitors, including larotrectinib (LOXO- 101; NCT02576431) and entrectinib (NCT02568267), both of which have shown promising responses across tumor types.

“One great challenge [in precision medicine in thyroid cancer] is to identify each patient’s genotype and match them up with the best clinical trial to demonstrate efficacy toward health-authority approvals in rare patient populations,” Wirth noted. She urged that all patients undergo full genomic sequencing to determine targets for their disease.

Another step toward precision medicine in thyroid cancer, according to Wirth, is the examination of immunotherapy, including combinations with targeted therapies.

References:

1. Schlumberger M, Tahara M, Wirth LJ, et al. Lenvatinib versus placebo in radioiodine-refractory thyroid cancer. N Engl J Med. 2015;372(7):621-630. doi: 10.1056/NEJMoa1406470. 2. Mulligan LM. RET revisited: expanding the oncogenic portfolio. Nat Rev Cancer. 2014;14(3):173- 186. doi: 10.1038/nrc3680.
2. Mulligan LM. RET revisited: expanding the oncogenic portfolio. Nat Rev Cancer. 2014;14(3):173- 186. doi: 10.1038/nrc3680.
3. Cancer Genome Atlas Research Network. Integrated genomic characterization of papillary thyroid carcinoma. Cell. 2014;159(3):676-690. doi: 10.1016/j.cell.2014.09.050.
4. Brose MS, Cabanillas ME, Cohen EE, et al. Vemurafenib in patients with BRAF(V600E)-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.
5. Shah MH, Wirth LJ, Daniels GA, et al. Results of randomized phase II trial of dabrafenib plus trametinib in BRAF-mutated papillary thyroid carcinoma. J Clin Oncol. 2017;35(suppl; abstr 6022).
6. Subbiah V, Kreitman RJ, Wainberg ZA, et al. Efficacy of dabrafenib (D) and trametinib (T) in patients (pts) with BRAF V600E—mutated anaplastic thyroid cancer (ATC). J Clin Oncol. 2017;35(suppl; abstr 6023).