Newer Targeted Therapies Making an Impact in Many Subtypes of Thyroid Cancer

Marcia S. Brose, MD, PhD

Marcia S. Brose, MD, PhD

Targeted agents have produced new treatment options for patients with advanced thyroid cancers, with significant advances being seen this year in moving toward precision medicine for various thyroid cancer subtypes, according to Marcia S. Brose, MD, PhD.

Brose, a director of thyroid cancer therapeutics and of the Center for Rare Cancers and Personalized Therapy as well as an associate professor at the Abramson Cancer Center, The University of Pennsylvania in Philadelphia, briefly addressed much of the recent activity in the field in a presentation at the36th AnnualCFS.

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Currently the state-of-the-art for advanced thyroid cancer includes many targeted therapies that are widely used for the treatment of most patients with radioactive iodine (RAI)—refractory differentiated thyroid cancer (DTC), such as sorafenib (Nexavar) and lenvatinib (Lenvima). Brose indicated that cabozantinib (Cabometyx), a multikinase inhibitor, is also being added to this list following the promising results seen in a phase II study. The findings demonstrated an objective response rate (ORR) of 54% with cabozantinib in patients with RAI-refractory DTC. The median progression-free survival (PFS) had not yet been reached but showed a PFS rate of 64% at 12 months.Cabozantinib has already been approved for use in medullary thyroid cancer (MTC). A phase III trial has already been initiated to confirm the benefit with cabozantinib (NCT03690388). 

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Each form of DTC has differing genetic drivers, she explained. For example, in anaplastic thyroid cancer (ATC), which has been very difficult to treat, Brose mentioned, theBRAFmutations occur in approximately 20% to 50% of cases and in 40% to 50% of cases in papillary thyroid cancer (PTC), whereas in MTC,RETmutations—both germline and somatic—occur in 65% to 75% of cases.The majority of mutations occur in PTC or conventional follicular thyroid cancer (about 70%).

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Brose noted that RET inhibitors especially can have implications for treating more than 1 subtype of thyroid cancer asRETtranslocations are found in RAI-refractory DTC as well as MTC. In a study of 82 patients withRET-altered cancers,RETfusion—positive thyroid cancer was identified in 9 patients andRET-mutant MTC in another 29 patients.

“We have 2 agents now that are vying for patients [withRETalterations] in clinical trials,” Brose noted.

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In the phase I/II LIBRETTO-001 study, LOXO-292 was investigated in patients withRET-altered cancers, including 11% withRETfusion—positive thyroid cancer and 35% withRET-mutant MTC.She commented that treatment with Loxo-292 was second-line therapy or beyond for most patients. Among the patients with MTC, 23 (79%) had received prior treatment with cabozantinib or vandetanib (Caprelsa) and 13 (45%) had received both. Among the patients with RETfusion—positive thyroid cancer, 7 (78%) had received prior RAI and 7 had prior sorafenib or lenvatinib.

In theRET-mutant MTC population, the confirmed ORR was 56% (95% CI, 35%-75%) with 2 complete responses. And in theRETfusion—positive thyroid cancer population, the confirmed ORR was 78% (95% CI, 40%-97%). “If we look at the response rates we see that it really is robust…patients did remarkably well,” Brose said. Responses in theRET-mutant MTC andRETfusion—positive thyroid cancer groups were ongoing in 94% and 100% of patients, respectively.

“These are durable responses so far, certainly are getting into the range of the comparison with the kinase inhibitors where the responses were anywhere from a year to 18 months,” she added.

Brose noted that the study is being expanded into a phase II trial which will most likely be a registrational study.

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Another investigational RET inhibitor, BLU-667 also showed profound activity inRET-altered thyroid cancers in the phase I ARROW trial with 90% of evaluable patients demonstrating tumor shrinkage.

Of the 42 patients, 83% remained on treatment after more than 15 months, including the 19 patients who achieved a partial response. Responses were seen in patients irrespective of their prior treatment regimens. This trial is also expanding for the thyroid cancer cohort, Brose mentioned.

In both studies, responses were seen regardless of theRETalteration and both RET-targeted agents were well tolerated.

For patients with TRK alterations, which are noted in less than 5% of cases in PTC,²including in children, larotrectinib is another exciting targeted approach for patients who harbor TRK translocations, Brose remarked.

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In data pooled from 3 phase I/II studies of adult and pediatric patients with TRK fusion—positive cancers, 5 patients of a total of 55 had thyroid cancer. The overall ORR was 75% (95% CI, 61%-85%) by investigator assessment, including patients with thyroid cancer achieving partial responses. 

“What’s the excitement? While the VEGF receptor inhibitors do very well, there’s good activity and good duration of these progression-free survivals, they are toxic. They do have side effects, and while they are manageable side effects, [larotrectinib] has a very low side effect profile…. It’s incredibly exciting, especially when you’re going to be treating children with advanced thyroid cancer to have agents that have almost no side effects,” she said.

Brose also pointed to many treatments on the runway for patients with thyroid cancer, such asBRAFinhibitors for patients with ATC. Although the combination of dabrafenib (Tafinlar) and trametinib (Mekinist) was approved by the FDA for the treatment of patients with ATC with aBRAFV600E mutation in May 2018, Brose believes that additional follow-up registrational trials are still needed before it can be considered a standard of care. And many additional trials are ongoing to test additional mutation/translocation-directed agents in thyroid cancer subtypes.

References:

1. Brose MS, Shenoy S, Bhat N, et al. A phase II trial of cabozantinib for the treatment of radioiodine (RAI)-refractory differentiated thyroid carcinoma (DTC) in the first-line setting. Presented at: 2018 Multidisciplinary Head and Neck Cancers Symposium; February 15-17, 2018; Scottsdale, Arizona. Abstract 8.
2. Nikiforov YE. Molecular diagnostics of thyroid tumors.Arch Pathol Lab Med.2011;135(5):569-577. doi: 10.1043/2010-0664-RAIR.1.
3. Wirth LJ, Cabanillas ME, Sherman E, et al. Clinical activity of Loxo-292, a highly selective RET inhibitor, in patients with RET-altered thyroid cancers.Thyroid.2018;28(S1):Short call oral 6. doi: 10.1089/thy.2018.29071.sc.abstracts.
4. Hu M, Taylor M, Wirth LJ, et al. Clinical activity of selective RET inhibitor, BLU-667, in advanced RET-altered thyroid cancers: updated results from the phase 1 ARROW study.Thyroid.2018;28(S1):Short call oral 5. doi: 10.1089/thy.2018.29071.sc.abstracts.
5. Drilon A, Laetsch TW, Kummar S, et al. Efficacy of larotrectinib in TRK fusion-positive cancers in adults and children.N Engl J Med. 2018;378(8):731-739. doi: 10.1056/NEJMoa1714448.