**9. Role of targeted agents**

Primary chemoresistance is a commonly encountered issue in ATC that often results in a bad prognosis. Hence, newer therapeutic agents are being investigated in ATC, targeting various molecular alterations.

As mentioned above, one-fourth of the ATC is associated with mutation of BRAF and RAS [47]. A phase II trial was conducted in BRAF V600E-positive tumors including 36 patients with ATC, where the patients were treated with the BRAF inhibitor Dabrafenib plus the MEK inhibitor Trametinib. The treatment was well tolerated with an ORR of 56% (95% CI, 38.1–72.1%), with three complete responses and a median PFS and OS of 6.7 and 14.5 months, respectively [42, 43]. The combination was FDA approved in 2018 as 1st line therapy for BRAF V600E-positive ATC patients.

Unfortunately, acquired resistance to BRAF inhibitors due to secondary mutation of MAPK pathway or via PI3K/AKT/mTOR pathway is common in ATC, and hence newer targeted agents are needed. Around 2–3% of ATC patients will have a mutation of NTRK, ALK, or RET fusion.

For such mutation-positive ATC, very high response rates are reported with specific inhibitors in various trials. A pooled subgroup analysis of trials investigating the role of Larotrectinib in ATC showed a response rate of 29% in two out of seven patients [45, 48]. Similarly, long-lasting responses were also noted with Selpercatinib and Crizotinib in RET fusion ATC and ALK-rearranged ATC, respectively [44, 46]. However, these are small studies, some are equivalent to case reports and need more validation.

Inhibitors of PI3K/AKT/mTOR pathway like Everolimus were tested but showed no response [49]. Combination of Sorafenib and Temsirolimus also could not demonstrate a durable response [50].

Though anti-angiogenic agents, such as Lenvatinib, are approved in radioiodine refractory thyroid cancers, their role in ATC is controversial. Based on a single-arm phase II study with 51 ATC patients, Lenvatinib showed a median PFS benefit of 7.4 months, a median OS of 10.6 months, and an ORR of 24% [51]. However, a recent prospective phase II Lenvatinib trial was stopped due to futility as the interim analysis reported a very low response rate (2.9%) and survival outcome [52].
