*4.4. Multimodal Therapy*

Considering the promising data about single regimens, many clinicians proposed a multimodal therapy against ATC in order to reduce therapy resistance. Moreover, driver mutations such as BRAF were proposed as master regulators of immune TME in thyroid cancer [114,149]. Multimodal therapy against immune TME and main mutated pathways could induce a deep inhibition of ATC growth and progression, evading resistance mechanisms.

In 2018, Cabanillas et al. showed one case of locally aggressive unresectable ATC treated with neo-adjuvant therapy composed by dabrafenib, trametinib and pembrolizumab (DTP) [150]. Interestingly, the patient had a relevant response, allowing a complete surgical resection followed by postoperative chemoradiation. Likewise, other 4 clinical cases have recently been reported about DTP use as neoadjuvant therapy in ATC, with unexpected high PFS (19.5, 95% CI: 13.75–24.5, months) [151].

Immunotherapy has been proposed also in adjuvant therapy with dabrafenib and trametinib or lenvatinib. Iyer et al. [152] used pembrolizumab as salvage therapy in 5 patients treated with dabrafenib and trametinib, 1 with trametinib, and 6 with lenvatinib. Although 2 patients experienced PD, 5 patients had PR and 5 had SD and, from the start of targeted therapies, the median OS was 10.4 months (95% CI = 6.02, 14.83, range 5.4–40 months) [152]. In this series, fatigue, anemia and hypertension were the most common AEs associated with this combination and drug-induced rash and altered mental status (likely related to PD) induced drug interruption [152]. Similarly, Dierks et al. showed interesting results about lenvatinib and pembrolizumab combined treatment both in ATC and PDTC: 5/6 patients with ATC reached CR/PR and 2/2 with PDTC obtained PR [153]. Similarly, nivolumab (anti-PD1 antibody) was added to vemurafenib in patients affected by metastatic ATC, obtaining a prolonged response (more than 20 months) [154]. According to these results, new clinical trials are ongoing (e.g., NCT03181100).

In 2017, 6 patients with PDTC and 2 with ATC were enrolled to receive sorafenib and temsirolimus (mTOR inhibitor) in a non-randomized clinical trial. In one hand, results in patients with PDTC were encouraging and 4 patients reached PR and 2 SD; on the other hand, one patient with ATC had PR and the other one had PD [155]. Furthermore, 14% of enrolled patients discontinued the treatment for toxicity and most common adverse events grade ≥ 3 were hyperglycemia, fatigue, anemia, and oral mucositis [155].
