Progressive Radioiodine-Refractory Papillary Thyroid Cancer Without an Actionable Oncogenic Driver

This protocol applies to patients with papillary thyroid carcinoma that is refractory to radioiodine and actively progressing — where comprehensive biomarker testing has confirmed the absence of any actionable oncogenic driver alteration.

Clinical Scenario

The patient has radioiodine-refractory (RAIR), progressive papillary thyroid carcinoma. Tissue-based biomarker testing has been performed and has excluded all actionable driver alterations: no NTRK fusion, no RET fusion, no BRAF V600E mutation, and no ALK fusion. This testing is essential prior to initiating systemic therapy, as it rules out eligibility for biomarker-linked targeted therapies and confirms the appropriate treatment pathway.

Systemic Treatment Approach

For this patient population, first-line systemic therapy involves a multikinase inhibitor (MKI). There is a preferred first-line agent within this class, as well as an identified alternative. The complete selection criteria, agent, and individualisation guidance are contained in the full protocol.

Treatment Goal

Stable or minimally progressive disease: the sum of the longest diameters of target lesions increases by less than 20%, with no new metastatic foci on sequential imaging.

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References

DOI: 10.1177/10507256251363120

Tissue-based biomarker testing to identify actionable oncogenic driver alterations in RAIR DTC should be performed prior to initiating systemic therapy for progressive disease.
For patients with progressive RAIR DTC without an actionable biomarker-linked FDA-approved first-line therapy, MKI therapy with either lenvatinib or sorafenib is recommended. In most cases, lenvatinib is the preferred first-line MKI.
Disease extent is stable or minimally progressive if the sum of the longest diameters of the target lesions increases less than 20% in the absence of new metastatic foci on sequential imaging.

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