Navigating the 2026 ASCO Guideline Update on Managing Thyroid Cancer

For the oncology clinician, a new American Society of Clinical Oncology (ASCO) guideline update represents a definitive shift toward a biomarker-first approach, particularly in the management of radioiodine (RAI)-refractory differentiated thyroid cancer (DTC), medullary thyroid cancer (MTC), and anaplastic thyroid cancer (ATC).

“The evidence base for any clinical practice recommendations is built on the characteristics of the patients who participated in the underlying studies. Broad enrollment in clinical trials is essential for clinicians to assess the generalizability of trial results and understand safety and efficacy across populations,” Nabil F. Saba, MD, FACP, professor and vice chair in the Department of Hematology and Medical Oncology, the Inaugural Lynne and Howard Halpern Chair in Head and Neck Cancer Research, professor in the Department of Otolaryngology at Emory University School of Medicine, director of the Head and Neck Cancer Medical Oncology Program, and the leader of the Multidisciplinary Head and Neck Program at Winship Cancer Institute of Emory University, and co-authors wrote in the paper.

Hierarchical Recommendations for RAI-Refractory DTC

The guideline provides a clear algorithm for patients with progressive, RAI-refractory DTC. While Multikinase inhibitors (MKIs) have long been the standard, the 2026 update elevates genomically targeted therapies to frontline consideration when a driver mutation is present.

• First-Line (No Actionable Mutation): Lenvatinib (Lenvima) is recommended as the preferred first-line agent over sorafenib (Nexavar), based on superior response rates and progression-free survival (PFS).
• First-Line (Genomically Altered): For patients with identified fusions or mutations, targeted therapy should be initiated upfront:
• RET Fusions: Selpercatinib (Retevmo).
• NTRK Fusions: Larotrectinib (Vitrakvi) or entrectinib (Rozlytrek).
• BRAF V600E: Dabrafenib (Tafinlar) plus trametinib (Mekinist), although the evidence for upfront use in DTC is noted as having lower strength compared to ATC.
• Subsequent-Line: Cabozantinib (Cabometyx) is the standard recommendation for patients who progress on prior VEGFR-targeted therapy.

Aggressive Pathologies: ATC and PDTC

The 2026 guideline emphasizes the urgency of molecular testing in ATC, where the window for intervention is narrow.

• ATC Management: For BRAF V600E–mutated ATC, the combination of dabrafenib and trametinib is the gold standard. For non-mutant (wild-type) ATC, the guideline suggests lenvatinib with or without pembrolizumab, highlighting the growing, selective role of immunotherapy in this aggressive subtype.
• Poorly Differentiated (PDTC): Recognizing the paucity of dedicated trials, ASCO suggests extrapolating from DTC and ATC data. Systemic therapy with MKIs (lenvatinib) remains the primary intervention, with molecularly targeted agents used where applicable.

Medullary Thyroid Cancer (MTC)

The landscape for MTC has been redefined by the success of highly selective RET inhibitors.

• First-Line: For patients with RET-mutated or RET fusion-positive MTC, selpercatinib should be offered. If patients are RET wild-type in the first-line setting, cabozantinib or vandetanib (Caprelsa) should be offered.
• Immunotherapy Vs Targeted Agents: Patients who are receiving first-line care or subsequent lines of therapy should not be offered immunotherapy outside of a clinical trial.

Clinical Implementation and Monitoring

ASCO highlighted barriers to implementation, including increased awareness for frontline practitioners, survivors, and caregivers, along with the ability to provide adequate resources. Cost implications may play a role and should be part of the shared-decision making process. Patient access should also be considered, as not all patients have consistent access to care. Geographic disparities can also impact the receipt and type of care.

Clinicians are advised to monitor for the specific toxicity profiles of MKIs (e.g., hypertension, proteinuria, and palmar-plantar erythrodysesthesia).

Key Takeaway: The move from "which drug" to "which mutation" requires oncologists to secure tissue or liquid biopsies early in the journey to ensure patients receive the most potent and least toxic therapy first.

Reference

Saba NF, Ismaila N, Adkins D, et al. Systemic Treatment of thyroid cancer: ASCO Guideline. J Clin Oncol. Published online April 1, 2026. doi:10.1200/JCO-26-00235