Thyroid carcinomas comprise distinct pathologic subtypes. However, advancements in characterizing the molecular tumorigenesis of thyroid cancers have changed the treatment paradigm in the past decade. Genetic profiling has become an integral component of personalizing cancer care. Oral kinase inhibitors are currently standard-of-care therapies for progressive, radioactive iodine (RAI)–refractory differentiated thyroid carcinomas (DTCs) and medullary thyroid carcinomas (MTCs). Sorafenib, lenvatinib, and cabozantinib are multikinase inhibitors approved for patients with metastatic RAI-refractory DTC, whereas vandetanib and cabozantinib are approved for patients with MTC. Management of thyroid carcinomas has evolved such that targeted therapies have become therapeutic options for patients with BRAF , RET , NTRK , ALK , and ROS1 alterations and even have reported efficacy in anaplastic thyroid carcinomas. In this article, we review the advances made over the years in the treatment of metastatic thyroid carcinoma and focus on the systemic therapies that have recently transformed the treatment landscape of advanced disease.

Lorlatinib is an oral third-generation inhibitor of anaplastic lymphoma kinase (ALK) with activity in advanced ALK-positive non-small cell lung cancer (NSCLC) in both the first and subsequent line setting. Superior systemic and intracranial efficacy of lorlatinib over crizotinib, a first-generation ALK tyrosine kinase inhibitor (TKI), in treatment-naïve patients with advanced ALK-positive NSCLC was demonstrated by the phase 3 CROWN trial. Lorlatinib retains anti-tumor effect against single and some compound ALK resistance mutations after disease progression on first- and second-generation ALK TKIs. Currently, alectinib, brigatinib, ceritinib, crizotinib and lorlatinib are approved for treatment of advanced ALK-positive NSCLC. However, no head-to-head studies have directly compared lorlatinib to second-generation ALK inhibitors. Herein, we aim to provide an overview of the efficacy and safety of lorlatinib and discuss where lorlatinib stands in the therapeutic approach to advanced ALK-positive NSCLC.

Human epidermal growth factor receptor 2 (HER2) alterations can occur as gene mutations, gene amplification or protein overexpression. DESTINY-Lung01 and DESTINY-Lung02 demonstrated the efficacy of trastuzumab deruxtecan in the subsequent line setting in patients with unresectable or metastatic HER2-mutated non-small-cell lung cancer (NSCLC). Trastuzumab deruxtecan has not been studied in select patients with HER2-amplified NSCLC. Here, we present the first reported case of metastatic HER2-amplified NSCLC treated with trastuzumab deruxtecan with a durable response to therapy.

Malignant pleural mesothelioma (MPM) is a heterogeneous cancer composed of distinct molecular and pathologic subtypes. Unfortunately, MPM is aggressive, and current therapies for advanced, unresectable disease remain limited to cytotoxic chemotherapy and immunotherapy. Our understanding of the genomic landscape of MPM is steadily growing, while the discovery of effective targeted therapies in MPM has advanced more slowly than in other solid tumors. Given the prevalence of alterations in tumor suppressor genes in MPM, it has been challenging to identify actionable targets. However, efforts to characterize the genetic signatures in MPM over the last decade have led to a range of novel targeted therapeutics entering early-phase clinical trials. In this review, we discuss the advancements made thus far in targeted systemic therapies in MPM and the future direction of targeted strategies in patients with advanced MPM.

Pleural mesothelioma (PM) is a rare and aggressive cancer. Standard of care for unresectable disease consists of chemotherapy, vascular endothelial growth factor inhibition, immunotherapy, or combinations thereof. Despite recent therapeutic advances, validated diagnostic and prognostic biomarkers are lacking, and no targeted therapies have been approved by the U.S. Food and Drug Administration (FDA) to date. Given the growing body of research investigating molecular alterations in PM, this review summarizes emerging diagnostic and prognostic biomarkers, discusses potentially targetable molecular alterations, and examines ongoing trials directed at targeting specific molecular mechanisms in this disease.

Human papillomavirus (HPV)-associated head and neck squamous cell carcinomas (HNSCCs) are a subtype of virally driven tumours with favourable responses to definitive therapy. However, disease relapse or progression is clinically challenging due to limited effective treatment options. Circulating tumour DNA (ctDNA) technology has emerged in the past decade, and it remains an active area of research in head and neck cancers. A variety of assays for the analysis of HPV ctDNA in patients with HPV-positive HNSCC have been developed and studied, though standardization in HPV ctDNA testing has yet to be established. Studies show promise in HPV ctDNA as a prognostic biomarker and predictor of treatment response and risk for recurrence. Growing evidence suggests that absolute HPV ctDNA quantification, as well as dynamic changes in HPV ctDNA concentration, can potentially inform outcomes and guide decisions about therapy. The aim of this article is to review the clinical utility of HPV ctDNA as a biomarker in HNSCC.