A patient with advanced BRAF-mutant ATC who recovered with a combination of the anti-PD1 nivolumab and the BRAF V600E targeted drug vemurafenib is shown, indicating further studies using biomarker-based gene- and immune-targeted agents, including in combination, are needed in ATC.
Abstract
Anaplastic thyroid cancer (ATC) is a rare and aggressive tumor with a historical median survival of less than six months. Most patients have advanced disease at the time of diagnosis. Traditional cytotoxic chemotherapy has not shown survival benefits. Molecular testing and next-generation sequencing are used to identify specific targets for patients with ATC. If positive for BRAF V600E mutation, patients can be treated with BRAF/MEK inhibitors. Other therapies include tyrosine kinase inhibitors (e.g., lenvatinib) and recently immune checkpoint inhibitors which have shown remarkable results in a subset of patients, including when used along with targeted therapy. An illustrative case of a patient with advanced BRAF-mutant ATC (respiratory failure on a ventilator) who recovered with a combination of the anti-PD1 nivolumab and the BRAF V600E targeted drug vemurafenib is shown. Further studies using biomarker-based gene- and immune-targeted agents, including in combination, are needed in ATC.
This article examines contemporary treatment strategies for advanced non-small cell lung cancer (NSCLC) with a BRAF gene mutation, which is observed in approximately 5% of NSCLC patients. The significance of molecular genetic testing to detect the BRAF V600E mutation in all patients diagnosed with advanced NSCLC is underscored. The article describes the principles guiding the selection of treatment regimens for NSCLC with BRAF V600E mutation, highlighting the need to use targeted therapies in the first line due to their association with the highest objective response rates and survival outcomes. Various factors should be considered when selecting the first-line regimen, including the Eastern Cooperative Oncology Group (ECOG) performance status, the presence of intracranial metastases, concurrent medical conditions, and the patient’s tolerance to antitumor therapy. Detailed results from a phase II PHAROS clinical study evaluating the efficacy and safety of encorafenib in combination with binimetinib in patients with metastatic NSCLC exhibiting the BRAF V600E mutation are presented. This study reported the most favorable overall survival to date in treatment-naive patients with BRAF V600E-mutated metastatic NSCLC, with an overall survival of 47.6 months, surpassing that achieved with other systemic therapies. Hence, the implementation of molecular genetic testing to identify driver mutations prior to initiating treatment, alongside first-line targeted therapy, is a critical factor in improving survival rates for patients with advanced NSCLC and the BRAF V600E mutation.
L. Bolotina· Journal of Modern Oncology· 0 citations
Anaplastic thyroid cancer (ATC) is a rare, highly aggressive malignancy, responsible for a disproportionate share of thyroid cancer–related mortality and with limited therapeutic options. We reported results from a phase II trial (NCT03181100) in which ATC pts received atezolizumab plus targeted therapy: BRAF V600E (vemurafenib + cobimetinib) or RAS/NF mutant (cobimetinib). mOS was longer in the BRAF V600E cohort (43 months, 95% CI 16-NE) than the RAS/NF mutant cohort (8.7 months, 95% CI 5.1-37.0), but outcomes overlapped; pts with BRAF V600E had OS as short as 81 days, while pts with RAS/NF mutations had OS up to 1702 days. We sought to identify pre-treatment molecular features associated with OS, independent of oncogene status.
Clinical NGS was performed on all tumors; whole-exome and transcriptome sequencing were available for pretreatment samples (n=14,16). Germline/somatic mutations, copy number alterations, and structural variants were assessed. Differential gene expression (DGE), gene set enrichment, and predefined gene profiles were analyzed. Patients were stratified by OS (>2-year vs <2-year).
Among <2-year OS pts (n=9), 6 were RAS-mutant and 3 BRAF V600E; among >2-year OS pts (n=7), 5 were BRAF V600E and 2 RAS-mutant. Three pts were still alive (3.4–4.3 yrs), 2 BRAF V600E and 1 RAS-mutant. No co-mutations were associated with OS. DGE (≥3-fold) between short (<2-year) and long (>2-year) OS pt tumors showed longer OS tumors to express epithelial/differentiation (e.g., PAX8) and immune activation programs, including antigen presentation (MHC-II) and inflammatory signaling, whereas shorter OS pt tumors were enriched for epithelial-to-mesenchymal transition, hypoxia and oncofetal markers, independent of mutation status. DGE of BRAF V600E-only tumors showed longer OS to be associated with immune and antigen presentation signatures with retained differentiation markers, whereas shorter OS corresponded with increased receptor tyrosine kinase signaling and extracellular matrix remodeling genes. DGE in RAS-mutant-only tumors showed shorter OS to be associated with increased proliferative, angiogenic, and mesenchymal/stromal gene profiles. Longer OS corresponded with higher epithelial/differentiation marker and metabolic/secretory programs. In addition, MAPK/ERK activity was associated with improved OS in BRAF V600E pts, but reduced OS in pts with RAS mutations, consistent with differences in targeted therapy.
Survival in ATC is associated with baseline transcriptional programs rather than driver mutation status alone. Specific differentiation and immune activation features are associated with longer OS, whereas mesenchymal, hypoxic, and proliferative programs are associated with shorter OS. These associations differ by cohort, supporting integrated molecular stratification beyond oncogene status to inform prognosis and therapeutic strategies in ATC.
Brian A. McKinley, Haifeng Zhu, Rare Tumor Initiative Team, Ramona Dadu, Jennifer R. Wang, Naifa L. Busaidy, Sabitha Prabhakaran, P Andrew. Futreal, Maria E. Cabanillas, Scott E. Woodman. Specific cancer cell and immune features mediate atezolizumab-regimen clinical benefit in anaplastic thyroid cancer (ATC) independent of BRAF or RAS oncogenic status [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Breaking Barriers in the Fight against Rare Cancers; 2026 Jul 18-20; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2026;86(14_Suppl):Abstract nr A053.
Brian McKinley, Haifeng Zhu, Rare Tumor Initiative Team et al.· Cancer Research· 0 citations
Background: Mortality from thyroid cancer is driven by advanced forms of the disease. While second-line therapies have been approved and recognized in thyroid cancer guidelines, development of toxicity and resistance requires addition of salvage treatments. Methods: This retrospective cohort study evaluates the utility of pemetrexed as single agent or in combination with carboplatin for advanced radioiodine refractory differentiated and anaplastic thyroid cancer (ATC) treated at Memorial Sloan Kettering Cancer Center between December, 2023, and December, 2025. Our primary outcome was best overall response, and secondary outcomes were progression-free survival and disease-specific survival. Results: Twenty-two patients (11 with ATC), 68% females, and 95% with distant metastatic disease, received pemetrexed single agent or in combination with carboplatin as a fourth-line therapy for a median duration of about 5 months. Median time to pemetrexed initiation was 73 months. Partial response (PR) was observed in 6/22 (27%) of all patients and in 5/11 (45%) with non-ATC. Median progression-free survival was 148 days for all tumors and 375 days for patients with non-ATC. One patient with ATC remains on pemetrexed/carboplatin with a PR to therapy. Conclusions: Pemetrexed single agent or in combination with carboplatin has comparable efficacy to approved second-line therapies for advanced thyroid cancer. Prospective Phase II and III clinical trials are needed to confirm the efficacy of this salvage therapy.
Laura Boucai, Rodrigo Fano, Eric J. Sherman et al.· Thyroid· 0 citations
Collectively, the advances are an indication of a transition to the personalized, mechanism-driven treatment strategies that would prolong the survivability of patients with advanced thyroid cancer, conquer resistance, and reduce systemic toxicity.
Tanmoy Sarkar, Ruhi Arisha, S. Sengupta et al.· Clinical and Translational O...· 0 citations
The standard first-line treatment for patients with recurrent or metastatic nasopharyngeal carcinoma (R/M-NPC) is currently a combination of a programmed cell death protein-1 (PD-1) blockade and gemcitabine-cisplatin. However, effective options beyond second-line settings are limited, and a recommended regimen is currently unavailable. This report presents a case study highlighting the significant efficacy of onatasertib, a dual mechanistic target of rapamycin (mTOR) 1/2 inhibitor, in overcoming resistance to immunotherapy in patients with R/M-NPC. A 28-year-old female patient who was diagnosed with nasopharyngeal carcinoma (NPC) experienced tumor relapse following progression on multiple lines of therapy, including immunotherapy. Subsequently, the patient participated in a phase I/II study (TORCH-2) investigating the combination of onatasertib and toripalimab in patients with advanced solid tumors. The patient achieved a nearly complete remission (CR) and experienced a progression-free survival (PFS) of 16 months. This unique case report highlights the efficacy of onatasertib, a dual mTOR1/2 inhibitor, in treating patients with R/M-NPC who have developed resistance to immunotherapy. The occurrence of a grade 2 serious adverse event (AE) underscores the importance of monitoring patients closely during treatment and the need to adjust dosages when necessary to minimize AEs. Meanwhile, it is important to note that the small sample size in this case is a significant limitation. Therefore, further randomized clinical trials are required to evaluate the efficacy and safety of this combination treatment in patients with acquired immunotherapy resistance and R/M-NPC.
Peipei Zhang, Zhanpeng Zhang, Jun Liu et al.· Frontiers in Pharmacology· 0 citations
Neoadjuvant therapy aims to reduce tumor size, increase resectability, eliminate micrometastases, and improve outcomes for patients with advanced non‑small cell lung cancer (NSCLC). Platinum‑based chemotherapy was the standard neoadjuvant treatment strategy in the past. In recent years, the emergence of targeted therapy and immunotherapy has significantly promoted neoadjuvant strategies. Immune checkpoint inhibitors (ICIs) such as programmed cell death 1 (PD-1) inhibitors, programmed cell death ligand 1 (PD-L1) inhibitors, and cytotoxic T lymphocyte associated protein 4 (CTLA-4) inhibitors represent established therapeutic agents in the treatment of NSCLC. In terms of targeted therapy, tyrosine kinase inhibitors (TKI) against driver genes such as epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) have shown promising potential in patients with driver mutations. Meanwhile, numerous clinical studies have demonstrated that neoadjuvant combination therapy can markedly improve pathological complete response (pCR) rates and event‑free survival (EFS). The CheckMate-816 trial confirmed that nivolumab plus chemotherapy outperforms chemotherapy alone. However, there are still several challenges. Drug resistance, the gap between pathological response and long-term survival benefit, and the limited predictive accuracy of current biomarkers remain major challenges in neoadjuvant therapy. In the future, efforts should focus on the search for precise predictive tools to develop personalized treatment strategies. Validation of neoadjuvant combination regimens aimed at enhancing clinical efficacy and quality of life for NSCLC patients is ongoing. This review summarizes the current advances and future directions of neoadjuvant therapy for NSCLC.
Qianshuo Mao, H. Mo, Kaishang Zhang et al.· Critical reviews in oncology...· 0 citations
