A nonrandomized phase 2 clinical trial conducted at the University of Texas MD Anderson Cancer Center has shown promising results for a novel combination therapy approach in patients with anaplastic thyroid carcinoma (ATC), a rare and aggressive form of thyroid cancer. The study, funded by Genentech and the Rare Tumor Initiative at MD Anderson, was published on October 24, 2024, in JAMA Oncology.
The trial aimed to determine whether combining targeted therapy with immune checkpoint inhibition could improve overall survival (OS) in patients with ATC compared to historical controls. Forty-three patients were enrolled between August 3, 2017, and July 7, 2021, with 42 included in the primary analysis.
Patients were assigned to one of three cohorts based on their tumor's genetic profile: 1. BRAF V600E mutation: vemurafenib, cobimetinib, and atezolizumab 2. RAS or NF1/2 mutations: cobimetinib and atezolizumab 3. Non-BRAF/RAS/NF mutations: bevacizumab and atezolizumab
The study included systemic therapy-naive patients with active ATC disease and an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or lower. Notably, the trial allowed for alternative drug administration methods for patients who could not swallow pills, as well as bridging chemotherapy during the screening process. These inclusive criteria enabled the enrollment of a broader patient population more representative of real-world clinical scenarios.
Demographic data showed a median age of 66 years in cohorts 1 and 2, and 51 years in cohort 3. The majority of patients were white and non-Hispanic, with a relatively even distribution between males and females. Most patients had stage IVC disease at diagnosis, with distant metastases present at the start of the trial.
The primary endpoint of median OS across all three cohorts was 18.23 months (95% CI, 7.79-43.24), significantly exceeding the historical median OS of 5 months for ATC. Cohort 1 (BRAF-mutated) demonstrated particularly impressive results, with a median OS of 43.24 months (95% CI, 16-NE) and a median progression-free survival (PFS) of 13.93 months (95% CI, 6.60-64.13).
Overall response rates varied between cohorts, with 50% in cohort 1, 14% in cohort 2, and 33% in cohort 3. Notably, 15 patients (36%) across all cohorts received treatment for longer than 12 months, and 20 (48%) were alive at 2 years.
An important aspect of the study was the allowance for surgical intervention during the trial. Twelve patients with initially unresectable tumors became candidates for surgery following treatment, with 11 undergoing resection. Of these, 8 (73%) were still alive at the time of data cutoff, and 9 (81%) showed no viable ATC in their surgical specimens.
The safety profile of the combination therapies was generally consistent with known adverse events for the individual drugs. One death possibly related to trial participation occurred due to colonic perforation in cohort 1. Other notable serious adverse events included colitis, papilledema, retinopathy, left ventricular dysfunction, pneumonitis, pancreatitis, and esophageal perforation.
While the results are promising, the study has several limitations. The lack of a control arm is a common challenge in rare tumor research. Additionally, the allowance for surgery and radiation therapy during the trial may have contributed to improved survival outcomes, making it difficult to isolate the effect of the drug combinations alone.
The authors concluded that mutation-directed targeted therapy combined with PD-L1 inhibitor immunotherapy is a promising strategy to extend OS in patients with ATC. They emphasized the need for further studies, particularly in non-BRAF-mutated ATC, using more effective targeted agents.
The potential clinical impact of this study is significant. If confirmed in larger trials, this approach could dramatically improve outcomes for patients with ATC, a disease that has historically had very poor prognosis. The study's design, which allowed for more real-world patient scenarios, may also influence future clinical trial designs for rare and aggressive cancers.
Furthermore, the success of this genotype-directed approach underscores the importance of comprehensive molecular testing in ATC patients to guide treatment decisions. The high rate of surgical candidacy following treatment also highlights the potential for this combination therapy to serve as a neoadjuvant approach, potentially expanding treatment options for patients with initially unresectable disease.
As research in this area continues, medical professionals should be aware of these emerging combination strategies and consider referring ATC patients for molecular testing and clinical trials when appropriate. The results of this study represent a significant step forward in the treatment of this rare and aggressive cancer, offering hope for improved outcomes in a patient population that has long faced limited therapeutic options.
References
Cabanillas ME, Dadu R, Ferrarotto R, et al. Anti-Programmed Death Ligand 1 Plus Targeted Therapy in Anaplastic Thyroid Carcinoma: A Nonrandomized Clinical Trial. JAMA Oncol. 2024;10(12):1672-1680. doi:10.1001/jamaoncol.2024.4729
