Anti-Programmed Death Ligand 1 Plus Targeted Therapy in Anaplastic Thyroid Carcinoma: A Nonrandomized Clinical Trial

Abstract

Importance: Anaplastic thyroid carcinoma (ATC) is a rare and lethal cancer. Although progress has been made in recent years in patients with mutated BRAF tumors, those who respond initially eventually die of their disease; furthermore, there are no approved therapies for non-BRAF mutated tumors.

Objective: To determine whether treatment with matched-targeted therapy plus immune checkpoint inhibitors were associated with improved overall survival (OS).

Design, setting, and participants: A phase 2 trial at a single center, tertiary institution with parallel cohorts, assigning treatment with targeted therapy according to the tumor mutation status. Patients with mutated BRAF V600E tumors received vemurafenib/cobimetinib plus atezolizumab (cohort 1); those with mutated RAS (NRAS, KRAS, or HRAS) or NF1/2 tumors received cobimetinib plus atezolizumab (cohort 2). Patients without any of these variants were assigned to receive bevacizumab plus atezolizumab (cohort 3). Patients were enrolled from August 3, 2017, to July 7, 2021. All consecutive, systemic therapy-naive patients with ATC with active disease and who met eligibility criteria were considered for participation. The analysis was conducted in September 2023.

Interventions: Patients were assigned to targeted therapy based on the driver mutation as follow: BRAF V600E (cohort 1, vemurafenib plus cobimetinib), RAS/NF (cohort 2, cobimetinib), or non-BRAF/RAS/NF (cohort 3, bevacizumab). All received atezolizumab.

Main outcomes and measures: The primary outcome of the study was median OS of the entire targeted therapy cohort, compared with historical median OS of 5 months.

Results: Forty-three patients with ATC were enrolled in the targeted therapy cohorts, of which 42 were included in the primary analysis. The median OS in patients across these 3 cohorts was 19 months (95% CI, 7.79-43.24). Median OS and progression-free survival per cohort were as follows: cohort 1: 43 months (95% CI, 16-not estimable [NE]), 13.9 months (6.6-64.1); cohort 2: 8.7 months (95% CI, 5.1-37.0) and 4.8 months (1.8-14.7); cohort 3 (vascular endothelial growth factor inhibitor group): 6.21 months (4.1-NE) and 1.3 months (1.3-NE), respectively.

Conclusions and relevance: In this nonrandomized clinical trial, atezolizumab combined with targeted therapy resulted in a longer median OS than historical landmark, achieving the study's primary end point, with cohort 1 achieving the longest OS.

Trial registration: ClinicalTrials.gov Identifier: NCT03181100.

Figure 1.. Schema of Trial Design

All patients received atezolizumab as a part of their regimen, in addition to targeted therapy, assigned based on the driver mutation in their tumor. If patients were not eligible for their tumor mutation-determined cohort, they could be screened for another targeted-therapy cohort 1 to 3. If they were not eligible for cohorts 1 to 3 they were assigned to cohort 4, paclitaxel-based therapy with atezolizumab. The primary end point was based on the targeted-therapy cohorts 1 to 3.

Figure 2.. Oncoprint of Targeted Somatic Gene Variants of Tumors in Patients With Anaplastic Thyroid Cancer (ATC) Enrolled in Cohorts 1 to 3

Several Clinical Laboratory Improvement Amendments–certified panels were used to assay for mutations in oncogenes of ATC tumors, including liquid biopsy (shown in figure). The data shown represent the clinical sequencing conducted at or before the start of treatment. Genes that were wild type across all samples were removed from the analysis. The white space represents instances in which a gene was not assayed in a specific panel. CNV indicates copy number variation.

Figure 3.. Kaplan-Meir Curves for Overall Survival and Progression-Free Survival in Patients With Anaplastic Thyroid Cancer (ATC) Per Cohort

A, Overall survival curves for cohorts 1 to 3. B, Progression-free survival curves for cohorts 1 to 3. C and D, Waterfall plots are shown for the Response Evaluation Criteria in Solid Tumors (RECIST; version 1.1)–evaluable patients with ATC in cohorts 1 and 2, respectively. Best percent change from baseline in the target lesions in 30 patients with ATC are shown (17 in cohort 1 and 13 in cohort 2). One patient in cohort 1 had a large, nonmeasurable thyroid mass that was later resected and the patient is alive and disease-free. Six patients in cohort 2 had nonmeasurable disease, 1 died early before restaging, and 1 was not adequately restaged prior to surgical resection of their primary tumor (due to kidney insufficiency, the patient was not given contrast media; the patient is alive and disease-free). ^aPatients who underwent surgical resection of the primary tumor. Two patients (both alive at data cutoff) in cohort 1 had surgical resection of the primary tumor before a partial response was confirmed and therefore were counted as stable disease in the overall response rate.