Checkpoint Inhibition and Targeted Therapy Move the Needle in Anaplastic Thyroid Cancer

Microscopic photorealistic image of thyroid cancer cells - Generated with Google Gemini AI

Atezolizumab (Tecentriq) plus targeted therapy demonstrated longer median overall survival (OS) compared with historic controls in patients with anaplastic thyroid cancer, according to findings from a phase 2 study (NCT03181100). These findings warrant the continued investigation of checkpoint inhibition and targeted therapy in this population.

“Despite success with BRAF and MEK inhibitors, specifically for BRAF mutation, inevitably resistance occurs. Recognizing that these tumors have oncogenic driver mutations, but that invariably develop resistance to targeted therapy alone, we designed this novel trial combining atezolizumab with targeted therapy, hypothesizing that this approach would result in a significantly longer median OS, compared with historical controls,” authors of the study wrote in JAMA Oncology.

A total of 42 patients with anaplastic thyroid cancer were assigned to genetically matched targeted therapy cohorts: BRAF V600E variants, RAS or NF variants, or non-BRAF/RAS/NF variants. All patients were administered atezolizumab plus a targeted therapy according to their cohort. These were the BRAF inhibitor vemurafenib (Zelboraf) with the MEK inhibitor cobimetinib (Cotellic) for the BRAF V600E cohort, cobimetinib for the RAS/NF cohort, and the VEGF inhibitor bevacizumab (Avastin) in the non-BARF/RAS/NF cohort.

Study Results

With a median follow-up of 18.97 months (95% CI, 0.43-72.11), the median OS among all patients was 18.23 months (95% CI, 7.79-43.24). In cohort 1, the median OS was 43.24 months (95% CI, 16-not evaluable [NE]), and the median progression-free survival was 13.93 months (95% CI, 6.60-64.12). In cohort 2, the median OS was 8.74 months (95% CI, 5.12-36.96), and the median PFS was 4.80 months (95% CI, 1.84-14.69). The median OS in cohort 3 was 6.21 months (95% CI, 4.11-NE), with a median PFS of 1.35 months (95% CI, 1.35-NE).

Regarding response, the overall response rate was 31% in all cohorts, 50% in cohort 1, 14% in cohort 2, and 33% in cohort 3. One patient in cohort 1 achieved a complete response. Additionally, 12 patients had locoregional tumors that became resectable resulting from treatment.

PD-L1 Expression Testing

Thirty patients with available tissue were evaluated for PD-L1 expression. Twenty-seven patients (90%) had PD-L1 expression 5% of greater by tumor proportion score. However, there was no association between PD-L1 expression and OS, but study authors noted that 3 of 4 patients who had less than 5% PD-L1 expression had earlier disease progression between 2 and 4 courses of treatment.

Safety

In cohort 1, there was 1 patient death due to colonic perforation that was potentially related to trial participation. Further, in cohort 1, there was 1 caseof grade 2 colitis, 1 case of grade 3 papilledema due to optic nerve neuritis, 1 case of grade 1 retinopathy, 2 cases of grade 2 pancreatitis.

In cohort 2, there was 1 case of grade 1 colitis, 2 cases of grade 3 left ventricular dysfunction/decreased ejection fraction, and 1 case of grade 2 pneumonitis.

In cohort 3, there was 1 grade 2 case of esophageal perforation.

“In terms of safety, the adverse event and serious adverse event profile were expected with these combinations. There was only 1 event—colonic perforation—that led to the death of a patient in cohort 1. The likely cause was the immunotherapy, although colonic perforation has also been described with BRAF inhibitors,” study authors wrote.

REFERENCE:

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. Published online October 24, 2024. doi:10.1001/jamaoncol.2024.4729