Cobimetinib plus atezolizumab for RAS and NF1/2-mutated poorly differentiated thyroid carcinoma.
Authors: Hamidi Sarah , Dadu Ramona , Busaidy Naifa Lamki , Ferrarotto Renata , Gule-Monroe Maria , Liu Suyu , Fellman Bryan M. , Williams Michelle D. , Zafereo Mark E. , Wang Rui Jennifer , Lu Charles , Ning Matthew S. , McKinley Brian , Woodman Scott Eric , Duose Dzifa Yawa , Cabanillas Maria E. , Gunn Gary Brandon 
Published: July 2024

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Background: Poorly differentiated thyroid carcinomas (PDTC) are a subset of thyroid cancers characterized by high-grade pathologic features. They hold an intermediate position on the spectrum of follicular-derived thyroid cancers. Due to their more aggressive clinical behavior, PDTCs typically exhibit shorter responses to the usual kinase inhibitors (KIs) used in advanced differentiated thyroid cancers and develop resistance earlier on. In fact, median progression free survival (PFS) with single-agent lenvatinib in patients with PDTC in the SELECT trial (n=28) was 14.8 months. Although there are increasing data to support the use of immunotherapy plus KI combinations in anaplastic thyroid cancer, evidence demonstrating the efficacy of this strategy in PDTC is sparse. We aimed to study the safety and efficacy of atezolizumab combined with KIs in PDTC. Methods: We enrolledpatientswith PDTC in a single-center phase II prospective trial of atezolizumab plus mutation-determined targeted therapy (NCT03181100). Patients with RAS or NF- mutated tumors were treated with atezolizumab plus the MEK inhibitor (MEKi) cobimetinib. Primary outcome was median overall survival (mOS). Best response to therapy was assessed per RECIST v1.1; survival by the Kaplan-Meier method. Results: Eight patients with RAS/NF-mutated PDTC were enrolled. Median age at treatment start was 68.5 years. All patients had distant metastatic disease at time of enrollment. Prior to study entrance, 7/8 patients (88%) had surgical resection of the primary tumor, 6/8 (75%) radioactive iodine, 2/8 (25%) external beam radiation to the neck, and 3/8 (38%) bridging cytotoxic chemotherapy. All patients were naïve to KIs. Six (75%) patients had RAS mutations (1 HRAS, 3 KRAS, 2 NRAS) and 3 (38%) had NF mutations (2 NF1, 1 NF2). One patient’s tumor harbored both KRAS and NF2 mutations at baseline. PD-L1 score was positive in 3/4 evaluable specimens. Median duration of follow-up was 65 months. Best response to therapy was stable disease in 6/8 (75%), partial response in 1/8 (12.5%) and progressive disease in 1/8 (12.5%). mOS was 23 months (95% CI, 12.8 – 33.2) and median PFS was 7 months (95% CI, 2.4 – 11.6). 4/8 patients received radioactive iodine (RAI) while on systemic therapy. Median dose of RAI was 149 millicuries (range, 108 – 153). mOS was significantly longer in patients who received RAI (32 vs 16 months; p= 0.034). The combination of cobimetinib + atezolizumab was overall well tolerated, with an expected adverse event profile. Conclusions: In patients with metastatic PDTC driven by RAS or NFmutations, combination of the anti-PD-L1 atezolizumab with MEKi cobimetinib showed some clinical efficacy, although PFS was shorter than with single-agent lenvatinib. However, SELECT trial did not delineate responses by driver mutations. This combination could thus be considered in selected patients at high risk of complications with antiangiogenic KIs. Clinical trial information: NCT03181100 .