Atezolizumab plus taxane chemotherapy for the treatment of non-BRAF, non-RAS mutated anaplastic thyroid carcinoma: Final analysis.
Authors: Hamidi Sarah , Dadu Ramona , 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 , Gunn Gary Brandon , Busaidy Naifa Lamki , Cabanillas Maria E. 
Published: June 2024

e18070

Background: Anaplastic thyroid carcinoma (ATC) is an aggressive malignancy with a historical dismal prognosis. Although BRAF/MEK inhibitors have revolutionized the treatment of BRAF-mutant ATC, treatment options remain limited for those without a BRAF mutation. Single agent immunotherapy showed modest efficacy, while combination of immunotherapy with the anti-VEGF lenvatinib led to marked improvement in survival. Yet, given the locally advanced nature of this disease, many patients have contra-indications to antiangiogenics. We assessed the safety and efficacy of the anti-PD-L1 atezolizumab combined with taxane chemotherapy in patients with non- BRAF, non- RAS/NF mutated ATC with contra-indications to VEGF inhibitors. Methods: We enrolledpatientswith ATC in a single-center phase II prospective trial of atezolizumab plus mutation-determined targeted therapy (NCT03181100). Patients without a BRAF, RAS or NF mutation who had a contra-indication to anti-VEGF therapy (such as high risk for bleeding or fistula) were included in an exploratory cohort and were treated with nab-paclitaxel 100 mg/m2 on days 1, 8 and 15, combined with atezolizumab 1200 mg intravenously every 21 days. Paclitaxel could be substituted for nab-paclitaxel, but the latter was preferred as it does not require prophylactic steroids. Here we present results for this exploratory cohort. Best response to therapy was assessed per RECIST v1.1; survival by the Kaplan-Meier method. Results: Nine patients were enrolled in the exploratory cohort. All were naïve to systemic therapies, and 3/9 (33%) received prior bridging cytotoxic chemotherapy. Prior to study entrance, 6/9 (67%) had radiation therapy to the neck and 4/9 (44%) had surgery to resect the primary tumor. Seven (78%) had distant metastatic disease at time of enrollment. Most frequent baseline mutations were in TP53 (89%), APC (33%), PTEN (33%) and TERT promoter (33%). Median duration of follow-up was 4.4 months. Best response to therapy was partial response in 2 patients (1 confirmed and 1 unconfirmed), stable disease in 3 patients, and progressive disease in 4 patients. Overall response rate was 11 %, while disease control rate was 56%. Median OS was 4.44 months (95% CI, 1.12 –25.33) and median progression-free survival was 2.73 months (95% CI, 1.12 – 7.13). All patients had died at the time of data cut-off. Regarding treatment safety, the combination of atezolizumab plus taxane chemotherapy was overall well tolerated, with most adverse events being grade 2 or lower. Conclusions: Combination of atezolizumab plus taxane chemotherapy, although safe, offers limited additional survival benefit compared to single agent immunotherapy (median OS = 5.9 months) or the historical median OS of 5 months. Additional novel treatment strategies for patients with non- BRAF mutated ATC are warranted, especially when antiangiogenic drugs are contra-indicated. Clinical trial information: NCT03181100 .