Atezolizumab plus taxane chemotherapy for the treatment of non-<i>BRAF</i>, non-<i>RAS</i> mutated anaplastic thyroid carcinoma: Final analysis.
Authors: Sarah Hamidi, Ramona Dadu, Renata Ferrarotto, Maria Gule-Monroe, Suyu Liu, Bryan M. Fellman, Michelle D. Williams, Mark E. Zafereo, Rui Jennifer Wang, Charles Lu, Matthew S. Ning, Brian McKinley, Scott Eric Woodman, Dzifa Yawa Duose, Gary Brandon Gunn, Naifa Lamki Busaidy, Maria E. Cabanillas
Journal: Journal of Clinical Oncology (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/m 2 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 .