Cabozantinib plus atezolizumab in locally advanced/metastatic adrenocortical carcinoma: Results from a multi-cohort basket phase II trial, CABATEN/GETNE-T1914.
Authors: Grande Enrique , Benavent Viñuales Marta , Molina-Cerrillo Javier , Teule Alex , Jimenez-Fonseca Paula , Carmona-Bayonas Alberto , López Carlos , Garcia-Carbonero Rocio , Hierro Cinta , Custodio Ana , Martinez-Trufero Javier , Llanos Marta , Sevilla Isabel , Hernando Jorge , Gallego Jimenez Inmaculada , Alonso-Gordoa Teresa , Gallego Javier , Capdevila Jaume 
Published: February 2024

1 Background: Adrenocortical carcinoma (ACC) is a rare malignancy with a poor prognosis and limited therapeutic options. Immunotherapy and targeted therapy showed limited activity as single therapeutic strategies in ACC but synergism has been observed when combined in other genitourinary tumors such as Prostate and renal cell cancers. Therefore, we evaluated the activity and safety of cabozantinib plus atezolizumab in advanced/metastatic ACC. Methods: CABATEN was a prospective, multi-center, open-label, phase II study including patients with advanced and refractory endocrine and neuroendocrine tumors in 6 independent cohorts. Patients with locally advanced / metastatic ACC, ≥18 years old and ECOG 0-1 were included after progression to chemotherapy and/or mitotane. Prior treatment with cabozantinib or any immune checkpoint inhibitors was not allowed. Patients received atezolizumab 1200 mg IV Q3W plus cabozantinib 40 mg/day PO until progression or unacceptable toxicity. The primary endpoint was Objective Response Rate (ORR) by RECIST 1.1. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety. The study empowered a Simon II stage design, requiring 1 response out of 9 patients at 1st stage to continue accrual in a 2nd stage, for a total of 24 patients. Three responses out of the 24 patients were required in the 2nd stage to consider the study positive for the cohort. Results: From October 2020 to November 2022, 24 patients with ACC were included, 54.2% were female and the median age was 51 years. Most (87.5%) were metastatic at inclusion, 45.8% were functioning, and 20.8% presented hypercortisolism. Most patients (54.2%) had ≥ 2 prior lines of systemic therapy for advanced disease (chemotherapy 91.7%, mitotane 45.8%). Cabozantinib was administered for a median of 3 months (95% CI: 2.7-6.1) and required reduction to 20 mg/day in 20.8% of patients. Atezolizumab was administered for a median of 4.5 cycles (95% CI: 4-8). Treatment was discontinued mainly due to disease progression (79.2%). Treatment discontinuation due to toxicity occurred in 9 (9.7%) patients. The ORR was 8.3% (95% CI: 1-27), including two partial responses that lasted for 5.4 and 17.4 months respectively. After a median follow-up of 10.7 months (range: 2.1-25.7), the median PFS was 2.9 months (95% CI: 2.8-5.7) and the median OS was 13.5 months (95% CI: 8.8-NR). Treatment-related adverse events (grade ≥3) were observed in 20.8% of the patients, consisting of hypertension (12.5%), and transaminase increase (8.3%). Conclusions: Cabozantinib plus atezolizumab showed modest activity in locally advanced/metastatic ACC. Safety profile was consistent with previous reports. The existence of long lasting responders makes it worthwhile to continue investigating predictive factors that help select patients for this combination. Clinical trial information: EudraCT:2019-002279-32 / NCT04400474 .