AUTHOR=Ascierto Paolo A. , Cioli Eleonora , Chiarion-Sileni Vanna , Quaglino Pietro , Spagnolo Francesco , Guidoboni Massimo , Del Vecchio Michele , Peris Ketty , Queirolo Paola , Fioretto Luisa , Caracò Corrado , Paone Miriam , Sorrentino Antonio , Capone Mariaelena , Giannarelli Diana , Ferrara Gerardo , Massi Daniela , Trojaniello Claudia 

TITLE=Neoadjuvant plus adjuvant combined or sequenced vemurafenib, cobimetinib and atezolizumab in patients with high-risk, resectable BRAF-mutated and wild-type melanoma: NEO-TIM, a phase II randomized non-comparative study

JOURNAL=Frontiers in Oncology

VOLUME=13

YEAR=2023

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2023.1107307

DOI=10.3389/fonc.2023.1107307

ISSN=2234-943X

ABSTRACT=<sec><title>Background</title><p>Following the increased survival of patients with metastatic melanoma thanks to immunotherapy and targeted therapy, neoadjuvant approaches are being investigated to address the unmet needs of unresponsive and intolerant patients. We aim to investigate the efficacy of neoadjuvant plus adjuvant combined or sequenced vemurafenib, cobimetinib and atezolizumab in patients with high-risk, resectable <italic>BRAF</italic>-mutated and wild-type melanoma.</p></sec><sec><title>Methods</title><p>The study is a phase II, open-label, randomized non-comparative trial in patients with stage IIIB/C/D surgically resectable, <italic>BRAF</italic>-mutated and wild-type melanoma, with three possible treatments: (1) vemurafenib 960 mg twice daily from day 1 to 42; (2) vemurafenib 720 mg twice daily from day 1 to 42; (3) cobimetinib 60 mg once daily from day 1 to 21 and from day 29 to 42; and (4) atezolizumab 840 mg for two cycles (day 22 and day 43).</p><p>Patients will be randomized to three different arms: A) <italic>BRAF</italic>-mutated patients will receive over 6 weeks (1) + (3); B) <italic>BRAF</italic>-mutated patients will receive over 6 weeks (2) + (3) + (4); C) <italic>BRAF</italic> wild-type patients will receive over 6 weeks (3) + (4). All patients will also receive atezolizumab 1200 mg every 3 weeks for 17 cycles after surgery and after a second screening period (up to 6 weeks).</p></sec><sec><title>Discussion</title><p>Neoadjuvant therapy for regional metastases may improve operability and outcomes and facilitate the identification of biomarkers that can guide further lines of treatment. Patients with clinical stage III melanoma may especially benefit from neoadjuvant treatment, as the outcomes of surgery alone are very poor. It is expected that the combination of neoadjuvant and adjuvant treatment may reduce the incidence of relapse and improve survival.</p></sec><sec><title>Clinical trial registration</title><p><uri xlink:href="https://eudract.ema.europa.eu/protocol.htm" xmlns:xlink="http://www.w3.org/1999/xlink">eudract.ema.europa.eu/protocol.htm</uri>, identifier 2018-004841-17.</p></sec>