Nivolumab and ipilimumab in recurrent or refractory cancer of unknown primary: a phase II trial

作者：Maria Pouyiourou, Bianca N. Kraft, Timothy Wohlfromm, Michael Ståhl, Boris Kubuschok, H. Löffler, Ulrich Thorsten Hacker, G Hübner, Lena Weiss, Michael Bitzer, Thomas Ernst, Philipp Schütt, Thomas Hielscher, Stefan Delorme, Martina Kirchner, Daniel Kazdal, Markus Ball, Klaus Kluck, Albrecht Stenzinger, Tilmann Bochtler, Alwin Krämer · 发表于：Nature Communications · 年份：2023 · DOI：10.1038/s41467-023-42400-5 · 被引用次数：40 · 研究领域：Cancer Diagnosis and Treatment、Head and Neck Cancer Studies、Oral and Maxillofacial Pathology

Abstract Cancer of unknown primary has a dismal prognosis, especially following failure of platinum-based chemotherapy. 10-20% of patients have a high tumor mutational burden (TMB), which predicts response to immunotherapy in many cancer types. In this prospective, non-randomized, open-label, multicenter Phase II trial (EudraCT 2018-004562-33; NCT04131621), patients relapsed or refractory after platinum-based chemotherapy received nivolumab and ipilimumab following TMB high vs. TMB low stratification. Progression-free survival (PFS) represented the primary endpoint; overall survival (OS), response rates, duration of clinical benefit and safety were the secondary endpoints. The trial was prematurely terminated in March 2021 before reaching the preplanned sample size ( n = 194). Among 31 evaluable patients, 16% had a high TMB ( > 12 mutations/Mb). Overall response rate was 16% (95% CI 6-34%), with 7.7% (95% CI 1-25%) vs. 60% (95% CI 15-95%) in TMB low and TMB high , respectively. Although the primary endpoint was not met, high TMB was associated with better median PFS (18.3 vs. 2.4 months) and OS (18.3 vs. 3.6 months). Severe immune-related adverse events were reported in 29% of cases. Assessing on-treatment dynamics of circulating tumor DNA using combined targeted hotspot mutation and shallow whole genome sequencing as part of a predefined exploratory analysis identified patients benefiting from immunotherapy irrespective of initial radiologic response.