Details

Autor(en) / Beteiligte

• Pouyiourou, Maria
• Kraft, Bianca N.
• Wohlfromm, Timothy
• Stahl, Michael
• Kubuschok, Boris
• Löffler, Harald
• Hacker, Ulrich T.
• Hübner, Gerdt
• Weiss, Lena
• Bitzer, Michael
• Ernst, Thomas
• Schütt, Philipp
• Hielscher, Thomas
• Delorme, Stefan
• Kirchner, Martina
• Kazdal, Daniel
• Ball, Markus
• Kluck, Klaus
• Stenzinger, Albrecht
• Bochtler, Tilmann
• Krämer, Alwin

Titel

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

Ist Teil von

• Nature communications, 2023-10, Vol.14 (1), p.6761-21, Article 6761

Ort / Verlag

London: Nature Publishing Group UK

Erscheinungsjahr

2023

Quelle

MEDLINE

Beschreibungen/Notizen

• 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. Standard of care for unfavorable-risk cancer of unknown primary (CUP) comprises platinum-based chemotherapy as first-line treatment, however therapeutic options remain limited. Here the authors report the results of a phase II trial of combined nivolumab (anti-PD1) and ipilimumab (anti-CTLA4) in patients with unfavorable CUP.