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

Maria Pouyiourou, Bianca N. Kraft, Timothy Wohlfromm, Michael Stahl, Boris Kubuschok, Harald Löffler, Ulrich T. Hacker, Gerdt 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 and Alwin Krämer ()
Additional contact information
Maria Pouyiourou: University of Heidelberg
Bianca N. Kraft: University of Heidelberg
Timothy Wohlfromm: University of Heidelberg
Michael Stahl: Evangelische Kliniken Essen-Mitte
Boris Kubuschok: Augsburg University Medical Center and Bavarian Cancer Research Center (BZKF), Partner Cite Augsburg
Harald Löffler: Marienhospital Stuttgart
Ulrich T. Hacker: University Cancer Center Leipzig (UCCL), Leipzig University Medical Center
Gerdt Hübner: Ameos Krankenhausgesellschaft Ostholstein
Lena Weiss: University of Munich
Michael Bitzer: University Hospital Tübingen
Thomas Ernst: Jena University Hospital
Philipp Schütt: Onkologische Gemeinschaftspraxis
Thomas Hielscher: German Cancer Research Center (DKFZ)
Stefan Delorme: German Cancer Research Center (DKFZ)
Martina Kirchner: University of Heidelberg
Daniel Kazdal: University of Heidelberg
Markus Ball: University of Heidelberg
Klaus Kluck: University of Heidelberg
Albrecht Stenzinger: University of Heidelberg
Tilmann Bochtler: University of Heidelberg
Alwin Krämer: University of Heidelberg

Nature Communications, 2023, vol. 14, issue 1, 1-21

Abstract: 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 TMBhigh vs. TMBlow 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 TMBlow and TMBhigh, 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.

Date: 2023
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DOI: 10.1038/s41467-023-42400-5

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