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- Title
Nivolumab and ipilimumab in recurrent or refractory cancer of unknown primary: a phase II trial.
- Authors
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
- 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. 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.
- Subjects
CANCER of unknown primary origin; CIRCULATING tumor DNA; DRUG side effects; PEMETREXED; NIVOLUMAB; WHOLE genome sequencing; IRINOTECAN; CISPLATIN
- Publication
Nature Communications, 2023, Vol 14, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-023-42400-5