Van Dijk and Gil-Jimenez et al. described a feasibility trial in patients with muscle-invasive urothelial cancer (N=24) treated with two doses each of ipilimumab and nivolumab before surgery, which resulted in extensive primary tumor regression in most (58%) cases. Surprisingly, baseline tumoral T cell density and inflammatory signatures did not correlate with treatment responses; mutation burden showed a trend. Baseline B cell signatures negatively correlated with therapy response. On-treatment samples were enriched in tertiary lymphoid structures in complete responders, an effect that was limited if patients received corticosteroids.
Contributed by Maartje Wouters
ABSTRACT: Preoperative immunotherapy with anti-PD1 plus anti-CTLA4 antibodies has shown remarkable pathological responses in melanoma(1) and colorectal cancer(2). In NABUCCO (ClinicalTrials.gov: NCT03387761), a single-arm feasibility trial, 24 patients with stage III urothelial cancer (UC) received two doses of ipilimumab and two doses of nivolumab, followed by resection. The primary endpoint was feasibility to resect within 12 weeks from treatment start. All patients were evaluable for the study endpoints and underwent resection, 23 (96%) within 12 weeks. Grade 3-4 immune-related adverse events occurred in 55% of patients and in 41% of patients when excluding clinically insignificant laboratory abnormalities. Eleven patients (46%) had a pathological complete response (pCR), meeting the secondary efficacy endpoint. Fourteen patients (58%) had no remaining invasive disease (pCR or pTisN0/pTaN0). In contrast to studies with anti-PD1/PD-L1 monotherapy, complete response to ipilimumab plus nivolumab was independent of baseline CD8(+) presence or T-effector signatures. Induction of tertiary lymphoid structures upon treatment was observed in responding patients. Our data indicate that combined CTLA-4 plus PD-1 blockade might provide an effective preoperative treatment strategy in locoregionally advanced UC, irrespective of pre-existing CD8(+) T cell activity.
Author Info: (1) Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam, the Netherlands. (2) Department of Molecular Carcinogenesis, Netherlands Cancer Institute, Amsterdam, t
Author Info: (1) Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam, the Netherlands. (2) Department of Molecular Carcinogenesis, Netherlands Cancer Institute, Amsterdam, the Netherlands. Oncode Institute, Utrecht, the Netherlands. (3) Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland. (4) Department of Urology, Netherlands Cancer Institute, Amsterdam, the Netherlands. (5) Department of Pathology, Netherlands Cancer Institute, Amsterdam, the Netherlands. (6) Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam, the Netherlands. (7) Department of Pathology, Netherlands Cancer Institute, Amsterdam, the Netherlands. (8) Department of Pathology, Netherlands Cancer Institute, Amsterdam, the Netherlands. (9) Core Facility Molecular Pathology & Biobanking, Netherlands Cancer Institute, Amsterdam, the Netherlands. (10) Core Facility Molecular Pathology & Biobanking, Netherlands Cancer Institute, Amsterdam, the Netherlands. (11) Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland. (12) Department of Radiology, Netherlands Cancer Institute, Amsterdam, the Netherlands. (13) Department of Molecular Carcinogenesis, Netherlands Cancer Institute, Amsterdam, the Netherlands. Department of Pathology, Netherlands Cancer Institute, Amsterdam, the Netherlands. (14) Department of Biometrics, Netherlands Cancer Institute, Amsterdam, the Netherlands. (15) Department of Radiology, Netherlands Cancer Institute, Amsterdam, the Netherlands. (16) Division of Molecular Oncology and Immunology, Netherlands Cancer Institute, Amsterdam, the Netherlands. (17) Department of Molecular Carcinogenesis, Netherlands Cancer Institute, Amsterdam, the Netherlands. Oncode Institute, Utrecht, the Netherlands. (18) Department of Pathology, Netherlands Cancer Institute, Amsterdam, the Netherlands. (19) Oncode Institute, Utrecht, the Netherlands. Division of Molecular Oncology and Immunology, Netherlands Cancer Institute, Amsterdam, the Netherlands. (20) Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland. (21) Department of Molecular Carcinogenesis, Netherlands Cancer Institute, Amsterdam, the Netherlands. Oncode Institute, Utrecht, the Netherlands. (22) Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam, the Netherlands. Division of Molecular Oncology and Immunology, Netherlands Cancer Institute, Amsterdam, the Netherlands. (23) Department of Urology, Caritas St. Josef Medical Centre, University of Regensburg, Regensburg, Germany. (24) Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam, the Netherlands. ms.vd.heijden@nki.nl. Department of Molecular Carcinogenesis, Netherlands Cancer Institute, Amsterdam, the Netherlands. ms.vd.heijden@nki.nl.
