Voorwerk and Slagter et al. report on a phase 2 clinical trial of 66 triple-negative breast cancer patients treated with nivolumab preceded by low-dose irradiation or chemotherapy. In this ‘pick-the-winner’ trial design, pretreatment with doxorubicin or cisplatin upregulated inflammatory and immune-related gene profiles in tumors and increased objective response rates compared to cyclophosphamide or irradiation. Responders showed higher PD-L1 on immune cells, reduced circulating carcinoembryonic antigen levels, and increased TCR infiltration, clonality and diversity on treatment (particularly in the doxorubicin arm); mutational burden did not correlate with response.
Contributed by Alex Najibi
The efficacy of programmed cell death protein 1 (PD-1) blockade in metastatic triple-negative breast cancer (TNBC) is low(1-5), highlighting a need for strategies that render the tumor microenvironment more sensitive to PD-1 blockade. Preclinical research has suggested immunomodulatory properties for chemotherapy and irradiation(6-13). In the first stage of this adaptive, non-comparative phase 2 trial, 67 patients with metastatic TNBC were randomized to nivolumab (1) without induction or with 2-week low-dose induction, or with (2) irradiation (3 x 8 Gy), (3) cyclophosphamide, (4) cisplatin or (5) doxorubicin, all followed by nivolumab. In the overall cohort, the objective response rate (ORR; iRECIST(14)) was 20%. The majority of responses were observed in the cisplatin (ORR 23%) and doxorubicin (ORR 35%) cohorts. After doxorubicin and cisplatin induction, we detected an upregulation of immune-related genes involved in PD-1-PD-L1 (programmed death ligand 1) and T cell cytotoxicity pathways. This was further supported by enrichment among upregulated genes related to inflammation, JAK-STAT and TNF-alpha signaling after doxorubicin. Together, the clinical and translational data of this study indicate that short-term doxorubicin and cisplatin may induce a more favorable tumor microenvironment and increase the likelihood of response to PD-1 blockade in TNBC. These data warrant confirmation in TNBC and exploration of induction treatments prior to PD-1 blockade in other cancer types.
Author Info: (1) Division of Molecular Oncology & Immunology, The Netherlands Cancer Institute, Amsterdam, the Netherlands. (2) Division of Molecular Oncology & Immunology, The Netherlands Canc
Author Info: (1) Division of Molecular Oncology & Immunology, The Netherlands Cancer Institute, Amsterdam, the Netherlands. (2) Division of Molecular Oncology & Immunology, The Netherlands Cancer Institute, Amsterdam, the Netherlands. Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, Amsterdam, the Netherlands. Oncode Institute, Utrecht, the Netherlands. (3) Department of Pathology, The Netherlands Cancer Institute, Amsterdam, the Netherlands. (4) Department of Biometrics, The Netherlands Cancer Institute, Amsterdam, the Netherlands. (5) Department of Pathology, The Netherlands Cancer Institute, Amsterdam, the Netherlands. Department of Pathology, Ghent University Hospital, Ghent, Belgium. (6) Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, the Netherlands. (7) Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, the Netherlands. (8) Genomics Core Facility, The Netherlands Cancer Institute, Amsterdam, the Netherlands. (9) NanoString Technologies, Inc., Seattle, WA, USA. (10) NanoString Technologies, Inc., Seattle, WA, USA. (11) Department of Radiation Oncology, The Netherlands Cancer Institute, Amsterdam, the Netherlands. (12) Department of Radiation Oncology, The Netherlands Cancer Institute, Amsterdam, the Netherlands. (13) Department of Radiology, The Netherlands Cancer Institute, Amsterdam, the Netherlands. (14) Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, the Netherlands. (15) Oncode Institute, Utrecht, the Netherlands. Division of Tumor Biology & Immunology, The Netherlands Cancer Institute, Amsterdam, the Netherlands. (16) Division of Molecular Oncology & Immunology, The Netherlands Cancer Institute, Amsterdam, the Netherlands. (17) Core Facility Molecular Pathology & Biobanking, The Netherlands Cancer Institute, Amsterdam, the Netherlands. (18) Department of Radiology, The Netherlands Cancer Institute, Amsterdam, the Netherlands. (19) Department of Biometrics, The Netherlands Cancer Institute, Amsterdam, the Netherlands. (20) Department of Biometrics, The Netherlands Cancer Institute, Amsterdam, the Netherlands. (21) Department of Biometrics, The Netherlands Cancer Institute, Amsterdam, the Netherlands. (22) Department of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, the Netherlands. (23) Department of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, the Netherlands. (24) Division of Molecular Oncology & Immunology, The Netherlands Cancer Institute, Amsterdam, the Netherlands. Department of Gastrointestinal Oncology, The Netherlands Cancer Institute, Amsterdam, the Netherlands. (25) Department of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, the Netherlands. (26) Division of Molecular Oncology & Immunology, The Netherlands Cancer Institute, Amsterdam, the Netherlands. Department of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, the Netherlands. (27) Department of Pathology, GZA-ZNA Ziekenhuizen, Antwerp, Belgium. Division of Research, Peter Mac Callum Cancer Center, Melbourne, Victoria, Australia. (28) Oncode Institute, Utrecht, the Netherlands. Division of Tumor Biology & Immunology, The Netherlands Cancer Institute, Amsterdam, the Netherlands. (29) Department of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, the Netherlands. (30) Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, Amsterdam, the Netherlands. Oncode Institute, Utrecht, the Netherlands. (31) Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, the Netherlands. Department of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, the Netherlands. (32) Division of Molecular Oncology & Immunology, The Netherlands Cancer Institute, Amsterdam, the Netherlands. Oncode Institute, Utrecht, the Netherlands. (33) Division of Molecular Oncology & Immunology, The Netherlands Cancer Institute, Amsterdam, the Netherlands. Department of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, the Netherlands. (34) Division of Molecular Oncology & Immunology, The Netherlands Cancer Institute, Amsterdam, the Netherlands. m.kok@nki.nl. Department of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, the Netherlands. m.kok@nki.nl.
