Neoadjuvant nivolumab or nivolumab plus ipilimumab in early-stage triple-negative breast cancer: a phase 2 adaptive trial

Immune checkpoint inhibition (ICI) with chemotherapy is now the standard of care for stage II-III triple-negative breast cancer; however, it is largely unknown for which patients ICI without chemotherapy could be an option and what the benefit of combination ICI could be. The adaptive BELLINI trial explored whether short combination ICI induces immune activation (primary end point, twofold increase in CD8<sup>+</sup> T cells or IFNG), providing a rationale for neoadjuvant ICI without chemotherapy. Here, in window-of-opportunity cohorts A (4 weeks of anti-PD-1) and B (4 weeks of anti-PD-1 + anti-CTLA4), we observed immune activation in 53% (8 of 15) and 60% (9 of 15) of patients, respectively. High levels of tumor-infiltrating lymphocytes correlated with response. Single-cell RNA sequencing revealed that higher pretreatment tumor-reactive CD8<sup>+</sup> T cells, follicular helper T cells and shorter distances between tumor and CD8<sup>+</sup> T cells correlated with response. Higher levels of regulatory T cells after treatment were associated with nonresponse. Based on these data, we opened cohort C for patients with high levels of tumor-infiltrating lymphocytes (≥50%) who received 6 weeks of neoadjuvant anti-PD-1 + anti-CTLA4 followed by surgery (primary end point, pathological complete response). Overall, 53% (8 of 15) of patients had a major pathological response (<10% viable tumor) at resection, with 33% (5 of 15) having a pathological complete response. All cohorts met Simon's two-stage threshold for expansion to stage II. We observed grade ≥3 adverse events for 17% of patients and a high rate (57%) of immune-mediated endocrinopathies. In conclusion, neoadjuvant immunotherapy without chemotherapy demonstrates potential efficacy and warrants further investigation in patients with early triple-negative breast cancer. ClinicalTrials.gov registration: NCT03815890 .

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Journal
Nature Medicine
Published
2024-09-16
DOI
https://doi.org/10.1038/s41591-024-03249-3
Citations
53
Primary Topic
Cancer Immunotherapy and Biomarkers
Type
article
Field-Weighted Citation Impact
15.54

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article

Neoadjuvant nivolumab or nivolumab plus ipilimumab in early-stage triple-negative breast cancer: a phase 2 adaptive trial

Marta López‐Yurda, Ton N. Schumacher, Marloes G. J. van Dongen, Elisa Champanhet et al.
53 citations
Nature Medicine
Cancer Immunotherapy and Biomarkers
15.54
article

Neoadjuvant nivolumab or nivolumab plus ipilimumab in early-stage triple-negative breast cancer: a phase 2 adaptive trial

Marta López‐Yurda, Ton N. Schumacher, Marloes G. J. van Dongen, Elisa Champanhet, Roberto Salgado, Koen Van de Vijver, Emile D. Kerver, Hannah Garner, Lodewyk F.A. Wessels, Joleen J.H. Traets, Maksim A. Chelushkin, Noor A. M. Bakker, Hugo M. Horlings, Olga I. Isaeva, Gabe S. Sonke, José G. van den Berg, Natasja Klioueva, Karin E. de Visser, Ekaterina Kalashnikova, Michiel de Maaker, Caroline A. Drukker, Claudette E. Loo, Sabine C. Linn, Marleen Kok, S. Luykx, Ritse M. Mann, Frederieke van Duijnhoven, Iris Nederlof, Diether Lambrechts, Bram Boeckx, Thomas Van Brussel, Christian U. Blank, Ingrid Hofland, A.L. Rolfes, Manon De Graaf, Victoria Skinner, Ingrid A.M. Mandjes, R. Gielen
article en
53 citations

Abstract

Immune checkpoint inhibition (ICI) with chemotherapy is now the standard of care for stage II-III triple-negative breast cancer; however, it is largely unknown for which patients ICI without chemotherapy could be an option and what the benefit of combination ICI could be. The adaptive BELLINI trial explored whether short combination ICI induces immune activation (primary end point, twofold increase in CD8<sup>+</sup> T cells or IFNG), providing a rationale for neoadjuvant ICI without chemotherapy. Here, in window-of-opportunity cohorts A (4 weeks of anti-PD-1) and B (4 weeks of anti-PD-1 + anti-CTLA4), we observed immune activation in 53% (8 of 15) and 60% (9 of 15) of patients, respectively. High levels of tumor-infiltrating lymphocytes correlated with response. Single-cell RNA sequencing revealed that higher pretreatment tumor-reactive CD8<sup>+</sup> T cells, follicular helper T cells and shorter distances between tumor and CD8<sup>+</sup> T cells correlated with response. Higher levels of regulatory T cells after treatment were associated with nonresponse. Based on these data, we opened cohort C for patients with high levels of tumor-infiltrating lymphocytes (≥50%) who received 6 weeks of neoadjuvant anti-PD-1 + anti-CTLA4 followed by surgery (primary end point, pathological complete response). Overall, 53% (8 of 15) of patients had a major pathological response (<10% viable tumor) at resection, with 33% (5 of 15) having a pathological complete response. All cohorts met Simon's two-stage threshold for expansion to stage II. We observed grade ≥3 adverse events for 17% of patients and a high rate (57%) of immune-mediated endocrinopathies. In conclusion, neoadjuvant immunotherapy without chemotherapy demonstrates potential efficacy and warrants further investigation in patients with early triple-negative breast cancer. ClinicalTrials.gov registration: NCT03815890 .

Nature MedicineVol. 30(11)
Leiden University Medical Center (NL), Peter MacCallum Cancer Centre (AU), The Netherlands Cancer Institute (NL), VIB-KU Leuven Center for Cancer Biology (BE), Antwerp University Hospital (BE), OLVG (NL), Oncode Institute (NL), Natera (United States) (US), Universitair Ziekenhuis Brussel (BE), Tergooi (NL), KU Leuven (BE)
American Association for Cancer Research, Breast Cancer Research Foundation, Global Fund for Women, Bristol-Myers Squibb, Pelotonia, Natera, Universiteit Leiden, Ministerie van Volksgezondheid, Welzijn en Sport, Nederlandse Organisatie voor Wetenschappelijk Onderzoek, Universitair Ziekenhuis Gent, KU Leuven, Peter MacCallum Cancer Centre, Leids Universitair Medisch Centrum, Oncode Institute
Good health and well-being
Openalex Percentile: Top 1%
Cancer Immunotherapy and Biomarkers
15.54
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