In an adaptive, window-of-opportunity phase II neoadjuvant trial in early breast cancer, Nederlof and Isaeva et al. report that 4 weeks of anti-PD-1 or anti-PD-1 + anti-CTLA-4 showed immune activation in 53% and 60% of patients, and clinical response correlated with higher pretreatment TILs. Based on these results, a new cohort requiring TILs ≥50% was initiated, which received 6 weeks of neoadjuvant anti-PD-1 + anti-CTLA-4, followed by surgery. 8 out of 15 patients achieved an MPR (<10% viable tumor), with 5 achieving a pCR. In pretreatment TMEs, higher tumor-reactive CD8+ T cells and Tfh cells, and shorter distances between tumor and CD8+ T cells correlated with response.
Contributed by Shishir Pant
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+ 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+ T cells, follicular helper T cells and shorter distances between tumor and CD8+ 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 .
Author Info: (1) Division of Tumor Biology and Immunology, The Netherlands Cancer Institute, Amsterdam, the Netherlands. (2) Division of Tumor Biology and Immunology, The Netherlands Cancer Ins
Author Info: (1) Division of Tumor Biology and Immunology, The Netherlands Cancer Institute, Amsterdam, the Netherlands. (2) Division of Tumor Biology and Immunology, The Netherlands Cancer Institute, Amsterdam, the Netherlands. (3) Division of Tumor Biology and Immunology, The Netherlands Cancer Institute, Amsterdam, the Netherlands. (4) Division of Tumor Biology and Immunology, The Netherlands Cancer Institute, Amsterdam, the Netherlands. (5) Division of Tumor Biology and Immunology, The Netherlands Cancer Institute, Amsterdam, the Netherlands. Oncode Institute, Utrecht, the Netherlands. (6) Division of Tumor Biology and Immunology, The Netherlands Cancer Institute, Amsterdam, the Netherlands. (7) Division of Tumor Biology and Immunology, The Netherlands Cancer Institute, Amsterdam, the Netherlands. Oncode Institute, Utrecht, the Netherlands. (8) Laboratory for Translational Genetics, Department of Human Genetics, KU Leuven, Leuven, Belgium. VIB Center for Cancer Biology, Leuven, Belgium. (9) Division of Tumor Biology and Immunology, The Netherlands Cancer Institute, Amsterdam, the Netherlands. (10) Biometrics Department, The Netherlands Cancer Institute, Amsterdam, the Netherlands. (11) Core Facility Molecular Pathology & Biobanking, The Netherlands Cancer Institute, Amsterdam, the Netherlands. (12) Laboratory for Translational Genetics, Department of Human Genetics, KU Leuven, Leuven, Belgium. VIB Center for Cancer Biology, Leuven, Belgium. (13) Division of Tumor Biology and Immunology, The Netherlands Cancer Institute, Amsterdam, the Netherlands. (14) Division of Tumor Biology and Immunology, The Netherlands Cancer Institute, Amsterdam, the Netherlands. (15) Biometrics Department, The Netherlands Cancer Institute, Amsterdam, the Netherlands. (16) Department of Pathology, UZ Gent - Universitair Ziekenhuis Gent, Gent, Belgium. Department of Pathology, The Netherlands Cancer Institute, Amsterdam, the Netherlands. (17) Department of Pathology, The Netherlands Cancer Institute, Amsterdam, the Netherlands. (18) Core Facility Molecular Pathology & Biobanking, The Netherlands Cancer Institute, Amsterdam, the Netherlands. (19) Department of Pathology, OLVG Hospital, Amsterdam, the Netherlands. (20) Department of Radiology, The Netherlands Cancer Institute, Amsterdam, the Netherlands. (21) Department of Radiology, The Netherlands Cancer Institute, Amsterdam, the Netherlands. (22) Department of Surgical Oncology, The Netherlands Cancer Institute, Amsterdam, the Netherlands. (23) Department of Surgical Oncology, The Netherlands Cancer Institute, Amsterdam, the Netherlands. (24) Medical Oncology Department, Tergooi Hospital - locatie Hilversum, Hilversum, the Netherlands. (25) Department of Oncology, OLVG Hospital, Amsterdam, the Netherlands. (26) Natera, San Carlos, CA, USA. (27) Department of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, the Netherlands. (28) Department of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, the Netherlands. (29) Department of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, the Netherlands. (30) Department of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, the Netherlands. Division of Molecular Oncology and Immunology, The Netherlands Cancer Institute, Amsterdam, the Netherlands. (31) Division of Tumor Biology and Immunology, The Netherlands Cancer Institute, Amsterdam, the Netherlands. Oncode Institute, Utrecht, the Netherlands. Department of Immunology, Leiden University Medical Center, Leiden, the Netherlands. (32) Department of Pathology, ZAS hospitals, Antwerp, Belgium. Division of Research, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. (33) Oncode Institute, Utrecht, the Netherlands. Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, Amsterdam, the Netherlands. (34) Department of Surgical Oncology, The Netherlands Cancer Institute, Amsterdam, the Netherlands. (35) Oncode Institute, Utrecht, the Netherlands. Division of Molecular Oncology and Immunology, The Netherlands Cancer Institute, Amsterdam, the Netherlands. Department of Hematology, Leiden University Medical Center, Leiden, the Netherlands. (36) Department of Pathology, The Netherlands Cancer Institute, Amsterdam, the Netherlands. (37) Laboratory for Translational Genetics, Department of Human Genetics, KU Leuven, Leuven, Belgium. VIB Center for Cancer Biology, Leuven, Belgium. (38) Division of Tumor Biology and 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.
