Abstract
Invasive lobular breast cancer (ILC) is the second most common histological breast cancer subtype, but ILC-specific trials are lacking. Translational research revealed an immune-related ILC subset, and in mouse ILC models, synergy between immune checkpoint blockade and platinum was observed. In the phase II GELATO trial (NCT03147040), patients with metastatic ILC were treated with weekly carboplatin (area under the curve 1.5 mg ml–1 min–1) as immune induction for 12 weeks and atezolizumab (PD-L1 blockade; triweekly) from the third week until progression. Four of 23 evaluable patients had a partial response (17%), and 2 had stable disease, resulting in a clinical benefit rate of 26%. From these six patients, four had triple-negative ILC (TN-ILC). We observed higher CD8+ T cell infiltration, immune checkpoint expression and exhausted T cells after treatment. With this GELATO trial, we show that ILC-specific clinical trials are feasible and demonstrate promising antitumor activity of atezolizumab with carboplatin, particularly for TN-ILC, and provide insights for the design of highly needed ILC-specific trials.
| Original language | English |
|---|---|
| Pages (from-to) | 535-549 |
| Number of pages | 15 |
| Journal | Nature Cancer |
| Volume | 4 |
| Issue number | 4 |
| DOIs | |
| Publication status | Published - 10 Apr 2023 |
Bibliographical note
Funding Information:Anti-PD-L1 was continued until disease progression according to RECISTv1.1 (ref. ), clinical progression or unacceptable toxicity. Before the start of carboplatin, after two cycles of carboplatin (2 weeks from baseline) and after two cycles of anti-PD-L1 (plus six weekly administrations of carboplatin, 8 weeks from baseline), blood was drawn, and sequential biopsies from a metastatic lesion were taken. The first six patients were included in a 3 + 3 phase Ib safety run-in part with the same treatment schedule and were included in the total number of participants. This investigator-initiated trial was sponsored by the NKI, and atezolizumab was provided by Roche. Patients were not financially compensated for their involvement in the study.
Funding Information:
We are grateful to the participants and their families for participating in the trial. We thank all supporting clinical trial staff, in particular M. Jansen, G. de Vries and the Departments of Medical Oncology, Radiology, Pathology and Dermatology of the participating centers. We thank the triallab of the NKI for handling incoming blood samples. We acknowledge the Scientific Administration departments of participating centers, particularly A. Jayakkumaran and M. Sondermeijer. We thank M. Holtkamp and K. Kersten for participant visits and supporting the scheduling of participants. We are grateful to the Core Facility of Molecular Pathology and Biobanking for the storage and handling of human tumor material and to the Genomics Core Facility, in particular R. Kluin, W. Brugman and C. van Steenis, for DNA and RNA sequencing. We thank M. Bruggeman, M. Duijst and C. Klaver for blood sample experiments and the Flow Cytometry Facility for support in these experiments. We acknowledge PALGA, the Dutch Pathology Registry, for enabling collection of archived material. We thank R. Meijer and J. Paardekooper Overman from Roche for enabling the trial and arranging supply of atezolizumab. R.S. is supported by the Breast Cancer Research Foundation (grant number 17-194). Research at the NKI is supported by institutional grants of the Dutch Cancer Society and of the Dutch Ministry of Health, Welfare and Sport. Research in the laboratory of M.K. is funded by the Netherlands Organization for Scientific Research (NWO-VIDI 09150172010043) and the Hendrika Roet fund. This work was supported by F. Hoffmann-La Roche, Ltd., Basel, Switzerland (no grant numbers apply). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.
Funding Information:
We are grateful to the participants and their families for participating in the trial. We thank all supporting clinical trial staff, in particular M. Jansen, G. de Vries and the Departments of Medical Oncology, Radiology, Pathology and Dermatology of the participating centers. We thank the triallab of the NKI for handling incoming blood samples. We acknowledge the Scientific Administration departments of participating centers, particularly A. Jayakkumaran and M. Sondermeijer. We thank M. Holtkamp and K. Kersten for participant visits and supporting the scheduling of participants. We are grateful to the Core Facility of Molecular Pathology and Biobanking for the storage and handling of human tumor material and to the Genomics Core Facility, in particular R. Kluin, W. Brugman and C. van Steenis, for DNA and RNA sequencing. We thank M. Bruggeman, M. Duijst and C. Klaver for blood sample experiments and the Flow Cytometry Facility for support in these experiments. We acknowledge PALGA, the Dutch Pathology Registry, for enabling collection of archived material. We thank R. Meijer and J. Paardekooper Overman from Roche for enabling the trial and arranging supply of atezolizumab. R.S. is supported by the Breast Cancer Research Foundation (grant number 17-194). Research at the NKI is supported by institutional grants of the Dutch Cancer Society and of the Dutch Ministry of Health, Welfare and Sport. Research in the laboratory of M.K. is funded by the Netherlands Organization for Scientific Research (NWO-VIDI 09150172010043) and the Hendrika Roet fund. This work was supported by F. Hoffmann-La Roche, Ltd., Basel, Switzerland (no grant numbers apply). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.
Publisher Copyright:
© 2023, The Author(s).
