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Durvalumab compared to maintenance chemotherapy in metastatic breast cancer: the randomized phase II SAFIR02-BREAST IMMUNO trial

Abstract

The impact of single-agent antibodies against programmed death-ligand 1 (PD-L1) as maintenance therapy is unknown in patients with metastatic breast cancer. The SAFIR02-BREAST IMMUNO substudy included patients with human epidermal growth factor receptor type 2 (Her2)-negative metastatic breast cancer whose disease did not progress after six to eight cycles of chemotherapy. Patients (n = 199) were randomized to either durvalumab (10 mg kg−1 every 2 weeks) or maintenance chemotherapy. In the overall population, durvalumab did not improve progression-free survival (adjusted hazard ratio (HR): 1.40, 95% confidence interval (CI): 1.00–1.96; P = 0.047) or overall survival (OS; adjusted HR: 0.84, 95% CI: 0.54–1.29; P = 0.423). In an exploratory subgroup analysis, durvalumab improved OS in patients with triple-negative breast cancer (TNBC; n = 82; HR: 0.54, 95% CI: 0.30–0.97, P = 0.0377). Exploratory analysis showed that the HR of death was 0.37 (95% CI: 0.12–1.13) for patients with PD-L1+ TNBC (n = 32) and 0.49 (95% CI: 0.18–1.34) for those with PD-L1 TNBC (n = 29). In patients with TNBC, exploratory analyses showed that the HR for durvalumab efficacy (OS) was 0.18 (95% CI: 0.05–0.71; log-rank test, P = 0.0059) in patients with CD274 gain/amplification (n = 23) and 1.12 (95% CI: 0.42–2.99; log-rank test, P = 0.8139) in patients with CD274 normal/loss (n = 32). Tumor infiltration by lymphocytes (CD8, FoxP3 and CD103 expressions) and homologous recombination deficiency did not predict sensitivity to durvalumab in exploratory analyses. This latter finding should be interpreted with caution since only one patient presented a germline BRCA mutation. The present study provides a rationale to evaluate single-agent durvalumab in maintenance therapy in patients with TNBC. Exploratory analyses identified CD274 amplification as a potential biomarker of sensitivity. Maintenance chemotherapy was more effective than durvalumab in patients with hormone receptor-positive and Her2-negative disease.

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Fig. 1: Kaplan–Meier plots of progression-free and overall survival.
Fig. 2: Kaplan–Meier plot of overall survival in TNBC according to PD-L1 expression.
Fig. 3: Kaplan–Meier plot of overall survival according to genomic markers.

Data availability

The datasets generated and analyzed (CEL files and HRD results) during the current study are available on synapse (https://www.synapse.org) under the ID syn22010057. Please read the wiki for more information about the contents of the syn22010057 folder (data access files, raw data, processed data).

Other data that support the findings of this study are available from the corresponding author upon request.

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Acknowledgements

We thank the patients and their families, as well as the investigators and staff involved in SAFIR02-BREAST and especially M.A., M.C., F.D., F.C., M.-P.S., M.D., C.L.-P., A.G., M.-A.M.R., W.J., B.Y., P.B., N.I., X.T., C.L., J.-C. T., T.L’H., J.-M.F., A.M. and F.D.P. We thank I.G. and J.A. for performing IHC analysis, as well as T.F. and A.L. for performing the statistical analyses and A.T.-D. for performing the bioinformatics analyses. We also thank I.B., E. R. and B.V. for valuable discussions on results. We are grateful to UNICANCER for promoting the clinical trial and especially to M.J. and A.J. in charge of the SAFIR02-BREAST clinical trial and all the members of their team that lead the monitoring of the clinical data, samples and genomic analyses. We are also grateful to the members of the Independent Data Monitoring Committee: N. Turner, S. Loibl, S. Novello, E. Felip, S. Litiere and D. Beltram. The study was funded by Fondation ARC, AstraZeneca and the Breast Cancer Research Foundation. AstraZeneca also supported the duvalumab supply to the study sites.

Author information

Authors and Affiliations

Authors

Contributions

T.B. designed the study, contributed to the writing and was involved in recruitment, clinical care and data returns. I.B. and E.R. supervised the genomic analyses of the trial. I.G. and J.A. performed the immunochemistry analyses. M.A., M.C., F.D., F.C., M.-P.S., M.D., C.L., A.G., M.-A.M.R., W.J., B.Y., P.B., N.I., X.T., C.L., J.-C.T., T.L’H., J.-M.F., A.M. and F.D.P. were involved in recruitment, clinical care and data returns. B.V. contributed to writing of the paper. A.T.D. supervised bioinformatics analyses. A.L. and T.F. ran all statistical analyses related to outcomes. M.J. and A.J. are the project managers of the SAFIR02-BREAST trial and centralized the collected samples and data. F.A. designed the study, is the principal investigator of the SAFIR02-BREAST trial, contributed to the writing and was involved in recruitment, clinical care and data returns. All authors approved the final manuscript and contributed to critical revisions of its intellectual content.

Corresponding author

Correspondence to Fabrice Andre.

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Competing interests

F.A. received research funding and served as speaker/advisor (compensated to the hospital) for Roche, AstraZeneca, Daiichi Sankyo, Pfizer, Novartis and Lilly. T.B. received research funding and served as speaker/advisor (compensated to the hospital) for Roche, Novartis, Pfizer, Seattle Genetic, Lilly and AstraZeneca. M.A. received research funding and served as speaker/advisor (compensated to the hospital) for Novartis, AstraZeneca, Seattle Genetics, AbbVie and Pfizer. M.C. received research funding and served as speaker/advisor (compensated to the hospital) for AstraZeneca, Novartis, AbbVie, Sanofi, Lilly, Pfizer, Sandoz, ACCORD, G1 Therapeutic, Pierre Fabre Oncology, Servier and Roche. F.D. received research funding and served as speaker/advisor (compensated to the hospital) for Roche, Novartis, Lilly, Pfizer, Eisai, MSD and AstraZeneca. C.L.-P. received research funding and served as speaker/advisor (compensated to the hospital) for AstraZeneca and Roche. A.G. received research funding and served as speaker/advisor (compensated to the hospital) for AstraZeneca, Pfizer, Novartis, Roche, MSD and Lilly. M.-A.M.R. received research funding and served as speaker/advisor for Pfizer, Novartis, Lilly, Roche, MSD and Myriad. W.J. received research funding and served as speaker/advisor for AstraZeneca, Eisai, Lilly, MSD, Novartis, Pfizer and Roche. B.Y. received research funding and served as speaker/advisor (compensated to the hospital) for AstraZeneca, Roche, Amgen, Novartis, GSK, ECS Progastrin, Pfizer, Merck Serono and Bayer. P.B. served as speaker/advisor for Roche, BMS, IPSEN, Janssen Cilag, Pfizer, Novartis, Astellas and EUSA Pharma. N.I. received research funding and served as speaker/advisor (compensated to the hospital) for Ipsen and Transgene. J.-C.T. received research funding and served as speaker/advisor (compensated to the hospital) for Pfizer and AstraZeneca. J.-M.F. received research funding and served as speaker/advisor for Pfizer and Eisai. J.A. received consultant fees from AstraZeneca, Bayer, BMS, MSD and Roche. The following authors have no disclosures: M.D., A.M., X.T., F.D.P., T.F., I.B., I.G., E.R., A.T.-D., A.L., M.J., A.J., F.C., M.-P.S., B.V., C.L., T.L’H. and F.D.

Additional information

Peer review information Javier Carmona was the primary editor on this article, and managed its editorial process and peer review in collaboration with the rest of the editorial team.

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Extended data

Extended Data Fig. 1 Study Design.

HER: Human Epidermal growth factor Receptor; HR: Hormone Receptor; CT: chemotherapy; CGH: comparative genomic hybridization; CNA: copy number alteration; CR: complete remission; PR: partial remision; SD: stable disease; ctDNA: circulating tumor DNA; FFPE: formalin-fixed paraffin-embedded; n: number of patient; R: randomization ratio.

Extended Data Fig. 2 CONSORT diagram.

CNA: copy number alterations; HRD: homologous recombination deficiency; IHC: immunohistochemistry; TRM: tissue-resident memory T cells; n: number of patient.

Extended Data Fig. 3 PFS in subgroups of interest.

The forest plot shows the hazard ratios (diamonds) and 95% two sided confidence intervals (error bars) estimated using an unadjusted Cox proportional hazard model in each subgroup. P-value for interaction between treatment arm and each parameter from a Cox proportional hazard model fitted with the parameter, the treatment arm, and an interaction term between treatment arm and parameter is reported. All statistical tests were two sided. No adjustment was made for multiple comparisons. No. Evts: number of events; No Pts: number of patients; PFS: Progression Free Survival; HR: Hazard Ratio; CI: confidence intervals (two-sided); TNBC: Triple Negative Breast Cancer; ECOG-PS: Eastern Cooperative Oncology Group-Performance Status; D: Durvalumab; MC: maintenance chemotherapy.

Extended Data Fig. 4 OS in subgroups of interest.

The forest plot shows the hazard ratios (diamonds) and 95% two sided confidence intervals (error bars) estimated using an unadjusted Cox proportional hazard model in each subgroup. P-value for interaction between treatment arm and each parameter from a Cox proportional hazard model fitted with the parameter, the treatment arm, and an interaction term between treatment arm and parameter is reported. All statistical tests were two sided. No adjustment was made for multiple comparisons. No. Evts: number of events; No Pts: number of patients; OS: Overall Survival; HR: Hazard Ratio; CI: confidence intervals (two-sided); TNBC: Triple Negative Breast Cancer; ECOG-PS: Eastern Cooperative Oncology Group-Performance Status; D: Durvalumab; MC: maintenance chemotherapy.

Supplementary information

Supplementary Information

Supplementary Tables 1–4

Reporting Summary

41591_2020_1189_MOESM3_ESM.pdf

Protocol for SAFIR02-BREAST v9.0 and statistical analysis report of the SAFIR02-BREAST IMMUNO substudy v5.3 (27th October 2020).

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Bachelot, T., Filleron, T., Bieche, I. et al. Durvalumab compared to maintenance chemotherapy in metastatic breast cancer: the randomized phase II SAFIR02-BREAST IMMUNO trial. Nat Med 27, 250–255 (2021). https://doi.org/10.1038/s41591-020-01189-2

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