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