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Pembrolizumab in soft-tissue sarcomas with tertiary lymphoid structures: a phase 2 PEMBROSARC trial cohort

Nature Medicine volume 28, pages 1199–1206 (2022)Cite this article

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Abstract

Immune checkpoint inhibitors (ICIs) show limited clinical activity in patients with advanced soft-tissue sarcomas (STSs). Retrospective analysis suggests that intratumoral tertiary lymphoid structures (TLSs) are associated with improved outcome in these patients. PEMBROSARC is a multicohort phase 2 study of pembrolizumab combined with low-dose cyclophosphamide in patients with advanced STS (NCT02406781). The primary endpoint was the 6-month non-progression rate (NPR). Secondary endpoints included objective response rate (ORR), progression-free survival (PFS), overall survival (OS) and safety. The 6-month NPR and ORRs for cohorts in this trial enrolling all comers were previously reported; here, we report the results of a cohort enrolling patients selected based on the presence of TLSs (n = 30). The 6-month NPR was 40% (95% confidence interval (CI), 22.7–59.4), so the primary endpoint was met. The ORR was 30% (95% CI, 14.7–49.4). In comparison, the 6-month NPR and ORR were 4.9% (95% CI, 0.6–16.5) and 2.4% (95% CI, 0.1–12.9), respectively, in the all-comer cohorts. The most frequent toxicities were grade 1 or 2 fatigue, nausea, dysthyroidism, diarrhea and anemia. Exploratory analyses revealed that the abundance of intratumoral plasma cells (PCs) was significantly associated with improved outcome. These results suggest that TLS presence in advanced STS is a potential predictive biomarker to improve patients’ selection for pembrolizumab treatment.

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Fig. 1: Flow chart of the study.
Fig. 2: Efficacy of pembrolizumab in patients with TLS-positive advanced sarcomas.
Fig. 3: Characterization of the determinants of response to pembrolizumab in TLS-positive sarcomas.

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Data availability

The datasets that support the findings of this study are not publicly available due to information that could compromise research participant consent. According to French/European regulations, any reuse of the data must be approved by the ethics committee ‘CPP du Sud-Ouest et d’ Outre-Mer III’, Bordeaux, France. Individual participant data that underlie the results reported in this article can be shared upon request to the corresponding author (A.I.). Proposals may be submitted up to 36 months following article publication.

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Acknowledgements

This study was sponsored by Institut Bergonié (Bordeaux, France). Funding was provided by MSD, the French Ministry, the Association pour la Recherche contre le Cancer, the Ligue contre le Cancer, INSERM, Sorbonne Université, Université de Paris, the French National Cancer Institute and the Agence Nationale de la Recherche (RHU CONDOR).

Author information

Author notes

  1. These authors contributed equally: A. Italiano, A. Bessede, M. Pulido.

Authors and Affiliations

  1. Department of Medical Oncology, Institut Bergonié, Bordeaux, France

    A. Italiano, M. Toulmonde & M. Spalato

  2. DITEP, Gustave Roussy, Villejuif, France

    A. Italiano

  3. University of Bordeaux, Bordeaux, France

    A. Italiano & F. Le Loarer

  4. Explicyte, Bordeaux, France

    A. Bessede, J. P. Guegan & C. Rey

  5. Unité de Recherche et d’Epidémiologie Cliniques, Institut Bergonié, Bordeaux, France

    M. Pulido, C. Bellera & C. Cantarel

  6. INSERM CIC, Bordeaux, France

    M. Pulido, C. Bellera & C. Cantarel

  7. Department of Medical Oncology, Institut de Cancérologie de L’Ouest, Nantes, France

    E. Bompas

  8. Department of Medical Oncology, Institut Curie, Paris, France

    S. Piperno-Neumann

  9. Department of Medical Oncology, Oncopole Toulouse, Toulouse, France

    C. Chevreau

  10. Department of Medical Oncology, Centre Oscar Lambret, Lille, France

    N. Penel

  11. Department of Medical Oncology, Institut Paoli Calmettes, Marseille, France

    F. Bertucci

  12. Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université Paris Cité, Paris, France

    C. Sautès-Fridman, A. Bougoüin & W. H. Fridman

  13. Equipe Labellisée Ligue contre le Cancer, Paris, France

    C. Sautès-Fridman, A. Bougoüin & W. H. Fridman

  14. Department of Imaging, Institut Bergonié, Bordeaux, France

    M. Kind

  15. Department of Pathology, University Hospital Centre of Nice, Nice, France

    B. Dadone-Montaudie

  16. Department of Pathology, Institut Bergonié, Bordeaux, France

    F. Le Loarer

  17. Department of Medical Oncology, Centre Léon Bérard, Lyon, France

    J. Y. Blay

Authors
  1. A. Italiano
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  2. A. Bessede
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Contributions

A.I., C.S.-F., C.B., M.P. and W.H.F. conceived and designed the study; B.D.-M. and F.L.L. performed histologic analyses; A.Bougoüin, C.S.-F. and W.H.F. performed TLS screening assays; E.B., S.P.N., C.Chevreau, N.P., F.B., M.K., J.P.G., A.Bessede, M.T., J.Y.B. and A.I. provided study material or treated patients; all authors collected and assembled the data; A.I., A.Bessede, C.Cantarel and J.P.G. developed the tables and figures; A.I., A.Bessede, C.S.-F. and W.H.F. conducted the literature search and wrote the manuscript; and all authors were involved in critical review of the manuscript and approved the final version.

Corresponding author

Correspondence to A. Italiano.

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Competing interests

A.Bessede, J.P.G. and C.R. are employees of Explicyte. A.I. received research grants from AstraZeneca, Bayer, BMS, Chugai, Merck, MSD, Pharmamar, Novartis and Roche and personal fees from Epizyme, Bayer, Deciphera, Lilly, Parthenon, Roche and Springworks. W.H.F. received a research grant from AstraZeneca and personal fees from Anaveon, AstraZeneca, Catalym, Elsalys, Novartis, OSE Immunotherapeutics and Parthenon. J.Y.B. received research grants from Bayer, GSK, Merck, Novartis, Pharmamar and Roche and personal fees from Bayer, GSK, Lilly, Novartis, Pharmamar and Roche. All other authors have no competing interests.

Peer review

Peer review information

Nature Medicine thanks Melissa Burgess and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling editor: Saheli Sadanand, in collaboration with the Nature Medicine team.

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Extended data

Extended Data Fig. 1 Representative image field with CD4/CD8/CD56/Foxp3/GzmA/DAPI multiplexed immunohistofluorescence panel on a soft-tissue sarcoma section.

Each panel represent a TLS structure with the corresponding staining.

Extended Data Fig. 2 Representative image field with CD27/Col1A1/Mum1/IgG/CD20/CD3/DAPI multiplexed immunohistofluorescence panel on a soft-tissue sarcoma section.

Each panel represent a TLS structure with the corresponding staining.

Extended Data Fig. 3 Representative example of a sarcoma expressing IgG at the surface of tumor cells.

Representative example of a sarcoma expressing IgG at the surface of tumor cells. A Undifferentiated spindle cell sarcoma of high grade of malignancy (hematoxylin eosin saffron staining) that B showed strong expression of IgG on immunofluorescence. There was a hybrid membranous and cytoplasmic pattern of staining (IgG staining in orange, DAPI counterstaining of nuclei). Twenty total cases were stained.

Extended Data Fig. 4 Antigen presenting cells tumor-infiltration is associated with anti-PD-1 response in TLS-positive sarcoma patients.

(a) Representative image field of a tumor area stained with CD83/CD1c/CD11c/CD68/HLA-DRA/DAPI multiplexed immunohistofluorescence (IHF) panel on a soft-tissue sarcoma section. IHF signals were unmixed for better discrimination. (b) Kaplan–Meier curves of PFS according to CD11c + /HLA-DR + High (n = 6) versus Low (n = 14) status. (c) Kaplan-Meir curves of OS according to CD11c + /HLA-DR + High (n = 6) versus Low (n = 14) status. (d) Kaplan–Meier curves of PFS according to CD68 + /HLA-DR + High (n = 5) versus Low (n = 15) status. (e) Kaplan-Meir curves of OS according to CD68 + /HLA-DR + High (n = 5) versus Low (n = 15) status.

Extended Data Table 1 Characteristics of the patients screened for TLS status (n = 240)
Full size table
Extended Data Table 2 Genes differentially expressed by TLS CD20 negative cells between responders and non-responders
Full size table
Extended Data Table 3 Two-sided Wilcoxon–Mann-Whitney analyses of the difference in TLS cell population estimates between Responders and Non-responders
Full size table
Extended Data Table 4 Two-sided Wilcoxon–Mann-Whitney analyses of the difference in stroma cell population estimates between Responders and Non-responders
Full size table

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Supplementary Table 1 and Figures 1–4.

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Italiano, A., Bessede, A., Pulido, M. et al. Pembrolizumab in soft-tissue sarcomas with tertiary lymphoid structures: a phase 2 PEMBROSARC trial cohort. Nat Med 28, 1199–1206 (2022). https://doi.org/10.1038/s41591-022-01821-3

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