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Presence of Intratumoural TLSs in Advanced STS as a Potential Predictive Biomarker to Improve Patients’ Selection for Pembrolizumab

Findings from the PEMBROSARC study on presence of tertiary lymphoid structures in patients with advanced soft tissue sarcomas
07 Jun 2022
Cancer Immunology and Immunotherapy;  Translational research

According to Prof. Antoine Italiano of the Department of Medical Oncology, Institut Bergonié in Bordeaux, France and colleagues, the results from the PEMBROSARC, a multicohort phase II study of pembrolizumab combined with low-dose cyclophosphamide in patients with advanced soft tissue sarcomas (STSs), support the predictive value of tertiary lymphoid structures (TLSs) for tailoring treatment with this anti-PD1 treatment. Both, the response rate and progression-free survival (PFS) were significantly higher in the TLS-enriched cohort than in the previous all-patient cohorts of the PEMBROSARC study, and all patients except one included in the previous all-patient cohorts harboured TLS-negative STSs. Latest findings from the PEMBROSARC are published on 26 May 2022 in the Nature Medicine.

The authors wrote in the study background that although historically, sarcomas represent the first tumour type for which immunotherapy approaches were associated with clinical benefit, none of the immune checkpoint inhibitors (ICIs) have been approved for the treatment of patients with sarcomas. Several phase II studies that investigated the outcomes of PD-1 or PD-L1 targeting in patients with advanced sarcomas included patients without any selection based on a biomarker strategy. Anecdotal responses were observed in some histological subtypes, which might be more sensitive to treatment, e.g. undifferentiated pleomorphic sarcomas or dedifferentiated liposarcomas. However, in an unselected population in the PEMBROSARC study, the clinical benefit was very limited.

To perform a more in-depth investigation of the therapeutic impact of ICIs in patients with sarcoma and its correlation with the sarcoma microenvironment, the same team previously conducted a large analysis of the immune landscape of sarcomas. By analyzing transcriptomic data from more than 600 STSs, they identified a subgroup of sarcomas classified as ‘immune high’ and characterised by elevated expression of a B cell-related gene signature, which was predictive of survival independently of the level of CD8-positive T cell infiltration. Immunohistochemistry analysis revealed that this class of sarcoma was characterised by the presence of intratumoural TLSs, which are ectopically formed aggregates of B cell follicles, follicular dendritic cells and CD4-positive and CD8-positive T cells previously shown to play a critical role in anticancer immunity in several tumour types.

Furthermore, a retrospective analysis of biopsy specimens from 47 patients included in the SARC028 study indicated that this B cell-related gene signature was highly predictive of response to pembrolizumab, suggesting that the presence of TLSs might represent a robust biomarker for tailoring ICIs in sarcoma patients. Based on these data, the study team amended the PEMBROSARC study to include a new cohort selected on the basis of the presence of TLSs to investigate the efficacy of pembrolizumab in patients with advanced sarcomas characterised by the presence of this potential biomarker.

The primary endpoint of the PEMBROSARC study was the 6-month non-progression rate (NPR). Secondary endpoints included objective response rate (ORR), PFS, overall survival (OS) and safety. The 6-month NPR and ORRs for cohorts in this study enrolling all comers were previously reported. In the latest article, the study team reports the results of a cohort of 30 enroled patients selected on the basis of the presence of TLSs.

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% and 2.4% in the all-comer cohorts.

The most frequent toxicities were grades 1 or 2 fatigue, nausea, dysthyroidism, diarrhoea and anaemia.

Exploratory analyses revealed that the abundance of intratumoural plasma cells was significantly associated with improved outcome.

The authors commented that for patients with advanced STS, there is an unmet clinical need in terms of treatment options. Their results represent prospective and direct evidence for using TLSs as a predictive biomarker for treatment of these patients with ICIs.

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).


Italiano A, Bessede A, Pulido M, et al. Pembrolizumab in soft-tissue sarcomas with tertiary lymphoid structures: a phase 2 PEMBROSARC trial cohort. Nature Medicine; Published online 26 May 2022. DOI: https://doi.org/10.1038/s41591-022-01821-3

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