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

• Published in: Nature Medicine Vol. 28; no. 6; pp. 1199 - 1206
• Main Authors: Italiano, A., Bessede, A., Pulido, M., Bompas, E., Piperno-Neumann, S., Chevreau, C., Penel, N., Bertucci, F., Toulmonde, M., Bellera, C., Guegan, J. P., Rey, C., Sautès-Fridman, C., Bougoüin, A., Cantarel, C., Kind, M., Spalato, M., Dadone-Montaudie, B., Le Loarer, F., Blay, J. Y., Fridman, W. H.
• Format: Journal Article Magazine Article
• Language: English
• Published: New York Nature Publishing Group US 01.06.2022; Nature Publishing Group
• Subjects: 631/250/1619; 692/308/2779/109/1941; 692/53/2423; 692/699/67/1059/2325; 692/699/67/1798; Anemia; Biomarkers; Biomedical and Life Sciences; Biomedicine; Cancer Research; Confidence intervals; Cyclophosphamide; Diarrhea; Immune checkpoint inhibitors; Immunotherapy; Infectious Diseases; Life Sciences; Metabolic Diseases; Molecular Medicine; Monoclonal antibodies; Nausea; Neurosciences; Patients; PD-1 protein; Pembrolizumab; Plasma cells; Santé publique et épidémiologie; Sarcoma; Survival; Targeted cancer therapy
• ISSN: 1078-8956; 1546-170X; 1546-170X; 1744-7933
• DOI: 10.1038/s41591-022-01821-3

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. In a trial of patients with soft-tissue sarcomas, clinical outcome measures following anti-PD-1 treatment were better in a cohort prospectively selected for the presence of intratumoral tertiary lymphoid structures than in other cohorts where most patients lacked these structures.