Pembrolizumab monotherapy for advanced chordoma

We applaud Jean-Yves Blay and colleagues1Blay JY Chevret S Le Cesne A et al.Pembrolizumab in patients with rare and ultra-rare sarcomas (AcSé Pembrolizumab): analysis of a subgroup from a non-randomised, open-label, phase 2, basket trial.Lancet Oncol. 2023; 8: 892-902Summary Full Text Full Text PDF Scopus (1) Google Scholar for their Article published in The Lancet Oncology, which provides further evidence that immune checkpoint inhibitors are most effective in alveolar soft part sarcoma2Somaiah N Conley AP Parra ER et al.Durvalumab plus tremelimumab in advanced or metastatic soft tissue and bone sarcomas: a single-centre phase 2 trial.Lancet Oncol. 2022; 23: 1156-1166Summary Full Text Full Text PDF PubMed Scopus (27) Google Scholar and SMARCA4-deficient sarcoma,3Takada K Sugita S Murase K et al.Exceptionally rapid response to pembrolizumab in a SMARCA4-deficient thoracic sarcoma overexpressing PD-L1: a case report.Thorac Cancer. 2019; 10: 2312-2315Crossref PubMed Scopus (57) Google Scholar but with regard to the use of immune checkpoint inhibitors in advanced chordoma, we wish to express some concerns. Before the advent of immune checkpoint inhibitor immunotherapy, VEGFR-targeted therapies, such as sorafenib4Bompas E Le Cesne A Tresch-Bruneel E et al.Sorafenib in patients with locally advanced and metastatic chordomas: a phase II trial of the French Sarcoma Group (GSF/GETO).Ann Oncol. 2015; 26: 2168-2173Summary Full Text Full Text PDF PubMed Scopus (77) Google Scholar and apatinib,5Liu C Jia Q Wei H et al.Apatinib in patients with advanced chordoma: a single-arm, single-centre, phase 2 study.Lancet Oncol. 2020; 21: 1244-1252Summary Full Text Full Text PDF PubMed Scopus (30) Google Scholar were popularly explored as treatment options in patients with advanced chordoma, and produced promising results. Although it is encouraging that patients treated with pembrolizumab had a higher partial response rate than did those treated with sorafenib and apatinib in previous studies, those treated with pembrolizumab displayed substantially worse progression-free survival rates than did those treated with sorafenib and apatinib (appendix). The median progression-free survival in pembrolizumab therapy (6·1 months) is much shorter than that seen with apatinib therapy (18 months). The source of this large disparity in progression-free survival between immune checkpoint inhibitors and VEGFR-targeted therapy for chordoma is unclear and necessitates further investigation. One hypothesis is that chordoma shows earlier drug resistance to immune checkpoint inhibitors than VEGFR-targeted agents, thus leading to the relatively early tumour progression seen in pembrolizumab therapy compared with sorafenib and apatinib therapy. The finding that partial response duration remains shorter with pembrolizumab therapy than with sorafenib and apatinib therapy supports this early immune checkpoint inhibitor-resistance hypothesis to some extent (appendix). If Blay and colleagues were inclined to publish additional details regarding the baseline characteristics of the patients with chordoma—such as primary tumour site, proportion of patients with distant metastasis, specific metastatic organs and previous surgery, radiotherapy, and systemic treatment history—these characteristics could be compared with those reported in the studies by Bompas and colleagues4Bompas E Le Cesne A Tresch-Bruneel E et al.Sorafenib in patients with locally advanced and metastatic chordomas: a phase II trial of the French Sarcoma Group (GSF/GETO).Ann Oncol. 2015; 26: 2168-2173Summary Full Text Full Text PDF PubMed Scopus (77) Google Scholar and Liu and colleagues5Liu C Jia Q Wei H et al.Apatinib in patients with advanced chordoma: a single-arm, single-centre, phase 2 study.Lancet Oncol. 2020; 21: 1244-1252Summary Full Text Full Text PDF PubMed Scopus (30) Google Scholar to gain a better understanding of the comparative efficacy of pembrolizumab and VEGFR-targeted agents. Finally, we would be interested to know how many of the 34 patients with chordoma underwent unsuccessful VEGFR-targeted therapy before the initiation of pembrolizumab therapy, and what influence previous VEGFR-targeted therapy had on subsequent outcomes. It would be intriguing to find out whether pembrolizumab therapy could improve outcomes in patients with advanced chordoma who did not respond to VEGFR-targeted therapy. In summary, we consider the outcomes of pembrolizumab monotherapy for advanced chordoma to be unsatisfactory, particularly regarding progression-free survival. Future studies on the effect of combined immune checkpoint inhibitor immunotherapy and VEGFR-targeted therapy might elucidate a role for immune checkpoint inhibitors in patients with advanced chordoma. SMB and WY are co-senior authors. XH, CW, and WH are co-first authors. We declare no competing interests. Download .pdf (.11 MB) Help with pdf files Supplementary appendix Pembrolizumab monotherapy for advanced chordoma – Authors' replyWe thank Xianglin Hu and colleagues for their interest and questions on the AcSé Pembrolizumab trial in chordoma,1 a rare sarcoma with no standard treatments in advanced phase.2–5 Full-Text PDF