Pembrolizumab monotherapy for advanced chordoma – Authors' reply

We thank Xianglin Hu and colleagues for their interest and questions on the AcSé Pembrolizumab trial in chordoma,1Blay 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; 24: 892-902Summary Full Text Full Text PDF Google Scholar a rare sarcoma with no standard treatments in advanced phase.2Bompas 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, 3Liu 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, 4Lebellec L Chauffert B Blay JY et al.Advanced chordoma treated by first-line molecular targeted therapies: outcomes and prognostic factors. A retrospective study of the French Sarcoma Group (GSF/GETO) and the Association des Neuro-Oncologues d'Expression Française (ANOCEF).Eur J Cancer. 2017; 79: 119-128Summary Full Text Full Text PDF PubMed Scopus (43) Google Scholar, 5Le Cesne A Chevreau C Perrin C et al.Regorafenib in patients with relapsed advanced or metastatic chordoma: results of a non-comparative, randomised, double-blind, placebo-controlled, multicentre phase II study.ESMO Open. 2023; 8101569Summary Full Text Full Text PDF Scopus (0) Google Scholar Their Correspondence raises two questions regarding the previous treatments of patients with chordoma in the trial, and the comparison of single-arm prospective trials in chordoma and rare cancers. Regarding the first question, with a median follow up of 13·1 months (IQR 4·3–19·7), the median progression-free survival with pembrolizumab for the chordoma subgroup was 6·1 months (95% CI 4·6–11·5). Nine patients with chordoma were pretreated with antiangiogenics (sorafenib or regorafenib), and their progression-free survival and overall survival were similar compared with those who were not pretreated (appendix). The second question is more complex. Several single-arm prospective trials of targeted agents in chordoma have been reported testing tyrosine-kinase inhibitors such as imatinib, erlotinib, and everolimus. Several trials with VEGFR tyrosine-kinase inhibitors, including sorafenib and apatinib, are discussed by Hu and colleagues. In addition, one double-blind randomised clinical trial investigating regorafenib versus placebo5Le Cesne A Chevreau C Perrin C et al.Regorafenib in patients with relapsed advanced or metastatic chordoma: results of a non-comparative, randomised, double-blind, placebo-controlled, multicentre phase II study.ESMO Open. 2023; 8101569Summary Full Text Full Text PDF Scopus (0) Google Scholar showed a median progression-free survival of 8·2 months (95% CI 4·5–12·9) with regorafenib versus 10·1 months (95% CI 0·8–not evaluable) with placebo. A retrospective study with 80 patients was also reported.4Lebellec L Chauffert B Blay JY et al.Advanced chordoma treated by first-line molecular targeted therapies: outcomes and prognostic factors. A retrospective study of the French Sarcoma Group (GSF/GETO) and the Association des Neuro-Oncologues d'Expression Française (ANOCEF).Eur J Cancer. 2017; 79: 119-128Summary Full Text Full Text PDF PubMed Scopus (43) Google Scholar Progression-free survival and overall survival in patients with chordoma differed considerably between these studies, decreasing from retrospective to single-arm prospective trial, and from single-arm prospective trial to randomised clinical trial. Median progression-free survival of 10·1 months with placebo indicates the need to carefully choose the right comparator for chordoma. Both antiangiogenics and PD-1 antibodies show activity in chordoma, but their compared levels of activity are unknown. Long-term follow up will need to be reported for all these studies. Indirect comparison requires effective sample sizes to be more than 30 after adjustment; otherwise, they will be unreliable. Unfortunately, small sample sizes are the main issue in this setting. Future studies in chordoma, including drug combinations, will need control groups. A randomised clinical trial was feasible in chordoma in a single country5Le Cesne A Chevreau C Perrin C et al.Regorafenib in patients with relapsed advanced or metastatic chordoma: results of a non-comparative, randomised, double-blind, placebo-controlled, multicentre phase II study.ESMO Open. 2023; 8101569Summary Full Text Full Text PDF Scopus (0) Google Scholar and so should be feasible internationally. No standard first-line treatment can emerge yet from the existing trials, and prospective international academic clinical studies are needed. Author declarations remain the same as in the published Article for J-YB, SC, NP, CM, and EB. FD reports research support from Unicancer, Insitut National du Cancer, and Ligue contre le Cancer. Download .pdf (.19 MB) Help with pdf files Supplementary appendix Pembrolizumab monotherapy for advanced chordomaWe applaud Jean-Yves Blay and colleagues1 for their Article published in The Lancet Oncology, which provides further evidence that immune checkpoint inhibitors are most effective in alveolar soft part sarcoma2 and SMARCA4-deficient sarcoma,3 but with regard to the use of immune checkpoint inhibitors in advanced chordoma, we wish to express some concerns. Full-Text PDF