The results of the rare and ultrarare sarcoma group in a French single-arm, phase II, multicohort basket AcSé Pembrolizumab study indicate that single agent pembrolizumab has substantial antitumour activity in patients with locally advanced or metastatic rare and ultrarare sarcomas refractory or resistant to standard therapy. Data support the PD-1/PD-L1 pathway as a potential therapeutic target, especially in chordoma, SMARCA4-deficient sarcoma or malignant rhabdoid tumour, and in alveolar soft part sarcoma, in locally advanced or metastatic disease progressing after standard treatments.

Once the AcSé Pembrolizumab basket study is complete, a central review will be performed in all cohorts to further investigate the findings. Nonetheless, the clinical activity of pembrolizumab needs to be further confirmed in expanded cohorts and prospective studies with a careful monitoring of real-world data according to Prof. Jean-Yves Blay of the Centre Léon Bérard, Université Claude Bernard Lyon 1 in Lyon, France, and colleagues who published the findings on 7 July 2023 in The Lancet Oncology.

The authors wrote in the background that a large proportion, comprising over 100 different histological and molecular subtypes and accounting for about 20% of all sarcomas, are rare or ultrarare, with an incidence of less than one case per 1000000 people per year. Due to their rarity, their natural history is often not precisely known and the design of clinical trials for these subtypes is complex. There is little clinical research on ultrarare sarcomas and fewer than 10% of patients with these histotypes have participated in prospective clinical studies.

In recent sarcoma trials, immune checkpoint inhibitors (ICIs) showed low efficacy in unselected patient populations with response rates ranging from 0-20% and median progression-free survival of 2-3.5 months. Combinations of ICI with VEGFR-2 inhibitor showed higher response rates, but without a control group. In all studies, response rates were particularly high in patients with alveolar soft part sarcomas. Atezolizumab has been granted FDA approval for the treatment of alveolar soft part sarcomas. The best response rates and tumour control rates were reported in patients with sarcomas expressing tertiary lymphoid structures, as confirmed in a prospective trial. A case series of chordoma also found positive benefits of ICIs.

Next-generation sequencing has enabled improved molecular characterisation of sarcoma subtypes, but the immune landscape of sarcoma and its link to these molecular subgroups is not yet completely characterised.

Given the limited knowledge on the efficacy of ICI for many rare sarcomas, the prospective AcSé Pembrolizumab basket study, initiated in 2017, included a rare sarcoma cohort to evaluate the activity of pembrolizumab in rare sarcomas, with a focus on subtypes in which higher response rates had been described. 

AcSé Pembrolizumab is an ongoing phase II, basket, multitumour study investigating the activity of pembrolizumab monotherapy in rare cancers. In the latest article published in The Lancet Oncology, the authors report the results obtained in patients with selected histotypes of rare sarcomas recruited at 24 French hospitals. Key inclusion criteria were age 15 years or older, ECOG performance status of 0-1, and advanced disease that was resistant to treatment. Patients were given pembrolizumab 200 mg intravenously on day 1 of every 21-day cycle for a maximum of 24 months. The primary endpoint was objective response rate at week 12 using RECIST v1.1, assessed by local investigators. The primary endpoint and safety were analysed in the intention-to-treat population. 

Between 4 September 2017 and 29 December 2020, 98 patients were enroled, of whom 97 received treatment and were included in analyses. Median age was 51 years, 53 patients (55%) were male, 44 (45%) were female; no data were collected on race or ethnicity. In total, 34 patients (35%) had chordomas, 14 (14%) had alveolar soft part sarcomas, 12 (12%) had SMARCA4-deficient sarcomas or malignant rhabdoid tumours, 8 (8%) had desmoplastic small round cell tumours, 6 (6%) had epithelioid sarcomas, 4 (4%) had dendritic cell sarcomas, 3 (3%) each had clear cell sarcomas, solitary fibrous tumours, and myxoid liposarcomas, and 10 (10%) had other ultrarare histotypes.

As of data cut-off on 11 April 2022, median follow-up was 13.1 months (range 0.1-52.8). At week 12, objective response rate was 6.2% (95% confidence interval 2.3-13.0), with no complete responses and 6 partial responses in the 97 patients. This increased to 17 patients with extended follow-up (4 with chordoma, 8 with alveolar soft part sarcoma, 3 with SMARCA4-deficient sarcoma or malignant rhabdoid tumour, 1 with desmoplastic small round cell tumour, 1 with epithelioid sarcoma), such that 11 responses, including 2 complete responses, occurred after 12 weeks. Best response rate differed significantly among histotypes with a close median response duration for all histotypes. The authors commented that although pembrolizumab has shown fast and lasting antitumour activity for other indications, they found a 12-week timepoint was too early for a meaningful analysis of responses in rare and ultrarare sarcomas.

The most common grade 3-4 adverse events were anaemia (8%), alanine aminotransferase and aspartate aminotransferase increase (6%), and dyspnoea (5%). A total, 86 serious adverse events were reported in 37 patients. Five deaths due to adverse events were reported, none of which were determined to be related to treatment (2 due to disease progression, 2 due to cancer, and 1 due to unknown cause).

The authors commented that the clinical activity of pembrolizumab in refractory setting needs to be further confirmed in expanded cohorts and prospective studies with a careful monitoring of real-world data. Studies that evaluate pembrolizumab as front-line therapy, maintenance therapy, or in combination with other treatment methods could be considered in such tumours at high risk of relapse, with international collaborations, and adapting to the extreme rarity of these entities to build trials leading to approval by health authorities.

The study was funded by the Ligue contre le cancer, INCa, MSD.


Blay J-Y, 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. The Lancet Oncology; Published online 7 July 2023. DOI: