In an investigator-initiated phase II study, objective responses according to RECIST v1.1 occurred in approximately one third (37%) of the patients with alveolar soft part sarcoma, many of whom had disease progression during previous systemic treatment. Responses were durable, and several were maintained for years after the final dose of atezolizumab.
The clinical and pharmacodynamic results of a single-group, phase II study are reported by Dr. Alice P. Chen of the Division of Cancer Treatment and Diagnosis, National Cancer Institute (NCI) in Bethesda, MD, US, and colleagues on 7 September 2023 in The New England Journal of Medicine
Alveolar soft part sarcoma is a rare malignancy that accounts for less than 1% of all soft-tissue sarcomas. The disease typically occurs in adolescents and young adults. Alveolar soft part sarcoma generally has an indolent course but has a poor prognosis and a high tendency for early metastatic spread, which is associated with 5-year overall survival ranging from 20-46%.
The defining molecular event in alveolar soft part sarcoma is a chromosomal translocation involving ASPL (also known as ASPSCR1) and TFE3. Two distinct ASPL-TFE3 fusion proteins have been identified that reportedly differ in transcriptional activity. However, to date, no clinical significance with respect to prognosis has been described for type 1 as compared with type 2 fusions.
When this study began, there was no established therapy for alveolar soft part sarcoma. The disease is largely resistant to traditional chemotherapies. Initial management through surgical resection, systemic treatment, or both is rarely curative. The tyrosine kinase inhibitor (TKI) pazopanib is approved by the US Food and Drug Administration (FDA) for soft-tissue sarcoma in general and is a treatment option for patients with alveolar soft part sarcoma.
In December 2022, based on independently reviewed results from this study, the FDA approved atezolizumab, an immune checkpoint inhibitor (ICI) targeting PD-L1, for the treatment of unresectable or metastatic alveolar soft part sarcoma in adult and paediatric patients 2 years of age or older.
The authors explained in the background that encouraging clinical responses in patients with alveolar soft part sarcoma to other ICIs that disrupt PD-L1 binding to PD-1 receptor, with or without a TKI, have been reported. However, most sample sizes were small, and the molecular mechanisms behind the responses were unclear. Tumour mutational burden and microsatellite instability, which are associated with the presence of tumour neoantigens and a high likelihood of response to ICI in many histologic types of cancer, are low in alveolar soft part sarcoma. In addition, some alveolar soft part sarcomas that are responsive to ICI lack the expression of PD-L1 or PD-1 proteins that are associated with response to ICI.
The study team conducted this investigator-initiated study to evaluate the efficacy of atezolizumab for alveolar soft part sarcoma and to investigate the hypothesis that the mechanism of activity of ICIs in this disease involves induced expression of missing immune checkpoint components. In the article, the authors report the clinical and pharmacodynamic results of a single-group, multicentre, phase II study of atezolizumab for the treatment of adult and paediatric patients with advanced alveolar soft part sarcoma.
Atezolizumab was administered intravenously at a dose of 1200 mg in patients who are at least 18 years old or 15 mg per kilogram of body weight with a 1200-mg cap in patients younger than 18 years once every 21 days. Study endpoints included objective response, duration of response (DoR), and progression-free survival (PFS) according to RECIST v1.1, as well as pharmacodynamic biomarkers of multistep drug action.
A total of 52 patients were evaluated. An objective response was observed in 19 of 52 patients (37%), with 1 complete response and 18 partial responses. The median time to response was 3.6 months (range, 2.1 to 19.1), the median DoR was 24.7 months (range, 4.1 to 55.8), and the median PFS was 20.8 months. Seven patients took a treatment break after 2 years of treatment, and their responses were maintained through the data cut-off date. No treatment-related grade 4 or 5 adverse events were recorded. Responses were noted despite variable baseline expression of PD1 and PD-L1.
The authors commented that tumour assessments were performed less frequently in patients who remained in this study for more than 1 year, which potentially affected the assessment of PFS results by 3 to 6 weeks. Still, the DoR and PFS achieved with atezolizumab are uncommon with other therapies used in alveolar soft part sarcoma, even in contexts like this one in which patients may have been enroled with indolent disease. In this study, tumour responses to atezolizumab typically occurred within the first 3 to 5 months, but three patients had received treatment for 1 year or longer before having a partial response. Late-onset responses to other ICIs have been reported in patients with alveolar soft part sarcoma.
The pharmacodynamic data show that many of the tumours harboured the molecular and cellular elements required for atezolizumab response at baseline, whereas other tumours lacked one or more such components before treatment but converted to a responsive phenotype during atezolizumab administration. Further study of the histologic breadth of this phenomenon, the molecular pathways involved, and the predictive power of biomarkers during early treatment is warranted.
Transcriptomic profiling results indicate that alveolar soft part sarcomas are among the most highly lymphocyte-infiltrated solid tumours in paediatric patients. Using multiplex immunofluorescence analyses, the study investigators detected dense and unimpeded cytotoxic T lymphocytes (CTL) tumour infiltrates in adults with alveolar soft part sarcoma. Furthermore, intratumoural CTLs with activated T-cell receptor were present by cycle 3 in all alveolar soft part sarcomas with evaluable biopsy specimens, indicative of antigen recognition. The source and identity of these antigens remain unknown.
A limitation of this study is that research biopsies, which were optional when the study began, were performed in only one of the patients whose initial response assessment was progressive disease. The authors commented that specimens from several rapidly progressing tumours would have enabled comparison against responsive tumours for a better understanding of response or resistance mechanisms. Future analyses of specimens that were obtained from patients in this study at the time their disease progressed, before the start of atezolizumab/bevacizumab combination therapy, are expected to provide additional insight.
The authors concluded that the results of this phase II study, which formed the basis of the recent FDA approval, support the use of atezolizumab as a safe and effective treatment for advanced alveolar soft part sarcoma. Further investigation is needed to inform clinical decisions regarding the duration of atezolizumab treatment, the usefulness and appropriate timing of treatment breaks, and the potential benefit of atezolizumab rechallenge after disease progression.
The study was supported in part by federal funds from the NCI, National Institutes of Health and in part by Genentech (a member of the Roche Group), which provided the atezolizumab used in the study and funding.
