Atezolizumab for Advanced Alveolar Soft Part Sarcoma

Abstract

Background: Alveolar soft part sarcoma (ASPS) is a rare soft-tissue sarcoma with a poor prognosis and no established therapy. Recently, encouraging responses to immune checkpoint inhibitors have been reported.

Methods: We conducted an investigator-initiated, multicenter, single-group, phase 2 study of the anti-programmed death ligand 1 (PD-L1) agent atezolizumab in adult and pediatric patients with advanced ASPS. Atezolizumab was administered intravenously at a dose of 1200 mg (in patients ≥18 years of age) or 15 mg per kilogram of body weight with a 1200-mg cap (in patients <18 years of age) once every 21 days. Study end points included objective response, duration of response, and progression-free survival according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1, as well as pharmacodynamic biomarkers of multistep drug action.

Results: 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 duration of response was 24.7 months (range, 4.1 to 55.8), and the median progression-free survival was 20.8 months. Seven patients took a treatment break after 2 years of treatment, and their responses were maintained through the data-cutoff date. No treatment-related grade 4 or 5 adverse events were recorded. Responses were noted despite variable baseline expression of programmed death 1 and PD-L1.

Conclusions: Atezolizumab was effective at inducing sustained responses in approximately one third of patients with advanced ASPS. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT03141684.).

Figure 1.. Patient Responses to Atezolizumab.

Time in the study (in months) as of July 31, 2022, is shown for each patient. The colors of the bars indicate the best response for each patient, and the time of the first complete or partial response is indicated by a diamond or circle, respectively. The dashed line indicates the median time to first response (3.6 months). One patient (asterisk) had an unconfirmed partial response. One patient (dagger) had a partial response according to Immune Response Evaluation Criteria in Solid Tumors (iRECIST).

Figure 2.. Best Target-Lesion Response.

The best percentage change from baseline in the target-lesion size is shown for each patient. The colors of the bars indicate the best response for each patient, and the dashed line represents a decrease of at least 30% in the target-lesion size. Patient 14 (asterisk) had an unconfirmed partial response. Patient 29 (dagger) had a partial response according to iRECIST but a best response of stable disease according to Response Evaluation Criteria in Solid Tumors, version 1.1, owing to an increase of more than 20% in target-lesion size before subsequent shrinkage (i.e., pseudoprogression). Patient 37 (double dagger) had a radiographic complete response of the target lesion, but bone abnormalities persisted.

Figure 3.. Kaplan–Meier Analysis of Progression-free Survival.

Kaplan–Meier estimates of progression-free survival are shown as of July 31, 2022. The dashed line indicates the median progression-free survival, and tick marks indicate unique censoring times. The gray-shaded areas indicate 95% pointwise confidence intervals, with standard errors obtained with the use of Greenwood’s formula (computed on the basis of log[survival]).

Figure 4. Pharmacodynamic Biomarkers in Tumor-Biopsy Specimens.

Multiplex immunofluorescence microscopy of core-needle tumor-biopsy specimens revealed the molecular target of atezolizumab (programmed death ligand 1 [PD-L1]–positive cells, red) and immune effector cells (CD8+ cytotoxic T lymphocytes [CTLs], green), dispersed among alveolar soft part sarcoma (ASPS) tumor cells expressing nuclear TFE3 (light blue). Some of these CTLs showed phosphorylation of the ζ chain of the T-cell receptor that is associated with antigen recognition (yellow, with example cells indicated by arrows). The nuclei of all TFE3-negative cells are dark blue from the DAPI (4′,6-diamidine-2-phenylindole) stain. Unlike in other cancers in which lymphocytes accumulate at tumor margins, CD8+ CTLs are widely dispersed into all areas of the ASPS tumor microenvironment in the four representative tumors shown here, which is consistent with unimpeded immune-cell migration. Patient 37, in the partial-response group, had increases in PD-L1 and CTL levels by a factor of 9 to 10 from the pretreatment baseline (left) to cycle 3 day 1 of treatment (right). Patient 24, in the partial-response group, and Patient 49, in the stable-disease group, had the persistent presence of PD-L1–positive cells and CTLs at baseline (left) and cycle 3 day 1 (right). Patient 31, in the stable-disease group, had both persistent and abundant PD-L1–positive cells and CTLs at baseline (left) and cycle 3 day 1 (right). The presence of molecular and cellular components that are required to respond to the mechanism of action of atezolizumab in nearly all the patients with evaluable tumor-biopsy specimens indicates that this cancer is primed to respond to immune checkpoint inhibitor therapy and is consistent with the high degree of clinical benefit conferred by atezolizumab therapy. Quantitation of each biomarker is presented in Table S5.