2019 Progress Report on Alveolar Soft Part Sarcoma – American Society of Clinical Oncology (ASCO) annual meeting

We selected to highlight 3 studies that were presented this year at the ASCO conference:

1.   Treatment of ASPS with anlotinib (a new oral tyrosine kinase inhibitor therapy), Clinical trial information: NCT02449343

2.   Combination treatment of ASPS with NKTR214 (immune modulator) and nivolumab (immune checkpoint inhibitor), Clinical trial information: NCT03282344

3.   Successful generation of patient-derived xenografts and cell lines for ASPS research

For more details please read below: 

1.   Efficacy and safety of anlotinib in advanced soft tissue sarcoma: results from one of multi-centers in a phase IIB trial (ALTER0203)

by Tang et al., 

Background:There is no standard therapy for soft tissue sarcoma (STS) patients progressing after first-line chemotherapy. Anlotinib significantly prolonged PFS in advanced STS patients in the earlier results of ALTER0203. In view of regional differences, we further analysis results from Affiliated Sixth People’s Hospital, Shanghai Jiaotong University, one center in this IIB trial. 

Methods:Patients aged from 18 to 70 with advanced STS, progressing after anthracycline-based chemotherapy (not adapted to alveolar soft part sarcoma (ASPS) and clear cell sarcoma (CSC)), angiogenesis inhibitor naive, at least one measurable lesion according to RECIST 1.1, were eligible. Patients were randomised in a 2:1 ratio to receive anlotinib (12 mg per day 2 weeks on and 1 week off) or placebo. Primary endpoint was progression free survival (PFS). Secondary endpoints were overall response rate (ORR), disease control rate (DCR).

Results:This center of ALTER0203 enrolled 48 eligible patients who received either anlotinib (n = 32) or placebo (n = 16). Leiomyosarcoma (LMS) (13/48), ASPS (12/48), synovial sarcoma (SS) (11/48) were major subtypes. The median PFS was 1.57 months (95% CI: 1.19-1.95) for placebo versus 6.27 months (95% CI: 1.89-10.65) for anlotinib (P= 0.009). ORR was 0% (0/16) for placebo versus 18.75% (6/32) for anlotinib (P= 0.16); DCR was 18.75% (3/16) for placebo versus 56.25% (18/32) for anlotinib (P= 0.02). The most common adverse events (AEs) were hypertension, elevated TSH, hypertriglyceridaemia (HTG). The most common Grade ≥3 AEs were menstrual disorder, hypertension, gamma glutamyl transferase (GGT) elevation and lipase elevation.

Conclusions:The efficacy and safety of anlotinib is further confirmed in advanced STS patients regarding regional differences. Clinical trial information: NCT02449343

2.   Pilot study of NKTR214 and nivolumab in patients with sarcomas

by D’Angelo et al., 

Abstract:

Background:Monotherapy checkpoint inhibitors have minimal efficacy in most patients with metastatic sarcoma. NKTR-214 is a CD122-preferential IL-2 pathway agonist that activates and expands natural killer and CD8+ T cells. Phase I/II data demonstrated the safety and efficacy of nivolumab plus NKTR-214 in multiple tumor types. A trial of NKTR-214 plus nivolumab was initiated in patients with selected sarcomas.

Methods:This is a multi-center pilot study enrolling patients (pts) failing prior regimens within 9 cohorts: leiomyosarcoma (LMS), undifferentiated pleomorphic sarcoma (UPS), dedifferentiated liposarcoma (DDLPS), chondrosarcoma (CS), osteosarcoma (OS), angiosarcoma (AS), alveolar soft part sarcoma (ASPS), synovial sarcoma/small blue round cell and other. Pts received NKTR 0.006mg/kg with nivolumab 360 mg every 3 weeks. Primary endpoint was objective response rate (ORR), secondary endpoints were adverse events (AEs), progression-free, overall survival (PFS, OS) and clinical benefit rate (CBR.) Pre/on treatment biopsies performed on patients for correlative studies including PD-L1 expression and TIL characterization by immunohistochemistry, whole exome sequencing and RNAseq.

Results:Enrollment completed with 10 patients in cohorts below. 50 pts enrolled (median age 58, range 14-80), 54% female. Median follow-up time is 13m. 50% of patients were refractory ≥3 lines of therapy. Grade 3/4 treatment related adverse events occurred in 26% of patients. 2% of patients stopped due to AEs. Median time to response was 3.6m. Responses seen in LMS, UPS, dedifferentiated CS; on-going in UPS/CS. Prolonged disease stability in DDLPS. 6 patients remain on treatment.

Conclusions:Nivolumab plus NKTR-214 was safe and tolerable in heavily pre-treated and refractory sarcoma patients. Responses were protracted overtime; on-going in UPS and dedifferentiated CS. Prolonged disease stability seen in DDLPS in patients. All correlative analyses are in progress and will be presented. Enrollment continues with plans to add a treatment naïve cohort. Clinical trial information: NCT03282344

3.   Successful generation of patient-derived xenografts and cell lines as preclinical models for sarcomas

By Kondo et. al.,

Background:The establishment of patient-derived preclinical models has been a challenge issue in sarcomas, because of the rarity of diseases. We report our successful experience in establishing patient-derived sarcoma xenografts and cell lines.

Methods:Tumor tissue samples from sarcoma patients undergoing surgery were collected by a team of orthopedicians and pathologists. Small tumor fragments were subcutaneously transplanted to immunodeficient NOG mice. The other part was used to establish a cell line using serum-containing media. The omics profiling was performed to examine the preservation of molecular backgrounds during the model establishment. Effects of FDA-approved drugs were examined in the established models.

Results:Since April 2014, tumor samples from 246 sarcoma cases have been processed. The sample characteristics are summarized in the table. Currently we have established PDXs and cell lines from 39 and 27 cases, respectively. Xenografts and cell lines were established from unique sarcomas such as CIC-DUX4 fusion positive sarcoma, extraskeletal osteosarcoma, primary leiomyosarcoma of bone, and alveolar soft part sarcoma. A take rate of xenografts and cell lines varied among the sarcoma types. Omics profiles considerably changed during the process of model establishment. Anti-cancer drugs with significant tumor suppressive effects were detected.

Conclusions:Our patient-derived cancer models will facilitate translational sarcoma research. The original biological features preserved in the xenografts and cell lines should be clarified to optimize the utility of sarcoma models. Currently, our cell lines are available for the academic researchers upon a request.

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Yosef Landesman, Ph.D.
President & Cancer Research Director
Cure Alveolar Soft Part Sarcoma International (iCureASPS)
e-mail: landesmany@yahoo.com