Investigators enrolled 34 patients 18 years or older with histologically confirmed malignant PEComa. Patients could not have had prior mTOR inhibitors. They received infusions of 100 mg/m2 nab-sirolimus on days 1 and 8 every 21 days until progression or unacceptable toxicity. Patients were a median age of 60 years and 44% were 65 or older; 82% were women, which is typical of the disease. Most patients (88%) had no prior systemic therapy for advanced PEComa.
Results
The drug was well tolerated, with toxicities similar to those of oral mTOR inhibitors. Treatment-related adverse events (TRAEs) occurring in 25% or more of patients were mostly grade 1 or 2 toxicities. Hematologic TRAEs included anemia (47%) and thrombocytopenia (32%) of any grade. Nonhematologic events of any grade included stomatitis/ mucositis (74%), dermatitis/rash (65%), fatigue (59%), nausea (47%), and diarrhea (38%), among others. A few grade 3 events occurred on study, most notably stomatitis/mucositis (18%). Severe adverse events (SAEs) were also uncommon, occurring in 7 of 34 patients (21%). Pneumonitis is common in orally administered mTOR inhibitors; 6 patients (18%) treated with nab-sirolimus had grade 1 or 2 pneumonitis.
Of the 31 evaluable patients, 13 (42%) had an objective response, all of which were partial responses (PR). Eleven (35%) had stable disease and 7 (23%) had progressive disease. The disease control rate, consisting of PR and stable disease, was 77%. The median duration of response had not been reached as of the data cutoff on May 10, 2019. At that time, it was 6.2 months (range, 1.5 to 27.7+). The median time to response was 1.4 months and the median progression-free survival (PFS) was 8.4 months. The PFS rate at 6 months was 61%. Three patients had received treatment for over a year and another 3 patients for more than 2 years.
Correlation with biomarkers
Of the 25 patients who had tissue suitable for next-generation sequencing, 9 had TSC2 mutations, 5 had TSC1 mutations, and 11 had neither mutation. Strikingly, 9 of 9 patients with TSC2 mutations developed a PR, while only 1 with a TSC1 mutation responded. One patient with no TSC1/2 mutation also responded and 2 patients with unknown mutational status responded. The investigators also analyzed pS6 status by immunohistochemistry—pS6 is a marker of mTOR hyperactivity. Twenty- five patient samples were available for analysis. Eight of 8 patients who were negative for pS6 staining did not have a response, while 10 of 17 (59%) who were pS6-positive had a PR.
In the discussion that followed, Winette van der Graaf, MD, of the Netherlands Cancer Institute in Amsterdam, noted that this study showed that biomarkers can be used for patient selection, although TSC2 mutations are not uniquely linked with response. She indicated a comparator with sirolimus would have been of great interest.
SOURCE: Wagner AJ, et al. J Clin Oncol 37, 2019 (suppl; abstr 11005).
The study was sponsored by Aadi Bioscience, Inc., and funded in part by a grant from the FDA Office of Orphan Products Development (OOPD).
Disclosures relevant to this presentation include contininstitutional research funding from Aadi Bioscience for Dr. Wagner and a few other abstract coauthors. Several coauthors are employed by Aadi Bioscience and have stock or other ownership interests. Dr. van der Graaf had nothing to disclose.
Cabozantinib Achieves Disease Control in GIST
The phase 2 EORTC 1317 trial, known as CaboGIST (NCT02216578), met its primary endpoint of progression-free survival (PFS) at 12 weeks in patients with metastatic gastrointestinal stromal tumor (GIST) treated with the tyrosine kinase inhibitor (TKI) cabozantinib. Twenty-four (58.5%) of the 41 patients in the primary study population, and 30 (60%) of the entire 50-patient population, were progression-free at 12 weeks. The study needed 21 patients to be progression- free for cabozantinib to warrant further exploration in GIST patients.