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A phase II study of everolimus in patients with advanced solid malignancies with TSC1, TSC2, NF1, NF2 or STK11
Siddhartha Devarakonda1, Bruna Pellini2, Luke Verghese1
1Division of Medical Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, USA.
Background:
Activation of the mTOR pathway has been implicated in the development of several malignancies and alterations in TSC1, TSC2, STK11 and NF1, can lead to the dysregulation of this pathway. Furthermore, mutations in TSC1 and NF2 are known to confer sensitivity to everolimus-an mTOR inhibitor. Based on these data, a single-arm, open label, single-institution phase II basket study was designed to assess the activity of everolimus in patients with solid malignancies whose tumors harbored mutations in TSC1, TSC2, NF1, NF2, or STK11.
Methods:
A total of 12 patients with histologically confirmed diagnosis of advanced solid tumors (metastatic, recurrent, or unresectable) with mutations in TSC1, TSC2, NF1, NF2 or STK11 genes, who had failed at least one line of standard of care systemic therapy, were enrolled to this open label, single-arm study. Presence of mutations in TSC1, TSC2, NF1, NF2 or STK11 genes was assessed using targeted-next generation sequencing (NGS). All eligible patients were treated with everolimus at an initial dose of 10 mg orally once daily in cycles of 28 days. The primary endpoint of this study was overall response rate (ORR).
Results:
Of 12 patients enrolled, 8 were evaluable for response at the end of 2 cycles. One complete response (CR) was observed (12.5%) and one patient (12.5%) had stable disease (SD), while six (75%) patients showed disease progression. Everolimus was overall well tolerated with anemia, decreased neutrophil and lymphocyte counts, peripheral edema and hyperglycemia representing the most common adverse events. One patient discontinued treatment due to a treatment related grade 4 pericardial effusion. Both patients with CR or SD had a diagnosis of lung adenocarcinoma with NF1 or STK11 mutations, respectively.
Conclusions:
Although this study failed to meet its prespecified ORR threshold for success of 30% or higher, exploratory analyses suggest potential activity for everolimus in a subset of patients with lung adenocarcinomas with STK11 or NF1 mutations. Further studies are necessary to systematically explore the clinical activity of everolimus, potentially as a combination therapy, in these patients.
Insights
Everolimus showed limited overall response in advanced solid tumors with specific gene mutations. However, exploratory analysis suggests potential benefit in lung adenocarcinoma patients with NF1 or STK11 mutations.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- The mTOR pathway is crucial in malignancy development.
- Mutations in TSC1, TSC2, STK11, and NF1 can dysregulate the mTOR pathway.
- TSC1 and NF2 mutations indicate sensitivity to everolimus, an mTOR inhibitor.
Purpose of the Study:
- To assess the activity of everolimus in patients with solid tumors harboring mutations in TSC1, TSC2, NF1, NF2, or STK11.
- To evaluate the overall response rate (ORR) as the primary endpoint.
Main Methods:
- A single-arm, open-label, phase II basket study.
- 12 patients with advanced solid tumors and mutations in TSC1, TSC2, NF1, NF2, or STK11 were enrolled.
- Mutation status was determined by targeted-next-generation sequencing (NGS).
- Patients received everolimus 10 mg orally once daily.
Main Results:
- Eight patients were evaluable for response.
- One complete response (12.5%) and one stable disease (12.5%) were observed.
- Six patients (75%) experienced disease progression.
- Everolimus was generally well-tolerated; common adverse events included anemia and hyperglycemia.
- The patient with complete response and the patient with stable disease had lung adenocarcinoma with NF1 or STK11 mutations, respectively.
Conclusions:
- The study did not meet the predefined ORR threshold of 30%.
- Exploratory analysis indicates potential activity of everolimus in a subset of lung adenocarcinomas with STK11 or NF1 mutations.
- Further research is warranted to explore everolimus, possibly in combination therapy, for these specific patient groups.
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