Phase II Study of Defactinib (VS6063) in Patients With Tumors With NF2 Loss: Results From the NCI-MATCH ECOG-ACRIN
Marjorie G Zauderer1, Opeyemi Jegede2, David M Jackman3
1Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, NY and Westchester Medical Center and New York Medical College, Valhalla, NY.
Purpose:
The NCI-MATCH trial assigned patients with solid tumors, lymphomas, or multiple myeloma to targeted therapies on the basis of identified genetic alterations from tumor biopsies. In preclinical models, neurofibromatosis 2 (NF2)-inactivated tumors display sensitivity to focal adhesion kinase (FAK) inhibition. The EAY131-U subprotocol evaluated the efficacy of defactinib, a FAK inhibitor, in patients with NF2-altered tumors.
Methods:
Patients whose tumors harbored an inactivating NF2 mutation on next-generation sequencing were assigned to subprotocol U. Defactinib 400 mg was given orally twice a day until progression or intolerable toxicity. The primary end point was objective response rate (ORR), secondary end points included toxicity, progression-free survival (PFS), and 6-month PFS.
Results:
Of 5,548 patients with sufficient tissue for genomic analysis, 57 patients were found to have NF2 alterations. Thirty-five patients ultimately enrolled and 33 were treated, with one not having central confirmation and two ineligible for outcome analysis. All patients had received previous treatment, with 52% having received three or more previous lines of therapy. The most common treatment-related toxicities were fatigue (36%), nausea (33%), and hyperbilirubinemia (27%), with 27% of patients having grade 3 toxicities. Median follow-up was 35.9 months with an ORR of 3% from one partial response in a patient with choroid meningioma. Among the 12 patients (40%) with a best response of stable disease, eight demonstrated some tumor shrinkage. Median PFS was 1.9 months, and six patients achieved a PFS >5.5 months. No correlation was identified between clinical outcomes and tumor histology or specific NF2 genotype.
Conclusion:
This protocol did not meet its prespecified primary end point. Defactinib monotherapy had limited clinical activity in this cohort of previously treated patients with solid tumors exhibiting NF2 loss.
Insights
Defactinib, a focal adhesion kinase inhibitor, showed limited efficacy in patients with neurofibromatosis 2 (NF2)-altered tumors. The NCI-MATCH trial subprotocol U did not meet its primary objective response rate endpoint.
Area of Science:
- Oncology
- Genetics
- Pharmacology
Background:
- The NCI-MATCH trial investigated targeted therapies for tumors based on genetic alterations.
- Preclinical studies indicated that neurofibromatosis 2 (NF2)-inactivated tumors are sensitive to focal adhesion kinase (FAK) inhibition.
Purpose of the Study:
- To evaluate the efficacy of defactinib, a FAK inhibitor, in patients with NF2-altered tumors within the NCI-MATCH trial (subprotocol U).
- To assess objective response rate (ORR), toxicity, and progression-free survival (PFS) for defactinib monotherapy.
Main Methods:
- Patients with inactivating NF2 mutations were enrolled in subprotocol U.
- Defactinib (400 mg orally twice daily) was administered until disease progression or toxicity.
- Primary endpoint was ORR; secondary endpoints included toxicity and PFS.
Main Results:
- Of 5,548 patients, 57 had NF2 alterations; 33 were treated with defactinib.
- The objective response rate (ORR) was 3% (one partial response). Median progression-free survival (PFS) was 1.9 months.
- Common toxicities included fatigue and nausea; 27% experienced grade 3 toxicities. No correlation between outcomes and histology or genotype was found.
Conclusions:
- The study did not meet its primary endpoint for defactinib efficacy in NF2-altered tumors.
- Defactinib monotherapy demonstrated limited clinical activity in this heavily pretreated patient cohort.
