Phase II Study of Defactinib (VS6063) in Patients With Tumors With NF2 Loss: Results From the NCI-MATCH ECOG-ACRIN Trial (EAY131) Subprotocol U

Abstract

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.

Figure 1:

EAY131-U CONSORT Diagram *Not enrolled to arm U (n=16); aMOI = actionable mutation of interest Reason unknown (n=4), deceased (3), patient refusal (2), uncontrolled blood pressure (1), no longer meet master protocol eligibility (1), medical decision for other reasons (1), cardiac function/LVEF (1), inadequate organ/marrow function (1), deteriorating performance status (1), treatment for new/brain metastases (1)

Figure 2:

A) This waterfall plot includes all patients who had measurable disease from which percent changes could be calculated (N=24, 6 patients with unevaluable disease). Response status categorization is indicated for each patient. Diseases are encoded by the color of each patient bar. B) This swimmer plot charts outcomes for all evaluable patients treated on the trials (N=25, 6 patients with radiographically unevaluable disease, but 1 of those patients had symptomatic progression of disease and was included). Diseases are encoded by the color of each patient bar. (CNS=central nervous system; Gyn. = gynecologic)

Figure 2:

A) This waterfall plot includes all patients who had measurable disease from which percent changes could be calculated (N=24, 6 patients with unevaluable disease). Response status categorization is indicated for each patient. Diseases are encoded by the color of each patient bar. B) This swimmer plot charts outcomes for all evaluable patients treated on the trials (N=25, 6 patients with radiographically unevaluable disease, but 1 of those patients had symptomatic progression of disease and was included). Diseases are encoded by the color of each patient bar. (CNS=central nervous system; Gyn. = gynecologic)

Figure 3:

A) Progression-free survival, as calculated by Kaplan-Meier, is graphed. B) Overall survival, as calculated by Kaplan-Meier, is graphed. C) Progression-free survival, as calculated by Kaplan-Meier, is graphed by tumor group. Indolent tumors, which included meningiomas, schwannomas, and spinal cord neurofibromatosis, were separated from the rest of the tumors in the cohort. D) Overall survival, as calculated by Kaplan-Meier, is graphed by tumor group. Indolent tumors which included meningiomas, schwannomas, and spinal cord neurofibromatosis, were separated from the rest of the tumors in the cohort.

Figure 3:

A) Progression-free survival, as calculated by Kaplan-Meier, is graphed. B) Overall survival, as calculated by Kaplan-Meier, is graphed. C) Progression-free survival, as calculated by Kaplan-Meier, is graphed by tumor group. Indolent tumors, which included meningiomas, schwannomas, and spinal cord neurofibromatosis, were separated from the rest of the tumors in the cohort. D) Overall survival, as calculated by Kaplan-Meier, is graphed by tumor group. Indolent tumors which included meningiomas, schwannomas, and spinal cord neurofibromatosis, were separated from the rest of the tumors in the cohort.

Figure 3:

A) Progression-free survival, as calculated by Kaplan-Meier, is graphed. B) Overall survival, as calculated by Kaplan-Meier, is graphed. C) Progression-free survival, as calculated by Kaplan-Meier, is graphed by tumor group. Indolent tumors, which included meningiomas, schwannomas, and spinal cord neurofibromatosis, were separated from the rest of the tumors in the cohort. D) Overall survival, as calculated by Kaplan-Meier, is graphed by tumor group. Indolent tumors which included meningiomas, schwannomas, and spinal cord neurofibromatosis, were separated from the rest of the tumors in the cohort.