Phase II Study of Nilotinib in Melanoma Harboring KIT Alterations Following Progression to Prior KIT Inhibition

Abstract

Purpose: Although durable responses can be achieved with tyrosine kinase inhibitors such as imatinib in melanomas harboring KIT mutations, the efficacy of alternative inhibitors after progression to imatinib and the activity of these agents on brain metastases are unknown.

Experimental design: We conducted a phase II study of nilotinib 400 mg twice a day in two cohorts of patients with melanomas harboring KIT mutations or amplification: (A) those refractory or intolerant to a prior KIT inhibitor; and (B) those with brain metastases. The primary endpoint was 4-month disease control rate. Secondary endpoints included response rate, time-to-progression (TTP), and overall survival (OS). A Simon two-stage and a single-stage design was planned to assess for the primary endpoint in cohorts A and B, respectively.

Results: Twenty patients were enrolled and 19 treated (11 in cohort A; 8 in cohort B). Three patients on cohort A [27%; 95% confidence interval (CI), 8%-56%] and 1 on cohort B (12.5%; 90% CI, 0.6%-47%) achieved the primary endpoint. Two partial responses were observed in cohort A (18.2%; 90% CI, 3%-47%); none were observed in cohort B. The median TTP and OS was 3.3 (90% CI, 2.1-3.9 months) and 9.1 months (90% CI, 4.3-14.2 months), respectively, in all treated patients.

Conclusions: Nilotinib may achieve disease control in patients with melanoma harboring KIT alterations and whose disease progressed after imatinib therapy. The efficacy of this agent in KIT-altered melanoma with brain metastasis is limited.

©2015 American Association for Cancer Research.

Figures

Figure 1

Representative images from two patients achieving radiographic responses in brain metastases with nilotinib. Magnetic resonance images of brain metastases present at baseline (Figure 1A) and after 4 months of therapy (Figure 1B) in a patient who achieved a minor response in extracranial metastases and a partial response in target brain metatases as demonstrated by the circled lesions are presented. The baseline brain MRI was performed 5 months after receiving stereotactic radiosurgery to left temporal, left parietal, right frontal, and right mid-cerebellar lesions and demonstrate the development of progression in the previously treated lesions and the development of numerous new infra and supratentorial hemorrahgic brain metastases (Figure 1A). Despite durable stability in the extracranial disease after 4 months of therapy and further reduction in the size of several of the brain metastases, there was progressing in non-target brain metastases (arrow). Magnetic resonance images of a brain metastasis present at baseline (Figure 1C) and after 2 months of therapy (Figure 1D) in a patient who achieved a partial response in a solitary brain metastases are presented. No prior radiotherapy or surgery was performed in this patient prior to initiation of study therapy.

Figure 2

Treatment Response Over Time to Imatinib and Nilotinib by Genetic Alteration of KIT.

Figure 3

Time-to-Progression and Overall Survival. Kaplan-Meier estimates of time-to-progression (Figure 3A) and overall survival (Figure 3B) in those enrolled on Cohorts A (dotted red lines) and B (solid blue line) are shown. The vertical lines indicate that patients’ data were censored. The median time-to-progression was 3·4 months (90% CI, 0·9 – 5·5) in Cohort A and 2·6 months (90% CI, 1·8 – 3·9) in Cohort B. Overall survival was 14·2 months [90% CI, 7·1 – ∞] in Cohort A and 4.3 months [90% CI, 3·5 – 11·9] in Cohort B.