1268P - NCI 9922: Phase II study of ibrutinib in treatment-refractory distant metastatic cutaneous melanoma (DMCM)

Abstract

Background: The IL-2 inducible kinase (ITK) is highly expressed in metastatic melanomas and molecular targeting and/or pharmacologic inhibition of ITK in preclinical melanoma models suppresses cell proliferation without inducing cell death (Carson CCR 2015). Ibrutinib suppresses proliferation of melanoma cell lines in low nM concentrations (Moschos ASCO 2017, TPS9592). We hypothesize that targeting DMCM with ibrutinib will induce antitumor responses, especially in high ITK-expressing melanomas. Methods: This is an open-label, single-arm, Simon’s 2-stage design, multicenter, phase II study for patients (pts) with DMCM refractory to or ineligible for PD-1 and MAPK inhibitors, if BRAFV600-mutant. Given that the IC50 of ibrutinib for ITK is > 10 times than Bruton’s tyrosine kinase’s, we administered ibrutinib at 840mg qd. We hypothesized that an ineffective drug will have a = <5% response rate and = <18% 6-month PFS rate. We present the results of the first stage. Results: 18 pts (13 males; median age 63.5, range 37-82; 14 with M1c disease; 4 with BRAFV600 mutation; 12 with performance status 1 or 2; 4 with resistance to 4 treatments; 5 with resistance to = >5 treatments) were enrolled. Median exposure to ibrutinib was 27.5 days (range 4-155). The most frequent all-grade side effects were fatigue (55%), anorexia (50%), gastrointestinal upset (44%), and anemia (39%). 4 grade IV (hyponatremia, sepsis, cytokine release syndrome, and constipation occurred 6% each) and 9 grade III events [hyponatremia (17%); pneumonia, hypertension, anemia, hypoalbuminemia, dehydration, lymphopenia occurred 6% each] were seen. No antitumor responses were seen. At a median follow-up of 5 months, all pts had progressed (median PFS was 1.3 months, range 0.2-5.5). 15 pts were discontinued from study due to progression and 14 pts had died from melanoma. Median OS was 5 months (range 0.3-10.4 months) in pts who died. Conclusions: In this treatment-refractory DMCM, high-dose ibrutinib did not induce any meaningful clinical benefit; therefore the study will not proceed to stage 2. Correlation between PFS and expression of ITK by melanoma cells and density of tumor-infiltrating T- and B-cells in pretreatment tumor specimens will be reported at the time of the meeting. Clinical trial identification: NCT03427398. Legal entity responsible for the study: NCI-CTEP. Funding: NCI-CTEP, Pharmacyclics. Disclosure: All authors have declared no conflicts of interest.