9511 Background: There are few treatment options for patients (pts) with advanced uveal melanoma (UM). MEK inhibition (MEKi) has demonstrated efficacy in a randomized Phase 2 trial (Carvajal et al, 2014), but resistance may be mediated via Akt signaling (Ambrosini et al, 2013). We hypothesized that adding an Akt inhibitor (Akti), GSK2141795 (GSK795), to the MEKi trametinib (TRAM) would improve progression-free survival (PFS) in pts with UM. Methods: We conducted an open-label Phase 2 trial where pts with advanced UM and no prior systemic or liver-directed therapy were randomized to one of two arms stratified by liver disease and LDH: TRAM 2mg daily (Arm A) or TRAM 1.5mg + GSK795 50mg daily (Arm B). Efficacy was assessed every 8 weeks (wk) by RECIST 1.1. Pts whose tumors progressed on TRAM could receive TRAM + GSK795. With 40 patients per arm, this design had 80% power to detect a PFS hazard ratio of 0.56 with a 5% one-sided alpha. A pre-planned futility analysis after 40 enrolled pts would cease accrual to an arm if <2/20 pts had objective responses. Matched biopsies at baseline and Day 15 were mandatory. Results: 40 pts were enrolled, of which 39 received ≥1 dose of study drug (N=18 TRAM; N=21 TRAM + GSK795). Median age 61, 55% male, 85% liver disease, 50% elevated LDH. One partial response was observed in each arm (16+ wk in Arm A, 8 wk in Arm B); thus, accrual was held on both arms. We did not detect a difference in median PFS between Arm B and Arm A (15.6 vs 15.7 wk; p=0.74, log rank). Median PFS for N=11 who crossed over to TRAM + GSK795 was 7.9 wk (range: 3.7-41+ wk). All pts had ≥1 adverse event (AE) at least possibly related to drug(s). AEs for TRAM included rash (100%, all Grade (G)1-2), diarrhea (72%, all G1-2), elevated AST/ALT (55%, 6% G3), mucositis (50%, all G1-2). 7/18 required dose reduction. AEs with TRAM + GSK795 included rash (81%, 14% G3), nausea (67%, all G1-2), diarrhea (62%, all G1-2), elevated AST/ALT (43%, 14% G3). 7/21 required dose reduction (2 TRAM, 3 GSK795, 2 both). There were no G4-5 AEs. Conclusions: The addition of Akti GSK795 to TRAM did not improve PFS, and objective responses were uncommon. Dose reductions for AEs were frequent. Ongoing analysis of 31 matched biopsies at baseline and day 15 is investigating therapeutic resistance. Clinical trial information: NCT01979523.
Combined BRAF and MEK inhibition (BRAF-MEK) is a standard therapy for patients with BRAF V600-mutant melanoma, but to the authors' knowledge, the tolerance, adverse event (AE) profile, and efficacy have not been well defined in the post-programmed cell death protein 1 (PD-1) setting.Patients with BRAF V600-mutant melanoma who received combined BRAF-MEK after prior PD-1-based therapy were assembled from 4 tertiary care centers in the United States and Australia. Dose modification was defined as a treatment break, dose reduction, or intermittent dosing. Rates of hospitalization and discontinuation due to AEs were collected, and overall survival (OS) was calculated using Kaplan-Meier methods from the time of the initiation of BRAF-MEK therapy.A total of 78 patients were identified as having received a BRAF-MEK regimen at a median of 34 days after the last dose of PD-1-based therapy. The majority of patients (86%) received the combination of dabrafenib and trametinib. Approximately 80% of patients had American Joint Committee on Cancer M1c or M1d disease. Sixty-five regimens (83%) had ≥1 dose modification. The median time to the first dose modification was 14 days; 86% occurred within 90 days and 71% involved pyrexia. Dose modifications were more common in patients receiving BRAF-MEK <90 days after the last dose of PD-1 and who were not receiving steroids. Of the dose modifications, 25 (31%) led to an AE-related hospitalization. Among 55 BRAF-naive patients, the median time receiving BRAF-MEK therapy was 5.8 months and the median OS was 15.6 months.The majority of patients receiving BRAF-MEK inhibition after PD-1 therapy require dose interruptions, and a significant minority require hospitalization for AEs. In this higher risk population, the median time receiving therapy and OS may be inferior to those presented in published phase 3 trials.
Ipilimumab is a first-in-class immunological checkpoint blockade agent and monoclonal antibody against Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4) that has demonstrated survival benefit and durable responses in patients with metastatic melanoma. To date, solid organ transplant recipients have been excluded from clinical trials with cancer immunotherapies on the basis of their concurrent treatment with immunosuppressive agents. We present the first case to our knowledge of a patient with advanced cutaneous melanoma receiving ipilimumab status post orthotopic liver transplantation with a partial response. Transaminitis was observed 4 months after administration of ipilimumab that resolved with close observation. No evidence of graft rejection has been observed to date. This case advocates for further investigation of the safety and efficacy of cancer immunotherapies in solid organ transplant recipients.
The treatment of metastatic melanoma has changed dramatically in the last decade with the introduction of immunotherapy and targeted therapy. A futile disease in the past is now treated with various options, resulting in improvement in progression-free and overall survivals, along with improvement in the quality of life. Having said that, the majority of patients with metastatic melanoma eventually succumb to the disease. Molecular profiling of each tumor in the advanced stage is standard of care now, as this would lead to individualized treatment options for each patient. Here, we present a rare case of fibroblast growth factor receptor 3 (FGFR 3) amplified metastatic melanoma, treated rather unconventionally with FGFR 3 inhibitor erdafitinib.
