Frequent subclinical macular changes in melanoma patients treated with combined BRAF/MEK inhibition and high dose hydroxychloroquine does not require dosing modification or discontinuation: preliminary results from a multi-institutional phase I/II clinical treatment trial for advanced metastatic BRAF mutant melanoma

Abstract

Purpose : To assess the potential ocular toxicity of a combined BRAF inhibition (BRAFi)/ MEK inhibition (MEki) /hydroxychloroquine (HCQ) regime used to treat advanced metastatic BRAF mutant melanoma.

Methods : Eight patients (31 to 69 years of age) with stage IV metastatic melanoma and BRAF^V600E mutations were enrolled in a phase I/II clinical trial. Treatment was with oral dabrafenib, 150mg bid, trametinib, 2mg/day, and HCQ, 400-600mg bid. Ocular toxicity was assessed (at baseline, one month, q/6 months) by ophthalmic examination, spectral domain optical coherence tomography (SD-OCT), near infrared (NIR) and short-wavelength (SW) autofluorescence (FAF) imaging, and with visual acuity (VA) and light-adapted static perimetry (10-2 protocol).

Results : Treatment outcome was striking: 7/8 patients responded, 7/7 with a complete response; most remain on study at 12-18+ months. Ophthalmic examinations confirmed no safety concerns. 7/8 patients showed shallow separation of the photoreceptor outer segment (POS) tip from the apical retinal pigment epithelium (RPE), two with trace subretinal fluid (SRF) at the foveal center. Changes were mostly foveal but could be traced to the pericentral retina. Structural changes subsided without drug holiday/dose modification. There were no inner retinal abnormalities or photoreceptor loss or significant changes in VA or in foveal or mean sensitivity in any of the patients with these abnormalities. There were no changes in RPE melanization or lipofuscin content by NIR- and SW-FAF, respectively.

Conclusions : BRAF/MEK/HCQ treatment was well tolerated from an ocular toxicity standpoint. Frequent subclinical separation of the POS from the apical RPE without obvious SRF or changes in vision contrasts with the central serous-like retinopathy reported with single agent MEKi. SD-OCT changes may be related to transient interference with the RPE phagocytic or pump functions reflecting effective BRAF/MEK inhibition. The addition of BRAF inhibitor and/or HCQ to MEKi may ameliorate the retinal changes. Longer observation intervals in larger groups of patients treated with this regime are needed to confirm the prevalence and significance of the changes.

This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.