REVERSIBLE ACUTE KIDNEY INJURY WITH HIGH GRADE PROTEINURIA ASSOCIATED WITH FAK AND MEK INHIBITION TREATMENT FOR METASTATIC MELANOMA

Jacqueline Evans¹, A/Prof Scott Wilson^1,2

¹Department of Renal Medicine, Alfred Health, Melbourne, Australia, ²Central Clinical School, Monash University, Melbourne, Australia

Background:

Focal adhesion kinase (FAK) and MEK inhibitor combination therapy is being trialled as treatment for metastatic Neuroblastoma-RAS (NRAS) mutant melanoma. FAK is a non receptor tyrosine kinase implicated in tumorigenesis, promoting cell survival and proliferation. Proteinuria is a known dose limiting side effect of FAK inhibition therapy. We report a case of acute kidney injury following FAK and MEK inhibition therapy, necessitating treatment cessation.

Case report:

A 70-year-old female with metastatic NRAS-mutant melanoma was enrolled in a Phase I trial investigating FAK inhibitor, IN10018, and MEK inhibitor, cobimetinib, combination therapy. On routine monitoring there was nephrotic range proteinuria, with urine protein creatinine ratio of 1873mg/mmol. Trial treatment was subsequently withheld. Two weeks later the patient presented with oliguric acute kidney injury. Serum creatinine was 279 µmol/L at the time of presentation and peaked at 501 µmol/L, from a baseline of 98 µmol/L one month prior. Autoimmune serology and imaging were non-contributory in identifying a cause for renal impairment. Renal biopsy showed significant acute tubular necrosis in regenerative phase with mild interstitial inflammation and background changes of mild interstitial fibrosis. Electron microscopy revealed partial foot process effacement. Management was supportive only. Renal function improved with proteinuria resolving fully and creatinine decreasing to 110 µmol/L two months post the cessation of the FAK inhibitor.

Conclusions:

FAK inhibition shows promise as anticancer therapy, particularly in combination with other agents. We present a case of heavily proteinuric acute kidney injury following IN10018 and cobimetinib combination treatment requiring withdrawal of trial therapy. This proposes acute glomerulonephropathy as an adverse effect from FAK and MEK inhibitor therapy.

Biography:

Bio to come