Vemurafenib

The purpose of combining targeted agents and immunotherapy is to achieve a chance of long-term tumor control in highly advanced patients. Between April 2012 and December 2013, 10 patients with metastatic melanoma were treated with a combination treatment of vemurafenib and ipilimumab as an individual treatment decision after detailed information and giving written informed consent. All the patients had advanced symptomatic disease, seven with elevated serum lactate dehydrogenase (LDH) levels and six with brain metastases on MRI. After clinical improvement under vemurafenib monotherapy (median 11.5 weeks), four cycles of ipilimumab were administered additionally. Combination treatment was tolerated well, with only two patients developing ≥ grade 3 elevation of transaminases; this was asymptomatic and resolved on cessation of BRAF inhibitor treatment. Staging 12 weeks after initiation of ipilimumab revealed partial response for five patients, stable disease for two, and disease progression for three.

The BRAF V600E mutation is commonly observed in papillary thyroid cancer (PTC) and predominantly activates the MAPK pathway. Presence of BRAF V600E predicts increasing risk of recurrence and higher mortality rate, and treatment options for such patients are limited. Vemurafenib, a BRAF V600E inhibitor, is initially effective, but cells inevitably develop alternative mechanisms of pathway activation. Mechanisms of primary resistance have been described in short-term cultures of PTC cells; however, mechanisms of acquired resistance have not. In the present study, we investigated possible adaptive mechanisms of BRAF V600E inhibitor resistance in KTC1 thyroid cancer cells following long-term vemurafenib exposure. We found that a subpopulation of KTC1 cells acquired resistance to vemurafenib following 5 months of treatment with the inhibitor. Resistance coincided with the spontaneous acquisition of a KRAS G12D activating mutation. Increases in activated AKT, ERK1/2, and EGFR were observed in these cells.