Case study

The PLX4032 melanoma trial ^(8–10)

Vemurafenib (PLX4032) is a drug designed to treat a subgroup of patients with metastatic and unresectable melanoma (a lethal skin cancer). Since the early phases of its development, PLX4032 had shown great potential in slowing the growth of melanoma skin cancer lesions.

In January 2010, a phase 3 randomised controlled trial of PLX4032 was carried out. The trial compared PLX4032 to an active control, dacarbazine, in terms of its ability to prolong patients’ survival. Dacarbazine was the only approved chemotherapy drug for advanced melanoma at the time, but it was notoriously ineffective.

Debates arose among physicians as many felt that it was unethical to randomise some patients to receive dacarbazine when PLX4032 had shown such promising results in earlier trials. Others insisted that this trial was the only way to know, for sure, that PLX4032 could improve length of survival, since this clinical outcome was never measured previously.     

The researchers went ahead with this trial but included a plan to perform interim analyses halfway through. Indeed, interim analyses performed in January 2011 demonstrated highly significant efficacy of PLX4032 over dacarbazine. The protocol was then amended to allow those in the control (dacarbazine) group to cross over to receive PLX4032. The drug subsequently underwent priority review by the U.S. FDA and was approved in August 2011 as a first line treatment.   

The results of the trial were published in the New England Journal ‘Improved Survival with Vemurafenib in Melanoma with BRAF V600E Mutation’ (Chapman et al, 2011).   

You can also read the personal stories of two cousin brothers, one allocated to PLX4032 and the other dacarbazine, in the New York Times article ‘New Drugs Stir Debate on Rules of Clinical Trials’ (Harmon, 2010).