The development of a new drug called vemurafenib heralds “a new era in the treatment of skin cancer”, according to The Independent.
Several newspapers have written about the drug, which has been tested in a trial involving 675 adult patients with previously untreated advanced skin cancer (melanoma). Patients were given either the new vemurafenib pill or injections of dacarbazine, the only licensed chemotherapy drug for advanced melanoma. Scientists found that vemurafenib reduced the risk of a person’s disease progressing and improved overall short-term survival. At six months, 84% of those who took vemurafenib were still alive, compared to 64% of those who took dacarbazine. The average survival with vemurafenib was estimated to be 5.3 months, compared to 1.6 months with dacarbazine.
As with all drugs, there were some side effects associated with vemurafenib, such as joint pain and skin complaints, with 18% of people taking the drug developing less aggressive skin tumours that could be removed by simple surgery. Longer-term follow-up will be needed to monitor the risk of such tumours and what happens to the people who develop them.
Although the results represent an advance in cancer treatment, vemurafenib is not a cure for melanoma as some newspapers have suggested. Instead, the drug has shown promising results in slowing the progression of melanoma that has spread to other parts of the body, rather than curing it.
Where did the story come from?
The study was carried out by researchers from Memorial Sloan-Kettering Cancer Center in New York and other research centres in the US, Europe and Australia. It was funded by Hoffmann-La Roche, the manufacturer of vemurafenib.
The study was published in the peer-reviewed New England Journal of Medicine.
The newspapers generally reported this study appropriately, though some of them presented overly high expectations of this treatment. The Daily Mail ’s headline said that the drugs “could offer years more life”, but the current study results do not demonstrate this. In this study, vemurafenib was found to improve average (median) survival by 3.7 months, rather than years. The BBC reported the proportions of the two groups using vemurafenib and dacarbazine who were still alive at six months, rather than only reporting the relative changes in survival. This helps readers to better understand the drug’s impact.
What kind of research was this?
This randomised controlled trial (RCT) assessed the effects of a new drug called vemurafenib for advanced (metastatic) melanoma. The drug was compared to the treatment currently used, the chemotherapy drug dacarbazine. An RCT is the best type of study for assessing the effects of new treatments compared to current treatments.
Metastatic melanoma (called stage IV cancer), where cancer has spread to other organs in the body, has a poor prognosis. Patients live for an average (median) of 8 to 18 months after diagnosis. In the UK and US, dacarbazine is the only chemotherapy drug licensed for the treatment of metastatic melanoma. This study also included patients whose cancer was at the stage just below this (stage IIIC), defined as having either an ulcerated melanoma that has spread to one to three lymph nodes, or one that has spread to four or more lymph nodes with or without ulceration.
About 40–60% of melanomas are reported to carry mutations in a gene called BRAF. These mutations cause the BRAF enzyme to be active all the time, which can contribute to uncontrolled cell division seen in cancerous cells. Vemurafenib inhibits the action of the mutant BRAF enzyme, and is being tested in people who carry BRAF mutations.
What did the research involve?
The researchers enrolled 675 adult patients with previously untreated stage IIIC or stage IV melanoma (the most advanced stages) that could not be removed surgically and that carried a BRAF mutation. To be eligible, they had to have a life expectancy of more than three months. They were randomly assigned to receive treatment with either vemurafenib or dacarbazine, and were followed up over time to see whether there were any differences between the drugs in outcomes of overall survival, tumour response or adverse events.
As vemurafenib is an oral treatment and dacarbazine an intravenous treatment, patients would have known which treatment they were receiving. However, because the outcomes being assessed were not subjective measures, the lack of blinding should not have influenced the recording of these events. Vemurafenib was given as a pill at a dose of 960mg twice a day. Dacarbazine was given intravenously at a dose of 1,000mg per square metre of body-surface area every three weeks. Doses could be reduced according to a set protocol if there were intolerable adverse effects. Treatment was stopped once the disease progressed.
Participants were assessed at the start of the study and every three weeks for tumour response, which was defined according to standard criteria. Researchers also monitored the participants for adverse events, the severity of which was graded according to a standard grading system. The main outcomes that the researchers were interested in were overall survival and being free of disease progression.
The researchers compared overall survival and the other outcomes of interest between the two groups. The current report comes from the interim analysis of the study, which was planned to take place after 98 deaths had occurred.
What were the basic results?
At six months, 84% of patients taking vemurafenib were alive, compared to 64% in the dacarbazine group. Vemurafenib reduced the risk of dying during the study by 63% compared to dacarbazine (hazard ratio [HR] 0.37, 95% confidence interval [CI] 0.26 to 0.55). The average (median) survival in the vemurafenib group was estimated to be 5.3 months, compared to 1.6 months with dacarbazine.
Vemurafenib also reduced the risk of a person’s tumour progressing by 74% (HR 0.26, 95% CI 0.20 to 0.33). Because of the improved results with vemurafenib, the board overseeing the study recommended that patients receiving dacarbazine should be treated with vemurafenib.
Adverse events that were more common with vemurafenib than dacarbazine included painful joints (arthralgia), rash, alopecia, keratoacanthoma (a fairly non-aggressive tumour of the hair follicle) and squamous-cell carcinoma (another type of skin cancer which rarely spreads to the body and can usually be completely cured using surgical removal). Side effects of low white blood cell count and vomiting were less common with vemurafenib than with dacarbazine. Dose modification or interruption due to adverse effects was needed in 38% of the vemurafenib group and 16% of the dacarbazine group.
How did the researchers interpret the results?
The researchers concluded that vemurafenib improved rates of both overall and progression-free survival in patients with previously untreated melanoma which carried the BRAF gene mutation. They suggest that future research could look at the effects of combining vemurafenib with other treatments.
This study used a good design to assess the effects of vemurafenib in people with advanced malignant melanoma. The study has shown that treatment with the drug is associated with a greater overall survival rate than treatment with dacarbazine, the only licensed chemotherapy drug for treating this stage of disease. As well as improving overall survival, vemurafenib reduced the risk of the disease progressing. As an oral treatment, some people may prefer vemurafenib to the intravenous dacarbazine.
There are a few points to note:
- Vemurafenib is only used in people who carry a BRAF mutation in their tumour. Therefore, not all patients with malignant melanoma would be suited to this treatment.
- So far, the study has only provided short-term follow-up. Longer-term monitoring will be needed to help determine how much life expectancy is improved.
- Improved overall survival does not necessarily mean a cure, particularly in these patients for whom the overall outlook is likely to remain poor. Average (median) survival in the vemurafenib group was estimated to be 5.3 months. With cancers that are capable of spreading to other sites in the body, the aim of treatment is to try to control the disease for as long as possible and to keep the person symptom-free.
- As with all drugs, vemurafenib was associated with some adverse events. In particular, 18% of people taking the drug developed keratoacanthoma (a type of skin tumour) or squamous-cell carcinoma. Though these are fairly non-aggressive cancers that should be completely curable by surgical removal, further long-term follow-up will be needed to study whether this increased risk persists, and what happens to people who develop these skin lesions. Further research will also be needed to understand why vemurafenib may have this effect.
These are promising results of a potential new drug for use in the treatment of metastatic malignant melanoma. Although in this study the drug has demonstrated an ability to slow the progression of malignant melanoma and extend survival by a few months, it is not a cure that can eradicate such advanced stage disease, as some news reports may have implied.
Vemurafenib is not currently licensed in Europe. Based on these results, it is likely that the manufacturers will apply for such a license, though safety and efficacy research and follow-up will continue.