Significant Survival Improvement for BRAF-Mutated Melanoma Patients

Vemurafenib (Zelboraf) was approved in August 2011 for metastatic melanoma patients whose tumors harbor the V600 mutation in the BRAF gene based on measured improvement in overall survival. This was the second drug approved for melanoma within a span of 5 months after a decade which produced few treatment options. In a phase III trial of previously untreated patients, vemurafenib showed an 84% survival at 6 months compared to 64% for the chemotherapy standard of care. Response rates were almost 50% compared to approximately 5% for the control arm.

Human metastatic melanoma cells stained with an H&E stain and magnified to 320x.

With a previous median survival time of 6–10 months in patients with metastatic melanoma, this second fast-acting option is an overdue welcome. What is unique about vemurafenib is the rapid onset of response: patients can see improvements within days or weeks and tumor shrinkage is witnessed as fast as within 2 weeks of commencing treatment.

While the data are encouraging, the median duration of follow-up for patients on vemurafenib in the phase III trial was only 4 months for the interim analysis. The question of durable response remained.

To partly answer the durability question, the results of a single-arm phase II trial of 132 patients, with a median follow-up of 12.9 months were published in February in the New England Journal of Medicine.

The results show a significant number of patients exhibiting a prolonged and durable response to vemurafenib therapy. The overall response was 53%, with only 14% of patients exhibiting signs of progressive disease. To put these results into context, previously, only about 10% of any metastatic melanoma patients responded to any type of treatment. The median overall survival rate was 15.9 months.

Toxicity of vemurafenib is generally tolerable and not severe in most instances. The toxic effects are predominantly manifested on the skin. Patients taking vemurafenib are photosensitive to light and must use precaution so as not to get severe sunburn from even minimal exposure to sunlight. The BRAF inhibitor is also associated with cutaneous squamous-cell carcinoma or keratoacanthoma. The lesions usually develop within the first 2–3 months of treatment and are generally treatable with excision. Other toxicities included arthralgia, rash, fatigue, and alopecia.

The other drug approved for metastatic melanoma is ipilimumab (Yervoy), an immunotherapy that harnesses the body’s own immune system to elicit a response to the tumor. In contrast to vemurafenib, the response to ipilimumab can take months in some patients. Between 15% and 20% of patients respond to ipilimumab, and the responses can be complete and durable for many years.

Melanoma patients now have real options, including many new therapeutics in clinical trials, both immunotherapies and targeted oral treatments. One potential option may soon be the combination of ipilimumab and vemurafenib. The manufacturers of the two drugs have teamed up to do a phase I/II trial in 50 patients to test the combination. The hope is that taking both drugs together will result in a rapid onset of response, and continue to a substantial, and long-term one.