Targeted drugs lengthen survival for melanoma patients

Orlando, Fla. - Though a cure for melanoma remains elusive, continued research has borne several promising treatment approaches with more targeted drugs that can help lengthen melanoma patients’ survival, buying them time until more effective treatments come to light.

“Until now, we did not really have good and truly effective treatments for melanoma and generally had to rely on traditional chemotherapy in patients with advanced stage melanoma,” said Abel Torres, M.D., chair, director of Mohs surgery, Loma Linda University School of Medicine, Loma Linda, Calif. “However, the use of new, more targeted therapies such as the BRAF inhibitors and others are proving to be promising in that patients’ progression-free survival times are increased, allowing for other potential drug therapies and those in the pipeline to mature.”

Although the BRAF inhibitors have been around for a while and can impact a small subset of patients, not all melanomas respond to them. According to Dr. Torres - who spoke at the Orlando Dermatology Aesthetic and Clinical Conference recently - only about 50 percent of melanomas arising in skin without chronic sun damage will have a BRAF mutation, which dwindles to only 10 percent of melanomas that arise in chronic sun damaged skin, limiting the use of this drug.

On-label therapies

Vemurafenib (Zelboraf, Roche) was the first BRAF inhibitor approved by the Food and Drug Administration for the treatment of melanoma, which has shown a six-month tumor progression-free survival reported as high as 84 percent of patients.

The problem with vemurafenib, however, and other BRAF inhibitors is that tumor resistance will eventually occur in almost 100 percent of patients on the drug, Dr. Torres says. This limitation, coupled with the side effects of the drug, such as an increase in the incidence of nonmelanoma skin cancers (i.e. squamous cell carcinoma), have rendered this treatment approach alone less than optimal.

Nevertheless, Dr. Torres says the spike in the development of nonmelanoma skin cancers as a result of BRAF inhibitor therapy has been reported to be reasonably addressed with the use of systemic retinoids such as acitretin and/or topical 5-FU (5-fluorouracil).

Another BRAF inhibitor currently being used for the treatment of melanoma is dabrafenib (Taflinar, GlaxoSmithKline). Although this drug can achieve similar survival outcomes as those with vemurafenib and also results in a lower incidence in the development of nonmelanoma skin cancers, the drug is also associated with toxic pyrexia, limiting its use, thus begging for the development of more effective therapeutic modalities.

Most recently, other types of medications such as the MEK inhibitors have been researched to try to prevent tumor growth. MEK inhibitors by themselves are not much more effective than BRAF inhibitors, Dr. Torres says; however, when used together with BRAF inhibitors, the combination therapy can result in an increase in the tumor progression-free survival from six months to more than nine months.

“This is a significant step forward because this combination therapy buys the patient more time for personal matters and until newer advances and breakthroughs in therapy are developed and come to the forefront,” Dr. Torres says.

Combo side effects

The downside of this combination therapy, however, is that patients will potentially have to deal with the combined side effects of both drugs, Dr. Torres says, possibly leading to an early termination of treatment. According to Dr. Torres, the most significant side effects of MEK inhibitors include retinal vein occlusion and other types of visual disturbances.

Other treatment approaches that have been researched include so-called “check point” inhibitors, which target the immune system to try and control melanoma disease.

“Up until now, the conventional wisdom has always been to target genetic mutations that promote the tumor, but these mutations can be varied by the melanoma. So, the new approach to therapy now is looking at not only targeting these mutations, but also targeting the immune system ‘suppression/brake’ (described by Hensin Tsao, M.D.) that melanoma promotes in order to keep the immune system from recognizing the tumor and destroying it,” Dr. Torres says.

Ipilimumab (Yervoy, Bristol-Myers Squibb) is a cytotoxic T-lymphocyte antibody-4 (CTLA-4) blockade drug that can bind to T-cells and reactivate the natural tumor surveillance and destruction, allowing the T-cells to actively target and destroy the tumor.

According to Dr. Torres, one of the issues with ipilimumab is that because the immune system is activated, many immune-related side effects can occur, including severe life-threatening diarrhea and colitis, and other types of inflammatory reactions. The other issue is that the effect of onset of the drug is slow.

Slow results

BRAF inhibitors act quickly, but their effect is limited, reflected in an approximate increase in progression free survival of about six months. In contrast, ipilimumab acts slowly and it can take up to six months before a therapeutic effect is seen; however, Dr. Torres says that case reports have shown a long-term survival, some out to four years.

The combination of the two drugs can result in a control over tumor growth with BRAF inhibitor in the first six months of therapy, Dr. Torres says, at which time ipilimumab can kick in and start working, potentially increasing overall patient survival.

One of the problems with this combination treatment is that one can’t predict which patients are going to respond to ipilimumab, and only a small number of patients actually do respond, Dr. Torres says. However, in those who do respond, their longer survival can gain them significant time.

Another promising therapy is the anti PD1 monoclonal antibody, which potentiates the downstream T-cell effector response and has been showing good results.

“We have seen tremendous advancements in the understanding and treatment of melanoma in the past five years or so, and these have led to actual therapies that are helping to prolong a tumor progression-free survival, and have the promise in improving overall survival,” Dr. Torres says. “If we can get a better handle on controlling the side effect in some patients, the combinations of these evolving therapies may result in helping patients live long-term with melanoma, even if it means having it as kind of a chronic disease, but at least controlling it enough that patients can function and have a productive life. This was unheard of in melanoma until recently.”

Disclosures: Dr. Torres is a consultant, lecturer and funded researcher for Genentech.