Improving upon Targeted Therapeutic Strategies for Patients with Advanced Melanoma

By Michael Postow, MD  |  Wednesday, September 18, 2013

For many years, advanced melanoma was treated with chemotherapy. Though chemotherapy helped some patients, typically benefit was transient. In 2002, however, a breakthrough discovery was made demonstrating that approximately 50 percent of melanomas have a mutation in the BRAF gene, which is believed to be responsible for driving melanoma growth.(1)

Following this discovery, investigators at Memorial Sloan Kettering have been at the forefront in characterizing the biology of BRAF-mutant melanoma and have led the clinical development of new treatment strategies targeting this abnormal protein.(2),(3)

As a result of our efforts, in recent years the US Food and Drug Administration has approved three new melanoma therapies for patients with BRAF-mutant melanoma: vemurafenib, dabrafenib, and trametinib.

Although these medications initially help the majority of patients with BRAF-mutant melanoma, resistance develops over time. We are now conducting a number of clinical trials in which we seek to improve upon the duration of time these therapies are successful by administering new BRAF inhibitors  in novel dosing strategies and combinations.

Data from recent laboratory experiments suggests that discontinuous BRAF inhibition may be preferable to continuous inhibition.(4) To capitalize on this treatment strategy, we have opened a clinical trial in which patients receive a new BRAF inhibitor, LGX818, in a similar discontinuous, pulsatile dosing schedule. We are hopeful that this will delay the onset of treatment resistance.

In cases in which patients do develop treatment resistance, we have a clinical trial in which we biopsy a melanoma tumor to identify the specific molecular alteration that may be responsible for the development of resistance. Once a possible mechanism has been determined, patients will be given a new agent that is specifically designed to target the abnormal protein or pathway believed to be responsible for resistance.

This trial is an example of the future direction of treatment, in which the biology of an individual’s tumor is analyzed and therapy is selected to provide the most-personalized treatment strategy possible.

NRAS-Mutant and KIT-Mutant Melanoma

About half of patients with melanoma have no mutation in the BRAF gene and are therefore not candidates for BRAF-directed therapy. In many of these patients, a mutation in another gene involved in the growth of melanoma, NRAS, is present. Traditionally treatment strategies for NRAS-mutant melanoma have been challenging. An investigational drug called MEK162, however, has recently shown promising efficacy for patients with NRAS-mutant melanoma, demonstrating the highest response rate yet reported for any targeted treatment in this molecular subgroup.(5)

For patients with NRAS-mutant melanoma, we have trials that provide access to MEK162, either alone or in combination with another experimental agent (LEE011). Laboratory research indicates that the addition of LEE011 increases the benefits of treatment strategies such as MEK162.

Patients with melanoma involving mucosal surfaces, acral surfaces such as the palms of hands or the soles of feet, or chronic sun-damaged skin have a reasonable chance of having a mutation or amplification in a gene called KIT. Our group has demonstrated that treatments that inhibit KIT, such as imatinib, can be effective in patients with alterations in this gene.(6)

To expand on our prior findings for patients with KIT-mutant melanoma, we now have trials through which we provide newer targeted treatments such as dasatinib.

Given the remarkable promise that targeted therapy has demonstrated for patients with advanced disease, we are conducting a number of trials to see if these approaches also can be helpful for patients with earlier-stage melanoma.

Even after excellent surgery to completely remove melanoma, patients who have had lymph node or subcutaneous “in-transit” melanoma are still at risk for developing distant metastatic disease. The only currently FDA-approved agent for these patients in this adjuvant setting is interferon-alpha.

Unfortunately, interferon-alpha can be associated with significant side effects and has not been shown across all studies to help patients live longer. We expect that better adjuvant treatment options will ultimately become available. For patients with high-risk BRAF-mutant melanoma, we have clinical trials under way investigating the use of dabrafenib, and possibly in the near future, the combination of dabrafenib and trametinib.

Molecular Abnormality

Therapeutic Setting

Agents

Phase

BRAF mutation

 

No prior BRAF inhibitor

LGX818 pulsatile dosing

II

Prior LGX treatment

LGX818 in combination with molecularly selected agent

I/II

Any prior BRAF inhibitor

LGX818 + LEE011

I

Untreated

Dabrafenib + Ipilimumab +/- Trametinib

I

NRAS mutation

Untreated or one prior immunotherapy

MEK 162 vs. Chemotherapy

III

Any prior therapy other than MEK inhibitor

MEK 162 + LEE011

I

KIT mutation

No prior KIT-directed treatment

Dasatinib

II

*Unapproved agents in above table include: LGX81 = BRAF inhibitor (Novartis), LEE011 = cell cycle inhibitor (Novartis), MEK 162 = MEK inhibitor (Novartis)