Multidisciplinary Team Tackles Personalized Medicine for Melanoma Patients with Normal BRAF Gene

A group of melanoma researchers and clinicians have received funding to address an important question in melanoma treatment: are there molecular targets for melanomas that do not harbor a mutation in the BRAF gene? And can we identify drug candidates for these new molecular targets? The Stand Up to Cancer (SUC2) philanthropic program and the Melanoma Research Alliance are jointly funding the 3-year, eight-institution endeavor.

“The project is an attempt to take the most advanced genomic and proteomic technologies and apply them to patients with melanoma for whom we have not yet identified a treatment target,” says Jeffrey Sosman, one of several principle investigators involved in the collaboration. Sosman is a medical oncologist specializing in melanoma at the Vanderbilt-Ingram Cancer Center in Nashville, Tennessee.

Sosman and his colleagues are aiming to determine whether a targeted therapy approach can help melanoma patients without BRAF mutations (BRAF wild-type). Since the development of oral targeted therapies that target the BRAF V600 mutation, which is found in approximately 40% to 50% of advanced melanoma patients, these patients have been split into two subgroups: BRAF-mutated and BRAF wild-type patients. U.S. Food and Drug Administration (FDA)-approved options for BRAF wild-type advanced melanoma patients include two immunotherapies (ipilimumab and interleukin-2) and chemotherapy. Patients are also encouraged to enroll in clinical trials. BRAF-mutated patients have the same options, but in addition, they have the option of receiving targeted therapies—vemurafenib and dabrafenib (the two oral BRAF V600 inhibitors) and trametinib (a MEK inhibitor). Targeted therapies are not yet available for BRAF wild-type patients.

The program will enroll BRAF wild-type patients , who will have their tumor samples sequenced and analyzed to determine potential genetic changes that could be targeted with any of 22 novel targeted drugs, supplied by pharmaceutical companies. A panel of clinicians, called a molecular tumor board, will assess each patient’s genomic information to determine which of these drugs, alone or in combination, could benefit the patient.

All 22 agents have already been tested in clinical trials to determine appropriate doses; some may also be approved by the FDA as single agents for different indications.

A clinical trial will enroll patients from any of the participating institutions, according to Sosman. The patients will be randomly selected in a 2:1 ratio to receive either the experimental therapy chosen by the molecular tumor board or to a standard therapy chosen by the patient’s clinician.

Among the targeted agents available for the trial are MEK, PI3K, AKT, and mTOR inhibitors, as well as agents that target growth factor receptor proteins and the colony stimulating factor receptor 1 protein, Sosman says.

The roster of drugs in the experimental pharmacy, and their potential combinations, is flexible and evolving. If other research shows that a particular drug combination is beneficial, says Sosman,” we hope we can bring these agents into our platform by working with pharmaceutical companies.”

The first patient in the clinical trial could enroll as early as within the next 2 months. A total of approximately 96 patients will enroll in the trial. The goal is a 30% improvement in tumor response (shrinkage or disappearance) using the personalized approach compared to standard therapies.

“If the targeted therapies are better, then we will need to close the study early, which would be great; that is the goal,” says Sosman.

The large-scope project also aims to identify any mutations that are as important as the BRAF V600 mutation in driving melanoma. Researchers will develop xenograft mouse models by taking patient tumor samples and implanting them into mice. The tumors that result will then be tested for their response to specific drugs or combinations.

The researchers have also compiled information from clinical trials, cancer genomic data, and other data in the public domain that will help to fine-tune the potential targeted options for patients on the experimental trial.

The research collaboration is an effort among at least eight institutions, and is led by Patricia M. LoRusso, DO, of the Karmanos Cancer Institute in Detroit, Michigan, and Jeffrey M. Trent, PhD, of the Translational Genomics Research Institute (TGen), a nonprofit organization developing new diagnostic tools and treatments, based in Phoenix, Arizona.

Launched in 2008, SU2C is funding several large collaborative efforts to address important questions in prostate (LINK), breast, and pancreatic cancers, among others. SU2C has provided  $6 million for the pilot melanoma clinical trial study, sequencing analysis, and preclinical modeling work. According to Sosman, the funding will support the genetic analysis by TGen, but the cost of therapies and patient care will likely need to be supplied through additional funding.