A team of investigators at Memorial Sloan-Kettering, led by medical oncologist Paul B. Chapman, has added to its extensive research focusing on the drug vemurafenib (Zelboraf®), a targeted therapy for patients with metastatic melanoma who have a mutation in the gene called BRAF. This mutation is seen in almost half of patients with melanomas.
A single case in which a patient was diagnosed with a second cancer while being treated with the drug provides new clues about how the drug functions. These findings, published online in the New England Journal of Medicine on November 7, are the result of collaborations among Memorial Sloan-Kettering experts in melanoma, leukemia, and pathology and three research laboratories.
“Laboratory studies done here at Memorial Sloan-Kettering, and now confirmed by other investigators, showed that in cells activated by certain genes other than BRAF, drugs like vemurafenib will cause further activation of the cells,” Dr. Chapman says. “As we have treated more and more patients, we expected to be faced with a problem like this eventually. By understanding the molecular pathways involved, we developed a strategy to address the problem in this patient.”
Memorial Sloan Kettering’s team was instrumental in the early research of vemurafenib. “Vemurafenib inhibits BRAF at the cellular level and shuts off these tumors when BRAF is mutated. With the use of this drug, we have seen tumors shrink rapidly in some patients,” says Dr. Chapman, who was the international principal investigator on the phase III clinical trial that led to the drug’s approval by the US Food and Drug Administration in August 2011.
Understanding the Side Effects of Treatment
The study describes a 76-year-old man who has advanced (stage IV) melanoma with the BRAF mutation and began receiving treatment with vemurafenib. Although his tumors shrank, he experienced significant fatigue, and blood tests revealed that he had an elevated white blood cell count.
After further tests, doctors at Memorial Sloan-Kettering diagnosed the patient with a second type of cancer: chronic myelomonocytic leukemia, a disease in which the body increases its production of white blood cells known as monocytes and has difficulty producing normal amounts of other types of blood cells.
“The patient already had this type of leukemia before he received vemurafenib,” Dr. Chapman explains, “but the number of leukemia cells was too low for us to notice. When we gave the vemurafenib, it stimulated these leukemia cells to grow while it was causing the melanoma to die.”
After the new diagnosis, doctors stopped the vemurafenib treatment, and the patient’s white blood cell counts began to return to normal. After a few weeks, he was able to resume treatment with vemurafenib. By making adjustments to the dose of the vemurafenib and cycling the patient on and off the drug based on his white blood cell counts, the drug was able to keep both his melanoma tumors and leukemia under control.
Drug Activity Revealed
This led the Memorial Sloan-Kettering team to hypothesize that the patient’s leukemia cells were being activated by a mutation in a gene in the same molecular pathway as BRAF. In the laboratory, the investigators confirmed that this was the case; there was a mutation in a gene known as NRAS, and vemurafenib was shown to activate the leukemia cells.
These findings suggested to the team that the multiplication and growth of the leukemia cells could be blocked with a drug called a MEK inhibitor. Laboratory studies confirmed this, but MEK inhibitors are still experimental and not yet approved for use in patients.
Moving forward, Memorial Sloan-Kettering investigators will continue to study vemurafenib. “This single case study is important for us because it helps us to better understand this targeted agent so that we can look toward the next steps in dose schedule and combination therapies,” Dr. Chapman says.