Cancer is bad news – especially when it mobilizes from one body part to another. Scientists call this migration of cancer cell metastasis. Interestingly, not all cancers do this. Some cancers never leave their place of origin. To figure out what makes a cell pack up and leave home, scientists have looked to genes for the answer.
New Gene Therapy
One such promising gene is called BRAF. The BRAF gene codes for a protein that is involved in normal cell division through the MAPK molecular pathway. In many cancers, however, a mutation in the BRAF gene causes the protein to have enhanced activity. A hyper-active BRAF protein is associated with ~50% of malignant cancers, according to the review by Davies.
Last week, the FDA announced an expedited approval of vemurafenib, or Zelboraf. Zelbroraf, administered orally, was approved for patients with a BRAF V600E mutation. The FDA also approved a gene test that will determine if a patient has the V600E mutation required for treatment. The signature “V600E” indicates that an amino acid, the building block of protein, has been swapped at the the 600th position of the protein chain. The amino acid exchanges causes the protein to have increased activity. Zelboraf inhibits the BRAF protein so that the cancerous cell functions more like a healthy cell.
Results Directly from Genentech’s Press Release
The FDA approval of Zelboraf is based on results from two clinical studies (BRIM3 and BRIM2) in people with BRAF V600E mutation-positive, inoperable or metastatic melanoma as determined by the cobas BRAF Mutation Test.
BRIM3 is a global, randomized, open-label, controlled, multicenter, Phase III study that compared Zelboraf to dacarbazine chemotherapy, a standard of care, in 675 patients with previously untreated BRAF V600E mutation-positive, unresectable (inoperable) or metastatic melanoma. The endpoints of BRIM3 were overall survival (OS) and investigator-assessed progression-free survival (PFS). Other endpoints included confirmed investigator-assessed overall response rate. BRIM2 is a global, single-arm, multicenter, open-label Phase II study that enrolled 132 patients with previously treated BRAF V600E mutation-positive, unresectable or metastatic melanoma. The primary endpoint of BRIM2 was confirmed overall response rate as assessed by independent review.
BRIM3: Previously Untreated BRAF V600E Mutation-Positive Unresectable or Metastatic Melanoma
- In BRIM3, the risk of death was reduced by 56 percent for people who received Zelboraf compared to those who received chemotherapy (hazard ratio [HR]=0.44, p<0.0001). At the time of analysis, median overall survival of patients receiving Zelboraf had not been reached and was 7.9 months for those receiving chemotherapy.
- People who received Zelboraf also had a 74 percent reduced risk of the disease getting worse or dying (PFS) compared to those who received chemotherapy (HR=0.26, p<0.0001). Median PFS was 5.3 months for those who received Zelboraf compared to 1.6 months for those who received chemotherapy.
- The confirmed investigator-assessed response rate (those who experienced tumor shrinkage) in people who received Zelboraf was 48.4 percent (1 percent complete responses and 47.4 percent partial responses) compared to 5.5 percent (partial responses) for those who received chemotherapy (p<0.0001).
- In BRIM2, Zelboraf shrank tumors in 52 percent of trial participants.
This therapy is particularly exciting because it is one of the first personalized approaches to cancer. As researchers learn more about the molecular origins of cancer, more individualized therapies will become available. This is true not only for cancer, but other diseases as well.