First credible treatment option for metastatic melanoma

August 26, 2010


One targeted cancer therapy nearing clinical application illustrates why patients and their families have new  hope as a result of such therapies. Scientists have known for some time that the most commonly mutated gene in melanoma – a leading cause of death in young adults – is called BRAF. However, efforts to disable this mutation met with only limited success until MGH’s Keith T. Flaherty, MD, tackled the problem. Dr. Flaherty and his colleagues reported in the August 26, 2010 issue of The New England Journal of Medicine that a BRAF-inhibiting drug, PLX4032, was successful in treating more than 80% of patients with metastatic melanoma tumors in a Phase I clinical trial – data that received widespread attention in the scientific and lay press.
                                   
The melanoma research community and patients have enthusiastically embraced this agent as the first credible treatment option for metastatic melanoma. Two additional MGH-based clinical studies of PLX4032 are now under way – a Phase II study in patients who have not responded to FDA-approved drugs (enrollment is complete) and a larger Phase III trial that compares PLX4032 with another melanoma drug, dacarbazine, in newly diagnosed patients.
 
In a related discovery, scientists have found that the BRAF mutation is also present in 10% of patients with ovarian, lung and colorectal cancers. To test its potential in these cancers, the Mass General Cancer Center is planning Phase II trials to determine whether PLX4032 works against these diseases and how well. It is worth noting that the initial results with PLX4032 also have led to the exploration of new combinations of therapies, such as the co-administration of BRAF and MEK inhibitors, which could result in greater antitumor activity or delay the appearance of resistance.  The development of the proposed Center for Targeted Therapies at the MGH Cancer Center will allow such studies to proceed with greater speed and efficiency

Progress in Battling Lung Cancer
Other promising drug research at MGH has focused on the rearrangement and abnormal fusion of two genes, ALK and EML4. When fused together, these two normal genes act as a cancer-causing gene. Researchers first identified this type of genetic reorganization in lymphomas, but the first demonstration of the effectiveness of targeted anti-ALK therapy occurred in lung cancer. A multi-institutional collaboration led by Mass General medical oncologists Eunice Kwak, MD, PhD, and Jeffrey Clark, MD, tested the effectiveness of an ALK inhibitor developed by Pfizer, Inc. in patients with lung cancer. ALK gene rearrangements are rare – occurring in only about 4 percent of lung cancers – but they represent a large number of patients given the prevalence of lung cancer in the general population. Further research has revealed that the ALK gene rearrangement is present in approximately 20 percent of lung cancers arising in nonsmokers.

Drs. Kwak and Clark and their collaborators tested lung tumors for the ALK gene rearrangement, and then enrolled patients with this abnormality into an early-phase clinical trial of a drug that inhibits ALK. Approximately 85 percent of lung cancer patients enrolled in the trial benefited from treatment, with many experiencing dramatic and long-lasting shrinkage of their tumors. Recently published in The New England Journal of Medicine, this study not only demonstrated a new treatment option for certain patients with lung cancer, but also showed the effectiveness of prescreening large numbers of tumors for a specific genetic abnormality and then directing a clinical trial to the patients who were most likely to benefit.
 
Clinical trials of ALK-positive lung cancer are ongoing at the Mass General Cancer Center. Medical oncologist Alice T. Shaw, MD, PhD, is leading an international phase 3 clinical trial of the ALK inhibitor, now called crizotinib.
Media Contacts: Katie Marquedant, (617) 726-0337, kmarquedant@partners.org
Sue McGreevey, 617 724-2764, smcgreevey@partners.org