B-Raf
In March 2010, we published two articles on this blog relating to Roche/Plexxikon’s PLX4032 for metastatic melanoma. The first article, dated March 2, described a Phase I clinical trial of the drug, based on an article about this trial in the New York Times (NYT). The second article, dated March 10, described Plexxikon’s discovery of PLX4032, using its proprietary “scaffold-based drug design” technology platform. The latter post is among the most popular articles on this blog.
Now the results of the Phase I trial of PLX4032 has been published in the August 26, 2010 issue of the New England Journal of Medicine (NEJM). (A subscription is required to read the full article.)
As we discussed in our previous articles, PLX4032 is a B-Raf (called “BRAF” in the NEJM paper and in some other publications) kinase inhibitor that is exquisitely specific for B-Raf carrying the V600E mutation. B-Raf(V600E) is the most common somatic mutation found in human melanomas. Researchers believe that B-Raf(V600E) is a “driver mutation” that is particularly critical for the malignant phenotype of human metastatic melanomas that carry the mutation. B-Raf(V600E) is constitutively activated, and melanomas carrying this mutation can proliferate independently of growth factor signaling, resulting in the runaway proliferation characteristic of the malignant phenotype.
The clinical trial described in the NEJM article was carried out by researchers at Plexxikon and Roche, in collaboration with academic researchers at five institutions in the United States and Australia. The trial was led by Keith T. Flaherty, M.D. (then at the University of Pennsylvania in Philadelphia, and now at the Massachusetts General Hospital Cancer Center [where he is Director of Developmental Therapeutics] and the Dana-Farber Cancer Institute in Boston) and Paul B. Chapman, MD (Memorial Sloan-Kettering Cancer Center).
As discussed in the NEJM article, the researchers conducted a multicenter Phase I dose-escalation trial of PLX4032 (which is orally available), followed by an extension phase in which patients were given the maximum dose that could be administered without adverse effects (960 mg twice daily). (The latter dose is the recommended Phase II dose.) A total of 55 patients (49 of whom had melanoma) were enrolled in the initial, dose-escalation portion of the trial. 32 additional patients, all of whom had metastatic melanoma with the B-Raf(V600E) mutation, were enrolled in the extension phase. Patients were given the drug twice a day until they had disease progression.
In the dose-escalation phase, among the 16 patients with melanoma carrying the B-Raf(V600E) mutation and who were receiving 240 mg or more of PLX4032 twice daily, 10 had a partial response (i.e., tumor shrinkage of at least 30%) and 1 had a complete response. Among the 32 patients in the extension cohort, 24 had a partial response and 2 had a complete response. The latter figure represents an 81% response rate. The estimated median progression-free survival among all patients was over 7 months.
Dose-limiting adverse effects included rash, fatigue, and joint pain.
The published results of this Phase I trial elicited great enthusiasm in the popular press and in such industry media as Fierce Biotech and BioWorld Online, and by oncologists who were interviewed for these articles. The oncologists said that they had never seen such a dramatic response in treatment of metastatic melanoma.
Because PLX4032 is targeted to a specific oncogenic mutation, Plexxikon and several industry commentators refer to the use of the drug as an example of personalized medicine. In parallel with development of PLX4032, Plexxikon and Roche Molecular Systems are developing a DNA-based companion diagnostic to identify patients whose tumors carry the B-Raf(V600E) mutation.
PLX4032 is on an accelerated path to potential registration. Parallel Phase II and Phase III clinical trials are in progress in previously treated and previously untreated patients, respectively, all who have metastatic melanoma carrying the B-Raf(V600E) mutation.
Meanwhile, the results of a Phase III trial (in 676 patients with advanced melanoma) of Medarex/Bristol-Myers Squibb’s (BMS’s) ipilimumab were published in the August 19, 2010 issue of the NEJM. Ipilimumab, unlike the targeted therapeutic PLX4032, is an immunomodulator that blocks cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) to potentate an antitumor T-cell response. Ipilimumab is a monoclonal antibody, unlike PLX4032 which is a small-molecule compound. In this NEJM article, the researchers reported that ipilimumab–given with or without the gp100 peptide vaccine–showed a median overall survival of 10 months, as compared to 6.4 months in patients receiving gp100 alone. Ipilimumab treatment also gave improved one-year survival compared with gp100 alone–46% versus 25%. Two-year survival was 24% in the ipilimumab group and 14 percent in the gp100 group. BMS has filed a Biologics License Application (BLA) for ipilimumab, and earlier this month (August 2010) received fast-track status from the FDA for the drug.
Ipilimumab treatment is associated with autoimmune toxicities (especially enterocolitis), which can be severe. These are usually reversible by treatment with high-dose steroids.
Decision Resources published our report on development of immunomodulators in treatment of cancer in 2007. This report includes a discussion of ipilimumab, and provides further information on its mechanism of action, adverse effects, etc., as well as on other immunomodualtors for treatment of cancer, some of which are now on the market.
We believe that it is important to pursue development of both targeted therapies and of immunomodulators for metastatic melanoma. This may provide oncologists a range of therapeutics (and of combinations of therapeutics) to treat this disease, which now has very few treatment options and a very poor prognosis.
The results with both PLX4032 and ipilimumab provide hope for better treatment of at least some classes of metastatic melanoma in the near future. However, as discussed in our March 2010 articles, even in the case of PLX4032 treatment of melanoma carrying the B-Raf(V600E) mutation, it will most likely be necessary to develop combination therapies in order to achieve long-lasting remissions or cures.
