On January 19, 2011, Plexxikon and Roche announced the results of an interim analysis of a large multicenter Phase 3 clinical study (the BRIM3 trial) of the targeted anticancer drug PLX4032 (which Roche has designated as RG7204). PLX4032 is a kinase inhibitor that is exquisitely specific for B-Raf carrying the V600E mutation [B-Raf(V600E)]. This is the most common somatic mutation found in human melanomas (accounting for approximately 50% of cases of this disease), and is a “driver mutation” that is particularly critical for the malignant phenotype of human metastatic melanomas that carry the mutation.
According to the Plexxikon and Roche press releases, the Phase 3 trial met its prespecified criteria for co-primary endpoints of overall survival and progression-free survival, as compared to a control arm, in which patients were treated with the current standard of care, dacarbazine. The safety profile was consistent with previous clinical studies of the drug.
Based on the results of the interim analysis, patients in the dacarbazine arm of the study will have the option to crossover to receive PLX4032. Moreover, the Expanded Access Program will be opened to previously untreated melanoma patients whose tumors carry the B-Raf(V600E) mutation. As the companies announced in November 2010, as the result of widespread demand from patients, oncologists, and patient advocates, they had been in discussion with global regulatory authorities regarding an Expanded Access Program for PLX4032. In late December 2010, the Expanded Access Program for PLX4032 was initiated. A cofounder of one of the patient advocate organizations pushing for expanded access to PLX4032 prior to its FDA approval, the Abigail Alliance, commented on this issue on our blog in November 2010.
The big news in Plexxikon and Roche’s report on the BRIM3 trial is that treatment with PLX4032 gave enhanced overall survival as companied with dacarbazine in previously untreated metastatic melanoma patients carrying the B-Raf(V600E) mutation. Although previous studies showed tumor shrinkage and enhanced progression-free survival (by approximately seven months) in the majority of PLX4032-treated patients as compared to dacarbazine, this is the first report that PLX4032 give enhanced overall survival. However, the companies did not report the extend of the enhanced overall survival. They plan to present comprehensive data from the BRIM3 trial at a major scientific meeting later this year. We expect that in due course the researchers that have been conducting the trial will publish the results in a peer-reviewed medical journal, as in the case of the published Phase 1 trial.
On November 8, 2010, Plexxikon and Roche reported preliminary results of a parallel open-label Phase 2 trial (designated BRIM2) of PLX4032 in previously treated metastatic melanoma patients whose tumors carried the B-Raf(V600E) mutation. Researchers who had been conducting that trial presented the data at the Seventh Annual International Melanoma Research Congress of the Society for Melanoma Research (SMR) in Sydney, Australia. Consistent with earlier Phase 1 trials, the BRIM2 trial showed that of the 132 patients enrolled, 3 patients had complete responses, and 66 had partial responses (i.e., tumor shrinkage of over 30 percent). The overall response rate was 52 percent, with a median duration of response of 6.8 months. At the time the results were reported, it was too early to gauge overall survival.
The Biopharmconsortium Blog has been following the PLX4032 story since March 2010. We have published several articles on the drug and on related scientific, clinical trial strategy, and business issues:
The last two articles discuss the novel personalized medicine (or “stratified medicine”) hypothesis-testing clinical trial strategy, which is especially applicable to highly targeted oncology drugs (such as PLX4032) for which the relevant biomarkers are available.
The dramatic results of the Phase 1 trials of PLX4032 (now confirmed by Phase 2 and Phase 3 trials) led some oncologists, as well as patient advocates, to question the ethics of conducting standard controlled Phase 3 trials in which some patients were placed in a dacarbazine arm. This question might apply to other drugs for cancer and other very serious diseases for which personalized medicine hypothesis-testing clinical trials indicate superior performance as compared to the standard of care. Such cases would at least call for establishment of Expanded Access Programs for such drugs, on a case-by-case basis.
The clinical trial community, as well as regulatory agencies such as the FDA and the European Medicines Agency, also need to continue to monitor and study the progress of the personalized medicine hypothesis-testing clinical trial strategy. This may led to modifications in clinical trial standards for approval if they deem they are warranted. We can also expect that patient advocates (including M.D. and non-physician advocates), as well as other stakeholders (e.g., third party payers) would be participating in that process.
In parallel with the development of PLX4032, Plexxikon and Roche Molecular Diagnostics are developing a DNA-based companion diagnostic to identify patients whose tumors carry B-Raf(V600E). The companies plan to launch PLX4032 together with the companion diagnostic, so that oncologists can readily identify patients who would benefit from treatment with the drug.
Despite the dramatic results with PLX4032, so far all patients treated with the drug eventually suffer relapses, and die of their disease. This presumably occurs because a fraction of tuner cells develop resistance to PLX4032. Oncologists, especially those who have been involved in the clinical trials of the drug, therefore advocate using PLX4032 as the basis for potentially still more effective treatments, especially combination therapies.
With respect to combination therapies, on January 6, 2011, Plexxikon announced that it had signed an agreement with Genentech (a member of the Roche group) to co-promote PLX4032 (RG7204) in the United States. Plexxikon will also codevelop PLX4032 with Genentech in addition to Roche. Plexxikon and Genentech are planning, beginning in the first quarter of 2011, to begin a Phase 1b clinical trial of a combination therapy of PLX4032 and Exelixis/Genentech’s oral, small-molecule MEK inhibitor RG7420/GDC-0973. MEK is downstream from B-Raf in the signaling pathway by which B-Raf(V600E) acts to produce the malignant phenotype. Researchers studying mechanisms by which PLX4032 resistance occurs have found evidence that suggests that combination therapy with PLX4032 and a MEK inhibitor may overcome resistance that occurs via some mechanisms. More generally, studies of mechanisms of PLX4032 resistance may provide means of developing specific combination therapies for different mechanisms of resistance, and of stratifying patients to determine which particular personalized combination therapy will best treat their disease.
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