ASCO Update: Dabrafenib Extends Progression-Free Survival in Metastatic Melanoma

Another update on Dabrafenib...

I know lots of these drugs have very funny names.  I read somewhere yesterday that drug companies do that to stop other drug from picking similar names when making same type of drugs.

I also like the last line of this article - still lots of work to do!: Dr. Atkins said, “Despite recent advances, metastatic melanoma is still a bad disease. We need to pause to celebrate but then begin work to raise the bar higher.”




Erin

ASCO Daily News > LBA8500 


Dabrafenib Extends Progression-Free Survival in Metastatic Melanoma, Has High Clinical Activity in Brain Metastases

Utilization of dabrafenib, the selective BRAF kinase inhibitor, has produced positive results compared with dacarbazine for the treatment of metastatic melanoma and has high clinical activity in brain metastases.
Updated results from the phase III BREAK-3 trial were presented on behalf of the trial group during Monday’s Melanoma Oral Abstract Session by Axel Hauschild, MD, of University Hospital, Schleswig-Holstein, Germany (Abstract LBA8500^). At the same session, John M. Kirkwood, MD, of the University of Pittsburgh Cancer Institute, reported the final data from BREAK-MB, a phase II trial in patients with brain metastases (Abstract 8501). Both studies included patients with confirmedBRAFV600E mutations.
The BREAK-MB phase II protocol for stage IV BRAF-positive melanoma enrolled patients with one or more intracranial metastases who had no prior brain therapy (Cohort A) or patients with disease progression following prior brain therapy (Cohort B).
Overall, 325 patients were screened and 172 patients were enrolled. Demographics and clinical characteristics were similar for the two cohorts: 70% male, 54% with elevated lactate dehydrogenase levels (LDH) levels, and 46% with two to four target brain metastases. Thirty-eight percent had received prior chemotherapy and 30% had received prior immunotherapy.
Dr. Kirkwood announced an unprecedented overall intracranial disease control rate of 81% in Cohort A and 89% in Cohort B for patients with V600E mutations, with a median duration of intracranial response of 20.1 weeks and 28.1 weeks, respectively. Both cohorts had an overall survival rate over 30%. Results were positive for overall intracranial response, overall response, and median progression-free survival.
A subset of 33 patients with BRAFV600K mutations had more limited responses to dabrafenib, with an overall response rate of 7% in Cohort A and 22% in Cohort B. However, the intracranial disease control rate was 33% for Cohort A and 50% for Cohort B; the overall disease control rate was 33% and 50%, respectively.
Serious adverse events occurred in 30% of the patients in both cohorts, 17% were related to study treatments. Only 2% of patients discontinued treatment due to toxicity and no deaths were attributable to dabrafenib therapy.
Dr. Kirkwood concluded that dabrafenib is safe, with unprecedented responses and overall survival, supporting its use as first-line therapy. This shifts the current paradigm of treatment for brain metastases to systemic therapy. In BREAK-3, patients with previously untreated, unresectable stage III or IV disease were stratified by stage after random allocation at a ratio of 3:1 to oral dabrafenib or intravenous dacarbazine.
Patients in the dacarbazine arm were allowed to cross over once progression was confirmed by independent review. The primary endpoint was investigatorassessed progression-free survival.
The trial enrolled 250 patients, 187 were allocated to the dabrafenib arm and 63 were given dacarbazine. Demographic and clinical characteristics were well-balanced between the two treatment groups. Approximately 60% of the patients were men, 65.6% had stage IV (M1c) disease, and 34.4% had elevated LDH levels.
Median investigator-assessed progression- free survival was 5.1 months for patients taking dabrafenib and 2.7 months for those receiving dacarbazine (hazard ratio [HR] = 0.30 [95% CI: 0.18–0.51]; p < 0.0001). Results from independent review were similar (6.7 months and 2.9 months, respectively, HR = 0.35, 95% CI: 0.20–0.61). Dr. Hauschild commented that the progression-free survival curves were similar whether the data were censored for crossover patients or not.
Subgroup analysis demonstrated dabrafenib to be superior regardless of performance status, LDH levels, age, gender, or disease stage. The confirmed overall response rate was 53% for patients taking dabrafenib and 19% for patients receiving dacarbazine. Maximum percent change in tumor size from baseline is illustrated in waterfall plots (Figs. 1 and 2). Dr. Hauschild did not address overall survival.
The most common adverse events for patients taking dabrafenib were skinrelated (hyperkeratosis [51%], palmarplantar hyperkeratosis [21%], and squamous cell carcinoma/keratoacanthoma [7%]), headache (17%), arthralgia (16%), and pyrexia (15%). Photosensitivity was seen in 3% of patients taking dabrafenib and 5% of patients receiving dacarbazine.
Few serious adverse events were reported, mainly squamous cell carcinomas (5%), pyrexia (4%), and new primary melanomas (2%). Both dabrafenib and dacarbazine were well-tolerated, with only 3% of patients discontinued due to adverse events in each group. Dr. Hauschild noted that the positive results from BREAK-3 have opened the pathway to combination trials with dabrafenib for stage IV melanoma, as well as adjuvant trials.
Discussant Michael B. Atkins, MD, of Georgetown Lombardi Comprehensive Cancer Center, commented that, based on the data from BREAK-MB, there is no reason to exclude patients with melanoma brain metastases from studies of dabrafenib; however, the study design did not address the use of stereotactic radiosurgery, an important therapeutic approach for these patients and one that should be explored in a clinical trial. Dr. Atkins noted that BREAK-3 establishes dabrafenib as the second BRAF inhibitor with proven efficacy and competition is good for patients and the oncology field.
In his closing remarks, Dr. Atkins said, “Despite recent advances, metastatic melanoma is still a bad disease. We need to pause to celebrate but then begin work to raise the bar higher.”

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