Gunter von Minckwitz, MD, PhD
Carboplatin shows promise in treating metastatic BRCA
-mutated triple negative breast cancer (TNBC), Gunter von Minckwitz, MD, director of the German Breast Group Research Institute, explained in his presentation Thursday at the 33rd Annual Miami Breast Cancer Conference.
Drawing upon a trio of recent studies of carboplatin as monotherapy and in combination with other agents, von Minckwitz suggested that further investigation of this drug in the TNBC-mutated DNA setting is warranted, although he acknowledged that as a subset, this patient group is relatively scarce and difficult to enroll in sufficient numbers for conclusive results.
Von Minckwitz discussed findings from the TNT phase III trial of carboplatin compared with docetaxel in TNBC patients and two other phase II trials of carboplatin added to neoadjuvant chemotherapy: CALGB 40603 and GeparSixto. The trials were not conclusive, and others may yield key additional data, he explained.
“There are two trials currently running. One is a neoadjuvant study, which is a phase III. They have one carboplatin arm in, so they will be able to confirm the data; and another trial is an adjuvant study, where carboplatin is given or not given as treatment after surgery, and that trial will also provide this data, which is what we need,” von Minckwitz said.
“The concept is that DNA-damaging agents should be specifically active in TNBC cancer and especially BRCA mutant tumor cells,” von Minckwitz noted in explaining the rationale for faith in carboplatin.
The TNT trial compared separate arms of carboplatin and docetaxel with crossovers to either of those drugs on progression in first-line, metastatic TNBC. Von Minckwitz praised the trial as having a clear and simple design based on being essentially monotherapy.
“The surprise here was to see that this specific agent [carboplatin] was more or less as good as the strongest taxane—the strongest mono-agent that was available. But that is because the right subgroup of patients was selected—the triple negative,” he said.
Median progression-free survival (PFS) for carboplatin was 3.1 months (95% CI, 2.5-4.2) versus 4.5 months for docetaxel (95% CI, 4.1-5.2). By this measure, “there was no clinically meaningful difference between the two treatments,” von Minckwitz concluded.
Where carboplatin stood out was in its effect on BRCA
mutation. For germline BRCA 1/2
mutation (n = 43), 68% of patients showed an objective response (OR) at cycles 3 or 6, versus 33.3% for docetaxel. For non-germline BRCA 1/2 mutation (n = 273), the relative OR percentages were 28.1% for carboplatin and 36.6% for docetaxel.
“This shows that carboplatin works much better in the BRCA
-mutant tumors. It would be inferior for the non-mutant, and it looks to be superior in the mutant tumor compared to the docetaxel,” von Minckwitz said.
In CALGB 40603, the addition of carboplatin to standard neoadjuvant chemotherapy increased pCR rates in patients with TNBC; however, the trial was too small for a significant determination, von Minckwitz said. There was also no BRCA analysis.
The GeparSixto trial led by the German Breast Group has shown strong improvement in pCR for TNBC patients with the addition of carboplatin to a neoadjuvant regimen, von Minckwitz said. At 3 years out, DFS was 85.8% for carboplatin patients, versus 76.1% for those who received no carboplatin. TNBC patients received paclitaxel and nonpegylated liposomal doxorubicin, as well as concurrent bevacizumab until undergoing surgery. Patients were randomly assigned to carboplatin (n =296) or no carboplatin (n = 299).
“We saw a significant improvement of DFS with carboplatin, which might be because the way carboplatin was given was weekly, so maybe it was better,” he said, adding that more conclusive data are needed, however.
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