Neoadjuvant Carboplatin Boosts Targeted Therapy Responses in Triple-Negative Breast Cancer

The addition of neoadjuvant carboplatin to a regimen of taxane-anthracycline chemotherapy and targeted therapy substantially increased pathological complete responses in patients with stage II/III triple-negative breast cancer (but not in patients with HER2-positive disease), according to findings of the randomized phase II GeparSixto study conducted by the German Breast Group.

“Several cohort studies reported on the neoadjuvant use of carboplatin in combination with docetaxel and trastuzumab, but until recently no randomized trial has shown the additive effect of platinum to standard type of treatment in the neoadjuvant setting,” noted lead investigator Prof. Gunter von Minckwitz of the University of Frankfurt and colleagues.

Women with previously untreated, unilateral or bilateral, non-metastatic primary invasive triple-negative or HER2-positive breast cancer were randomly assigned to receive carboplatin (n = 295) or no carboplatin (n = 293). All patients received paclitaxel 80 mg/m² plus non- pegylated liposomal doxorubicin 20 mg/m², once a week for 18 weeks. Patients with triple-negative breast cancer received bevacizumab 15 mg/kg intravenously every 3 weeks simultaneously with all cycles.  Patients with HER2-positive disease received an initial dose of trastuzumab 8 mg/kg intravenously and subsequent 6 mg/kg doses every 3 weeks, plus oral lapatinib 750 mg daily with all cycles. Patients assigned to receive simultaneous carboplatin received the drug once weekly at a dose of 2-0 area under curve (AUC) for 18 weeks (reduced to AUC 1-5 after an interim safety analysis). The dose could be further reduced to AUC 1-1 in the event of intolerable toxic side effects.

The primary outcome was the proportion of patients who achieved a pathological complete response (ypT0 ypN0) after neoadjuvant treatment. After 18 weeks, the addition of carboplatin led to an absolute increase of 16% in the proportion of patients with triple-negative breast cancer-- achieving a pathological complete response--but no effect was seen in patients with HER2-positive breast cancer. “The observed pathological complete response is the highest ever noted in neoadjuvant studies of the German Breast Group for these two breast cancer subtypes,” said von Minckwitz.“ However, the addition of carboplatin significantly increases hematologic and non-hematologic side effects.”

Toxicities were significantly more common in the carboplatin group than in the non-carboplatin group: grade 3 or 4 neutropenia in 65% of patients (n = 192) vs. 27% (n = 79), grade 3 or 4 anemia in 15% (n = 45) vs. <1% (n = 1), grade 3 or 4 thrombocytopenia in 14% (n = 42) vs. <1% (n = 1), and grade 3 or 4 diarrhea in 17% (n = 52) vs. 11% (n = 32). Consequently, carboplatin was more often associated with dose discontinuations of 48% (n = 141) vs. 39% (n = 114). When the dose of carboplatin was reduced from AUC 2-0 to 1-5, however, the frequency of grade 3 or 4 hematologic events decreased substantially, from 78% (n = 128) to 59% (n = 77).

“It seems that the dose reduction of carboplatin to AUC 1-5 not only reduced the incidence of hematologic and non-hematologic adverse events,” said von Minckwitz, “but also had no detrimental effect on efficacy in patients with triple-negative disease.” Thus, the investigators suggested, a dose of carboplatin at AUC 1-5 could achieve a better risk-benefit profile.

The phase III GeparOcto study will further explore the study regimen (with and without carboplatin), with pertuzumab instead of lapatinib for HER2-postive disease, and without bevacizumab for triple-negative disease. “We believe that with better tolerated targeted treatment components and carboplatin used at an AUC 1-5, as well as a learning curve on better dealing with this intense regimen, the feasibility of the regimen will become more acceptable,” the investigators concluded.