Carboplatin for Early TNBC? Depends on Who You Ask

Neil Osterweil

December 15, 2015

SAN ANTONIO — The addition of carboplatin to a standard neoadjuvant chemotherapy regimen significantly improves disease-free or event-free survival in patients with early-stage triple-negative breast cancer (TNBC), according to one study presented here at the San Antonio Breast Cancer Symposium (SABCS) 2015. But another study suggested that it doesn't.

The two studies also reached different conclusions on whether pathologic complete response (pCR) is a proven surrogate end point for event-free survival in clinical trials.

The first study, reporting early survival results from the phase 2 GeparSixto trial, indicated that at a median follow-up of 35 months, disease-free survival was better in TNBC patients who received carboplatin and bevacizumab in addition to paclitaxel and liposomal doxorubicin than in those who received the taxane and the anthracycline alone (85.8% vs 76.1%; P = .0325).

In addition, patients with TNBC who received carboplatin had significantly higher rates of pCR than those who did not receive carboplatin (53.2% vs 36.9%; P = .005), reported lead GeparSixto investigator Gunter von Minckwitz, MD, from Heidelberg University Hospital in Germany.

"GeparSixto supports the use of carboplatin as part of neoadjuvant treatments in all patients with triple-negative breast cancer," he said.

Dr Gunter von Minckwitz

The favorable prognosis of patients who achieved a pCR was confirmed and is independent of their germline BRCA status, Dr von Minckwitz added.

In contrast, in the second study of TNBC patients, known as CALGB 40603, also a phase 2 trial with carboplatin-containing groups (with or without bevacizumab), the investigators found that at a median follow-up of 39 months, pCR was prognostic of outcome in selected patients. However, they could not determine whether either carboplatin or bevacizumab offered additional benefit because the study was underpowered.

"On the basis of these results, at the present time, neither carboplatin nor bevacizumab should be considered part of the standard neoadjuvant chemotherapy regimen for stage II or III TNBC," said lead CALGB 40603 investigator William M. Sikov, MD, a medical oncologist at Women & Infants Hospital in Providence, Rhode Island, in meeting press materials.

The CALGB 40603 investigators also found that pCR is a "good surrogate for long-term outcomes on a patient level," Dr Sikov reported. But, in contrast to assertions by von Minckwitz et al, clinical trial data were lacking. "There remains no evidence that pCR rate can be used as a surrogate for event-free survival or overall survival on a trial level to compare regimens in triple-negative breast cancer," he added.

GeparSixto: Yes to Carboplatin for TNBC

The GeparSixto investigators previously found that carboplatin improved pCR rates in patients with TNBC but not HER2-positive breast cancer, and that germline BRCA status was a significant predictor of pCR (Lancet Oncol. 2014;15:747-756).

The trial, which compared a regimen of paclitaxel and nonpegylated liposomal doxorubicin with or without weekly carboplatin, did not meet its primary end point of a difference in pCR with carboplatin for the overall population of 595 patients with TNBC or HER2-positive breast cancer. The pCR rates were 36.9% without carboplatin and 43.7% with carboplatin, but the difference was not significant. However, as noted before, there was a significant pCR advantage with carboplatin for the 315 patients with TNBC.

At the SABCS, Dr von Minckwitz reported on early disease-free survival from the trial.

For the overall population, 3-year disease-free survival was 84.7% with carboplatin and 81.0% without, and the survival curves were superimposable. Similarly, for HER2-positive patients, there was no difference in disease-free survival (83.4% vs 86.7%).

But for the patients with TNBC, there was a difference in 3-year disease-free survival between carboplatin and no carboplatin (85.8% vs 76.1%; = .0325), which translated into a hazard ratio for carboplatin of 0.56 (P = 0.35).

CALGB 40603: The Jury Is Still Out

The randomized CALGB 40603 study had a 2 × 2 randomization scheme in which all patients received paclitaxel 80 mg/m² weekly for 12 weeks, plus one of three treatments: bevacizumab 10 mg/kg every 2 weeks for nine cycles; carboplatin to AUC 6 every 3 weeks for four cycles; or both carboplatin and bevacizumab, as previously reported by Medscape Medical News.

All patients went on to dose-dense chemotherapy with doxorubicin and cyclophosphamide for four cycles.

This early-phase trial was designed to look at pCR rates in the breast and axilla, but was not powered to compare individual treatment groups or to detect differences in recurrence-free or overall survival, Dr Sikov noted.

Rates of pCR in the breast were lower in patients who did not receive carboplatin than in those who did (46% vs 60%). The odds ratio (OR) for carboplatin was 1.76 (P = .001).

Rates of pCR in the breast were also lower in patients who did not receive bevacizumab than in those who did (48% vs 59%). The OR for the angiogenesis inhibitor was 1.58 (P = .0089).

This year, Dr Sikov reported that, for all patients, 3-year event-free survival was 74%, and 3-year overall survival was 83%.

The investigators also found that a pCR in the breast and axilla was associated with significantly better event-free survival (hazard ratio [HR], 0.30; 95% confidence interval [CI] 0.19 - 0.46) and overall survival (HR, 0.20; 95% CI, 0.11 - 0.36).

But they found no difference with the addition of carboplatin for either event-free survival (HR, 0.84; P = .36) or overall survival (HR, 1.15; P = .53). Bevacizumab was also not associated with improvements in event-free or overall survival.

As noted, the investigators found that pCR, although predictive of better outcomes on the individual level, is not an adequate surrogate for event-free survival on the trial level, a finding supported by a recent meta-analysis (Lancet. 2014;384:164-172) and other data.

What's an Oncologist to Do?

Well-designed trials in the neoadjuvant setting will be required before carboplatin can be recommended as routine therapy in early TNBC, said invited discussant Angela M. DeMichele, MD, MSCE, from the University of Pennsylvania School of Medicine in Philadelphia.

"I would say it's still an individualized decision. The hazard ratios suggest benefit, but currently there are not enough data to be conclusive. Moreover, the chemotherapy backbone and carboplatin dosing schedules may be critical to optimal efficacy, and we still don't know the long-term effect of the added toxicities of this drug," she said.

The GeparSixto investigators used a nonstandard chemotherapy backbone, with liposomal doxorubicin substituted for cyclophosphamide, noted a breast cancer specialist who was not involved in either study.

"In a clinical trial, you really should use a backbone regimen that we use in practice. The GeparSixto study didn't do that, but the CALGB study did," Steven J. Isakoff, MD, PhD, from the Massachusetts General Hospital Cancer Center in Boston, told Medscape Medical News.

"The bottom-line take-home message is that these studies don't seem to support going home and routinely adding platinum to the neoadjuvant chemotherapy regimens, and the decision to use it should be individualized for an appropriate given patient," he explained.

Dr Isakoff and Dr DeMichele both said it is reasonable to consider adding carboplatin when there is a need for rapid control of locoregional disease to improve the chances of successful surgery and/or decrease morbidity, and in patients at highest risk for relapse, such as those with stage III disease, or very young patients.

It is still not known whether platinum compounds can benefit patients with BRCA mutations. Careful selection of patients is important because of the added risks of both short- and long-term toxicities associated with these agents, they emphasized.

GeparSixto was supported by GSK, Roche, and Teva. Dr von Minckwitz is a speaker for Teva. CALGB 40603 was supported by the National Cancer Institute. Dr Sikov is a speaker for Eisai, has a contract with AbbVie, and has served on advisory boards (unpaid) for Celgene and AbbVie.

San Antonio Breast Cancer Symposium (SABCS) 2015: Abstracts S2-04 (GeparSixto) and S2-05 (CALGB 40603). Presented December 9, 2015.

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