by 7 months – with acceptable toxicity – vs. dual HER2 blockade alone in a randomized, open-label, phase 2 trial.
After a median follow-up of 20.7 months, the median progression-free survival (PFS) among 41 women who received trastuzumab and pertuzumab plus metronomic oral cyclophosphamide was 12.7 months, compared with 5.6 months among 39 women who received only trastuzumab and pertuzumab. Estimated PFS at 6 months was 73.4% and 46.2% in the groups, respectively (hazard ratio, 0.65), Hans Wildiers, MD, PhD, of University Hospitals Leuven, Belgium, and his colleagues reported in Lancet Oncology.
The most frequent grade 3-4 adverse events occurring in each group, respectively, were hypertension (12% and 15%), diarrhea (12% and 10%), dyspnea (10% and 5%), fatigue (5% and 8%), and pain (5% in each group). Thromboembolic events occurred in four patients (10%) receiving cyclophosphamide, while none occurred in the dual HER2 blockade-only group. Severe cardiac toxicities were occasionally observed in both groups.
Study subjects were women aged at least 70 years, or at least 60 years with confirmed functional restrictions. All had confirmed HER2-positive metastatic breast cancer and no prior chemotherapy for metastatic disease. They received either intravenous trastuzumab at a loading dose of 8 mg/kg, followed by 6 mg/kg every 3 weeks, and intravenous pertuzumab at a loading dose of 840 mg followed by 420 mg every 3 weeks (median of 6 cycles), or those same doses of trastuzumab and pertuzumab plus metronomic oral cyclophosphamide at a dose of 50 mg daily (median of 13 cycles). Subsequent treatment with trastuzumab emtansine in 29 patients who progressed during the study was active and well tolerated; the overall PFS at 6 months in this group of patients was 49.5% and median PFS was 5 months after starting trastuzumab emtansine.
“The results of this study indicate that the benefit of avoiding the side effects of chemotherapy with the use of dual anti–HER2 blockade only does not compensate for an important loss of activity in the metastatic setting,” the investigators wrote, concluding that “trastuzumab and pertuzumab plus metronomic oral cyclophosphamide, potentially followed by trastuzumab emtansine after progression, might delay the need for, or supersede, the use of taxane-based chemotherapy in this population.”
Further evaluation of this combination in a randomized phase 3 study is warranted, as the phase 2 findings do not provide “robust justification for a change in practice.” They do, however, provide a scientific framework for supporting more specific trials in older patients, who compromise nearly a third of breast cancer patients worldwide, and up to 50% in high-income countries, they said.
This study was funded by F Hoffmann-La Roche. Dr. Wildiers has received research grants from Roche, and personal fees to his institute from Roche, Amgen, Novartis, Pfizer, Puma, and Celldex. Other authors also reported receiving research or other support from Roche Products, Eisai, Novartis Pharmaceuticals UK, Astellas/Medivation, Astra Zeneca, Celgene, Daiichi-Sankyo, GE Oncology, Genentech, GlaxoSmithKline, Macrogenics, Merck Sharp & Dohme, Merus BV, Mylan, Novartis, Pfizer, Pierre Fabre, Sanofi, and Teva.
sworcester@frontlinemedcom.com
SOURCE: Wildiers H et al. Lancet Oncol. 2018 Feb 9. doi: 10.1016/S1470-2045(18)30083-4.