1. This phase 2, single-arm, multicenter trial found that in HER2-positive breast cancer patients demonstrating resistance to trastuzumab, the combination of pyrotinib and capecitabine improved progression-free survival and objective response rates while maintaining an adequate safety profile.
2. Results also indicate that different underlying mechanisms of trastuzumab resistance may impact disease progression and the response to treatment.
Evidence Rating Level: 1 (Excellent)
Approximately one-fifth of patients diagnosed with breast cancer are HER2-positive. Trastuzumab, also known as Herceptin, is a passive immunotherapy which, in this type of cancer, can significantly alter the course of the disease. However, a large proportion of breast cancer patients develop either primary resistance to the drug, which increases the risk of relapse, or earlier progression. There is some evidence that pan-HER tyrosine kinase inhibitors (TKIs) may be a solution to primary resistance to trastuzumab. Pyrotinib is one such irreversible pan-HER TKI, and capecitabine, an antimetabolite, has been shown to work synergistically with pyrotinib in advanced metastatic HER2-positive breast cancers. Thus, the current phase 2 trial investigated the efficacy of this combination in patients with primary trastuzumab-resistant HER2-positive breast cancer. A total of 100 patients from 16 clinical sites in China were enrolled in this single-arm trial. They received pyrotinib 400 milligrams per oral once daily and capecitabine 1000 mg/m2 orally twice daily for fourteen days in each 21-day cycle. Treatment continued until disease progression, intolerable toxicity, or withdrawal of consent. The standard of care in China in 2019 for trastuzumab-pretreated patients was trastuzumab plus vinorelbine, and the historical control median PFS was 5.78 months. The primary outcome, median PFS, was 11.8 months for the study group (95% CI 8.4-15.1). At the data cutoff date, 66 patients had either experienced disease progression or had died. The overall 1-year survival rate was 86.6%, but 25 deaths occurred over the course of the study. In a subgroup analysis of these primary trastuzumab-resistant patients, those who either had: rapid progression during adjuvant trastuzumab treatment (median PFS 8.2 months) or advanced disease within 6 months of initiating first-line trastuzumab (median PFS 5.6 months), had significantly lower median PFS than those who had progression within 12 months of completing adjuvant trastuzumab (median PFS 17.8 months; Ps < .05). All seven patients who achieved complete response to the treatment were from this latter subgroup. There were no differences in PFS between hormone receptor-positive versus negative patients (P = .765). Another 63 patients achieved a partial response to treatment. There was a disease control rate of 87% among all patients. From a safety perspective, 12 of the 100 patients required dose reductions of pyrotinib due to treatment-emergent adverse events (TEAEs), as did 37 patients requiring dose reductions of capecitabine. The most common TEAEs included diarrhea, palmar-plantar erythrodysesthesia syndrome, decreased neutrophil counts, hypokalemia, and anorexia. However, the combination of pyrotinib and capecitabine did not signal any new safety concerns and was well-tolerated relative to similar immunotherapies. The different subgroup median PFS’ could indicate underlying mechanisms of drug resistance which should be elucidated in future studies.
Click to read the study in BMC Medicine
Image: PD
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