In this single-center study, pyrotinib combined with trastuzumab and chemotherapy demonstrated promising efficacy in heavily pre-treated HER2 positive MBC (92.5% of the patients with prior trastuzumab and 52.5% with lapatinib), with a median PFS of 7.5 months and an ORR of 50%, which implies that half of the patients could still respond to pyrotinib-based regimen even in later-line settings.
As is well known, efficacy and safety of pyrotinib in patients with HER2-positive MBC have been verified in several pivotal studies. In the phase I study pyrotinib monotherapy demonstrated an ORR of 83.3% in trastuzumab-naive patients and 33.3% in trastuzumab-pretreated patients [14]. The benefit of continued use of trastuzumab beyond disease progression was also confirmed in earlier studies [8, 9]. The anti-tumor activity and favorable tolerability of dual HER2 blockade with TKI plus trastuzumab has been reported previously and mechanisms of synergistic interaction may involve enhanced apoptosis of cancer cells, increased stabilization and degradation of HER2 receptors, and reversion of resistance to trastuzumab by accumulation of HER2 receptors on the surface of breast cancer cells [20, 21]. Impressively, Murthy and colleagues reported that tucatinib, which was an investigational, oral, highly selective inhibitor of the HER2 tyrosine kinase, was an alternative regimen in heavily pre-treated metastatic breast cancer when combined with trastuzumab and capecitabine, with a median PFS of 7.8 months in the study population and 7.6 months in the brain metastases subgroup [19]. Another single-arm exploratory phase II trial has demonstrated that pyrotinib plus trastuzumab and albumin-bound paclitaxel generated an encouraging pCR rate and an ORR of 100% in the neoadjuvant setting [18]. To our knowledge, there exists no published data investigating the activity and safety of pyrotinib plus trastuzumab and chemotherapy in MBC patients previously treated. Our findings are fairly consistent with and further consolidate the above-mentioned data. The PFS duration reported here is similar with that in the HER2CLIMB trial. Noteworthy, the median PFS of BrM subset that have presumably worse prognosis, was numerically superior to that of the total population. The previous therapeutic lines may predominantly account for this result, since 32.5% of the total population versus 20.0% of BrM subgroup received ≥ 2 lines of therapy previously. Besides, concerning the patients with intracranial metastasis, the PFS duration estimated here (9.4 months) was also longer than that in the HER2CLIMB trial (7.6 months). The potent activity of pyrotinib per se for intracranial metastases may partly account for this finding. Another possible explanation is that local therapy for intracranial metastases (46.7% of the patients with brain metastases received local therapy) improved blood brain barrier permeability and thus the intracranial concentration of anti-tumor drugs increased.
Up to now, evidences on head-to-head comparison of TKI plus trastuzumab versus TKI alone are lacking. A randomized phase II trial, which was designed to assess the efficacy and tolerability of pyrotinib plus capecitabine versus lapatinib plus capecitabine in women with HER2-positive MBC previously treated with taxanes, anthracyclines, and/or trastuzumab, reported that the ORR was 78.5% and the median PFS was 18.1 months in the pyrotinib arm [15]. Similarly, PHENIX study showed that the ORR and median PFS of pyrotinib plus capecitabine were 68.6% and 11.1 months, respectively [17]. Numerically, these findings were superior to the data reported in our study, which might be partly attributed to different distribution of patient characteristics. The phase II study and PHENIX study enrolled patients with no more than 2 lines of prior treatment in the metastatic setting, and nearly 70% of the patients were trastuzumab-naïve. However, 67.5% of the patients in our study received ≥ 2 lines of therapy previously, and almost all patients had received prior trastuzumab for their metastatic disease [15]. Considering that 52.5% of our patients had been exposed to prior lapatinib, our data further implies the activity of pyrotinib beyond progression on lapatinib treatment. It follows that pyrotinib combined with trastuzumab and chemotherapy may offer a promising alternative for patients with heavily treated HER2-positive MBC, including those with BrM.
In addition, we further analyzed the predictive factors of PFS and found that liver or/and lung metastases was independent adverse factor for PFS, which suggested that patients without liver or/and lung metastases might better benefit from this combination therapy. This finding could provide guidance for patient selection and optimize clinical management.
Referring to safety, the overall incidences of TRAEs were similar to that of previous report and no new TRAEs were reported. The majority of TRAEs were Grade 1 or 2 in severity and most of TRAEs could be managed by dose reduction and supportive treatment. No one discontinued study treatment or died due to TRAEs. Diarrhea, usually occurring on days 4–14 after the first dose, is the most common TRAE which is mainly induced by pyrotinib and could be managed by dose reduction and loperamide, turning mostly tolerable after treatment administered for one month. The majority of diarrhea events were Grade 1 or 2, and 25% of them were Grade 3 or 4. Prophylaxis use of loperamide could effectively reduce incidence of diarrhea caused by neratinib. However, evidence is scarce supporting the prophylaxis use of loperamide in pyrotinib treatment. Of note, no cardiac-related events were recorded in our study. The low incidence of severe adverse events demonstrated the safety of pyrotinib plus trastuzumab in heavily pretreated MBC patients.
After all, the study is an initial single-center investigation based on a small Chinese cohort. Another limitation is the relatively low rate of standard care administration in previous lines of treatment among the enrolled patients. Only 6 patients received pertuzumab and trastuzumab as first-line therapeutic regimen and none of them had received TDM-1 treatment owing to financial and drug accessibility factors. Multi-center randomized controlled trials in larger cohorts are needed to further validate the efficacy and safety of this combination regimen.
In conclusion, pyrotinib in combination with trastuzumab and chemotherapy offer an active option with a favorable safety profile in heavily pre-treated patients with HER2-positive MBC, including those with brain metastases. Multi-center randomized controlled trials are warranted to validate the results.