Approximately 15–20% of patients with breast cancer overexpress the human epidermal growth factor receptor 2 (HER2) oncogene (1). This type of breast cancer exhibits an aggressive clinical behavior with higher rates of recurrence and metastasis (1). With the development of trastuzumab, as well as other anti-HER2 agents, such as pertuzumab, lapatinib, ado-trastuzumab emtansine, neratinib, and trastuzumab deruxtecan (2–7), the treatment and outcome of patients with HER2 positive (HER2+) metastatic breast cancer (MBC) have significantly improved. However, country-specific peculiarities should be considered. Specifically, neratinib, ado-trastuzumab emtansine, and trastuzumab deruxtecan are not available in all regions of the world. In addition, resistance to anti-HER2 treatment remains a challenge (1). Therefore, the continued development of novel anti-HER2 agents to further improve the efficacy of the treatment is important.

Pyrotinib is a novel oral, irreversible pan-ErbB tyrosine kinase inhibitor (TKI) that potently targets HER1, HER2, and HER4 (8). In fact, administration of pyrotinib plus capecitabine exhibited clinically meaningful results and acceptable tolerability in patients with HER2+ MBC in phase I, phase II, and phase III studies (9–12). In an open-label, multicenter, randomized phase II study, pyrotinib plus capecitabine treatment significantly improved the objective response rate (ORR; 78.5% vs. 57.1%, p = 0.01) and prolonged median progression-free survival (mPFS; 18.1 months vs. 7.0 months, p < 0.001) compared to lapatinib plus capecitabine. Moreover, the PHENIX study, a double-blinded, multicenter, randomized phase III study, reported that pyrotinib plus capecitabine significantly prolonged mPFS (11.1 months vs. 4.1 months, p < 0.001) and increased ORR (68.6% vs. 16.0%, p < 0.001) compared to capecitabine monotherapy (11). Recently, the phase III PHOEBE study reported that pyrotinib plus capecitabine, significantly prolonged the mPFS by 5.7 months compared with lapatinib plus capecitabine (12.5 vs. 6.8 months, p < 0.0001), thereby verifying the phase II findings (12). Though the overall survival (OS) data were not mature, a strong trend was observed toward prolonged survival following administration of pyrotinib plus capecitabine (12). However, these previous studies only included patients with HER2+ MBC who had previously received treatment with no more than two lines of systematic therapy. Pyrotinib was approved for use in China in August 2018 as a second-line standard-of-care for HER2+ MBC due to the remarkable results reported in the abovementioned phase II study, and is currently in phase I clinical trial in the United States (13). However, capecitabine is a chemotherapy regimen frequently used used in routine clinical practice, and it may cause many patients to have failed capecitabine treatment before they are able to receive pyrotinib-based therapy. Moreover, the treatment effect of pyrotinib combined with other chemotherapy drugs remains unclear, thereby limiting a clinician’s selection of chemotherapy drugs.

Vinorelbine is a semi-synthetic, antimitotic, microtubule destabilizing drug that has been shown to be effective and well-tolerated for the treatment of MBC (14). Two forms of this compound, intravenous and oral, are available for clinical use. The oral presentation not only has acceptable comparable efficacy and safety to the intravenous form, but it also allows patients to maintain their quality of life, as evidenced by the well-established patient preference for an oral formulation (15, 16). Moreover, vinorelbine has demonstrated efficacy and tolerability in combination with trastuzumab, lapatinib, or neratinib in clinical studies for patients with HER2+ MBC (17–19), which provides rationale for the evaluation of vinorelbine in combination with other anti-HER2 agents, such as pyrotinib. Furthermore, it is necessary to investigate new therapeutic options for the pyrotinib-based treatment regimen, particularly for patients who have failed capecitabine treatment.

We, therefore, conducted this multicenter study, which is the first, to our knowledge, to evaluate the efficacy and safety of pyrotinib plus vinorelbine in real-world HER2+ MBC and to provide a theoretical basis for clinical practice.

The advent of anti-HER2 therapy has greatly improved HER2-positive breast cancer prognosis. Specifically, pyrotinib is a novel anti-HER2 TKI that was recently approved in China. Our study showed promising effects of pyrotinib plus vinorelbine combination therapy with a median PFS of 7.8 months and an ORR of 34.3% in HER2+ MBC.

Evidence suggests that the strategy of trastuzumab plus pertuzumab combined with capecitabine for second-line treatment, maximizes mPFS to 11.1 months (21). Meanwhile, T-DM1 and lapatinib plus capecitabine have demonstrated a PFS of 9.6 and 8.4 months, respectively (4, 5, 22). In this study, the mPFS for patients with HER2+ MBC was observed to be 12.0 months and 6.4 months for second-line and third-or-higher-line pyrotinib plus vinorelbine treatments, respectively. Hence, pyrotinib plus vinorelbine could offer an alternative treatment as a second-or-higher-line treatment, to some extent.

However, our data were not as impressive as those for combined pyrotinib plus capecitabine reported in previous phase III trials with mPFSs of 11.1 and 12.5 months and ORRs of 68.6% and 67.2% (11, 12). Besides the obvious differences in chemotherapeutic drugs administered in combination with pyrotinib, the differences observed between our study and previous studies may have been caused by different population sample sizes and cohorts. For instance, the previous clinical trials included patients treated with no more than two lines of therapy, while some of the patients had not received any anti-HER2 therapy. However, in our cohort, 67% patients were treated with more than two lines of systematic therapy, and nearly all had received previous trastuzumab therapy. Therefore, our cohort represented a relative treatment refractory population, and the general population of HER2+ MBC patients in clinical practice were often heavily treated with multiple anti-HER2 agents. Hence, our study results provide data relevant to clinicians for the treatment of general metastatic HER2-positive BC patients in settings outside clinical trials. Additionally, the follow-up time for our study was relatively short (8.7 months) with more than 30% of patients still in treatment at the end of the period. Furthermore, the previous phase III trials excluded patients who were previously treated with lapatinib; meanwhile, 50.5% of patients in the present study were previously exposed to lapatinib. However, our study cohort included only a few patients who had been previously exposed to pertuzumab and/or T-DM1. Although pertuzumab and/or T-DM1 are commonly prescribed as front-line treatments for HER2-positive BC patients globally, in China, pertuzumab and T-DM1 was only newly approved, thereby limiting their usage in Chinese patients. Therefore, the role of pyrotinib in more heavily treated patients requires further global investigation.

Previous retrospective studies have also evaluated the efficacy and safety of pyrotinib-based regimens in real-world settings; however, the combination chemotherapy regimen used in these studies was mainly capecitabine (23, 24). A single-center retrospective study showed a mPFS of 6.3 months and an ORR of 29.5% in HER2+ MBC treated with pyrotinib-based treatment (23), whereas another multicenter analysis demonstrated an mPFS of 8.07 and ORR of 40.7% achieved by pyrotinib (24). However, few of the patients included in the two studies received combination pyrotinib and vinorelbine. Moreover, the mPFS for patients in second-line therapy was 12.0 months in our study, which is numerically higher than that reported for pyrotinib-based regimens in the previous multicenter retrospective study (8.1 months) (24), suggesting that pyrotinib plus vinorelbine is an effective treatment for HER2+ MBC, particularly as a second-line treatment.

The value of oral vinorelbine as a single agent for the treatment of MBC has been demonstrated in clinical trials indicating comparable efficacy and safety to intravenous vinorelbine. In our study, 74.2% and 25.8% of patients received oral vinorelbine and intravenous vinorelbine, respectively. Regardless of the drug formula, similar mPFSs were obtained when combined with pyrotinib. However, the oral formulation is easier to administer thus improving the quality of life in palliative settings and lowering the cost of medical care as it avoids hospitalization and reduces administration cost compared to the intravenous form (25, 26). Oral vinorelbine is thus a useful alternative to the intravenous form when combined with pyrotinib and deserves further clinical investigation.

Brain metastases frequently occur in HER2+ MBC compared to HER2 negative patients (1). For patients with brain metastasis, treatments are limited and prognosis remains poor, though anti-HER2 treatment was shown to improve survival in these patients (27–29). Meanwhile, the intracranial effect of trastuzumab remains controversial in brain metastasis patients as its large molecular structure hinders its ability to readily cross the blood-brain-barrier (BBB). Alternatively, anti-HER2 TKIs have become an important treatment strategy for these patients due to its small molecular size and high BBB penetrability. Indeed, a pooled analysis including 12 studies demonstrated that lapatinib plus capecitabine achieved s median pooled PFS of 4 months in HER2+MBC with brain metastasis (30). In the TBCRC022 trial, neratinib plus capecitabine also resulted in an mPFS of 5.5 and 3.1 months in lapatinib-naïve and lapatinib-treated HER2+ MBC patients with brain metastasis, respectively (31). Meanwhile, in our study, for the 23 patients with brain metastases, the mPFS was 6.3 months. Similarly, within the PHENIX study, a subgroup of patients with brain metastases had an mPFS of 6.9 months following combinatorial treatment with pyrotinib and capecitabine (11). However, considering the small number of brain metastases patients, larger scale clinical trials are warranted to verify the effectiveness of pyrotinib plus vinorelbine in patients with brain metastases.

Our results also revealed that the efficacy of pyrotinib plus vinorelbine therapy was significantly higher in lapatinib-naïve patients than in lapatinib-treated patients. In lapatinib-naïve group, pyrotinib plus vinorelbine therapy achieved an mPFS of 10.8 months, while a shorter mPFS of 5.6 months was observed in the lapatinib-treated group. In fact, the mPFS for the lapatinib-naïve group was numerically comparable to that of a neratinib plus capecitabine group (8.8 months), and better than that of a lapatinib plus capecitabine group (6.6 months) reported previously in the NALA study (22). Additionally, the mPFS in the lapatinib-treated group was numerically higher than that reported in the TBCRC022 trial (3.1 months) (31). Therefore, this is the first study, to our knowledge, to demonstrate the effectiveness of pyrotinib plus vinorelbine in patients following the failure of lapatinib-based treatment.

Pyrotinib plus vinorelbine therapy was generally well-tolerated with diarrhea found to be the most common grade 3 to 4 AE in the present study, which was consistent with reports of previous clinical trials (11, 12). However, all AEs were effectively controlled with treatment and did not lead to discontinuation of pyrotinib or vinorelbine treatment during the study. Notably, incidences of grade 3 or 4 neutropenia and leukopenia were present in 7.2% and 4.1% of patients in our study, respectively, which represented higher incidence than that reported in previous phase III clinical trials (11, 12), which was likely the result of the patients in our study being treated in combination with vinorelbine. In addition, no grade 3 to 4 hand-foot syndrome was reported, likely because no patients received capecitabine as a combined therapy. However, due to the retrospective nature of the study, missed AEs was unavoidable.

The current study has certain limitations. First, the retrospective and observational nature of the study may have resulted in missing data or possible recall and information bias. Second, the length of follow-up was relatively short and insufficient to allow for OS conclusions to be made. Nevertheless, our study also had certain associated strengths. First, it provides evidence to support the efficacy of combinatorial treatment with pyrotinib plus vinorelbine in real-world setting. Second, to our knowledge, this represents the first, and largest, observational case series available thus far. Finally, our results report the treatment pattern and safety data for pyrotinib plus vinorelbine in clinical practice, providing a theoretical basis for clinicians.

The combination of pyrotinib plus vinorelbine therapy demonstrated promising effects in HER2+ MBC with tolerable toxicity, particularly in patients administered the combination as a second-line treatment, and in those without prior lapatinib treatment. Pyrotinib plus vinorelbine also demonstrated promising anti-tumoral activity in patients with brain metastases. Additionally, oral vinorelbine offers a useful alternative to the intravenous form when combined with pyrotinib. However, additional clinical trials are required to further exploit the potential of pyrotinib plus vinorelbine.

The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding authors.

The studies involving human participants were reviewed and approved by Fudan University Shanghai Cancer Center. The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.

BW and RG conceived and designed the study. YL, HL, TL, WL, HW, and BS collected the data. YL and YQ performed the statistical analyses. YL wrote the manuscript. BW and RG reviewed and revised the manuscript. All authors contributed to the article and approved the submitted version.

This study was funded by the National Natural Science Foundation of China (NSFC) [Grant No. 81874114] and Shanghai "Rising Stars of Medical Talent" Youth Development Program [Grant No. AB83190002012023].

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.