Combination Therapy of Pyrotinib and Metronomic Vinorelbine in HER2+ Advanced Breast Cancer after Trastuzumab Failure (PROVE): A Prospective Phase 2 Study
Article information
Abstract
Purpose
Approximately 50%-74% of patients with metastatic human epidermal growth factor receptor 2 (HER2)–positive breast cancer do not respond to trastuzumab, with 75% of treated patients experiencing disease progression within a year. The combination of pyrotinib and capecitabine has showed efficacy in these patients. This study evaluates the efficacy and safety of pyrotinib combined with metronomic vinorelbine for trastuzumab-pretreated HER2-positive advanced breast cancer patients.
Materials and Methods
In this phase 2 trial, patients aged 18-75 years with HER2-positive advanced breast cancer who had previously failed trastuzumab treatment were enrolled to receive pyrotinib 400 mg daily in combination with vinorelbine 40mg thrice weekly. The primary endpoint was progression-free survival (PFS), while secondary endpoints included objective response rate (ORR), disease control rate (DCR), overall survival (OS), and safety.
Results
From October 21, 2019, to January 21, 2022, 36 patients were enrolled and received at least one dose of study treatment. At the cutoff date, 20 experienced disease progression or death. With a median follow-up duration of 35 months, the median PFS was 13.5 months (95% confidence interval [CI], 8.3 to 18.5). With all patients evaluated, an ORR of 38.9% (95% CI, 23.1 to 56.5) and a DCR of 83.3% (95% CI, 67.2 to 93.6) were achieved. The median OS was not reached. Grade 3 adverse events (AEs) were observed in 17 patients, with diarrhea being the most common (27.8%), followed by vomiting (8.3%) and stomachache (5.6%). There were no grade 4/5 AEs.
Conclusion
Pyrotinib combined with metronomic vinorelbine showed promising efficacy and an acceptable safety profile in HER2-positive advanced breast cancer patients after trastuzumab failure.
Introduction
Breast cancer prevails as the primary malignancy among Chinese women, especially in urban areas, with a rising incidence. Human epidermal growth factor receptor 2 (HER2)–positive breast cancer, characterized by the overexpression of the HER2 protein due to gene amplification, is notably aggressive and associated with a poorer prognosis compared to other subtypes. Approximately 20%-30% of breast cancer patients in China exhibit HER2 gene amplification/overexpression [1,2].
Trastuzumab emerges as a cornerstone therapeutic agent for HER2-positive breast cancer. The combination of pertuzumab, trastuzumab, and taxane serves as the standard first-line treatment while other trastuzumab-based therapies are recommended in third- or later-line settings [3]. However, pertuzumab was approved in China only recently, and its high-cost limits accessibility for many Chinese patients. Consequently, few patients in China have received pertuzumab treatment. In contrast, trastuzumab has been widely used in both early and metastatic settings, making trastuzumab resistance a significant challenge in the management of HER2-positive breast cancer [4].
Unlike trastuzumab, which binds to the extracellular domain of HER2, small-molecule tyrosine kinase inhibitor (TKI) targets the intracellular tyrosine kinase domain, inhibiting HER2 signaling even with extracellular domain alterations in trastuzumab-resistant patients [5]. Furthermore, pan-HER TKI enhances antitumor activity by inhibition of multiple HER family members, including epidermal growth factor receptor (EGFR), HER2, and HER3 [6-8]. Pyrotinib is an indigenous pan-HER TKI developed in China that gained rapid national approval in September 2018 for HER2-positive metastatic breast cancer [9]. Phase III PHENIX and PHOEBE studies validated the efficacy of pyrotinib in combination with capecitabine for trastuzumab-pretreated patients with advanced breast cancer with improvements in both progression-free survival (PFS) and overall survival (OS), thereby establishing the combination of pyrotinib and capecitabine as a preferred treatment option following trastuzumab resistance [10-12]. However, this combination was presented with notable gastrointestinal adverse events (AEs), particularly diarrhea, which was both the most common and severe AE. Over 30% of patients experienced grade ≥ 3 diarrhea, even with primary prophylaxis using loperamide [13-15]. Other chemotherapy drug, such as docetaxel, also had a high incidence of grade ≥ 3 diarrhea, when co-administrated with pyrotinib and trastuzumab [16,17]. Therefore, there is a need to identify alternative chemotherapy options with reduced gastrointestinal toxicity. Vinorelbine is a semi-synthetic vinca alkaloid that exerts its action on tubulin, effectively disrupting the formation of mitotic spindles essential for cell division. This mechanism confers its potent anti-proliferative effects [18]. A phase II study demonstrated that intravenous vinorelbine combined with trastuzumab and lapatinib were effective and safe in metastatic HER2-positive breast cancer patients [19]. Previous retrospective studies showed promising effects of pyrotinib plus oral vinorelbine in HER2-positive metastatic breast cancer patients pretreated with trastuzumab and taxane [20,21]. Vinorelbine can be administrated both orally and intravenously. Jiang et al. [22] phase II trial reported no significant difference between these two administration routes, but oral vinorelbine was associated with more gastrointestinal AEs and less myelosuppression. For the sake of convenience and economic factor, oral vinorelbine was selected. To reduce gastrointestinal toxicity, metronomic vinorelbine is administered at low doses. Metronomic vinorelbine demonstrated its good tolerance, even among elderly patients [23,24]. Moreover, metronomic vinorelbine was found to possess antiangiogenic, immunomodulatory, and cancer stem cell-targeting effects, rather than depending solely on the cytotoxicity of the maximum tolerated dose [25], which may provide synergistic effect when combined with other antitumor drugs. A phase I-A dose-escalation study has confirmed the safe administration of metronomic vinorelbine up to 50 mg thrice weekly, demonstrating sustained antitumor efficacy without significant toxicities or drug accumulation [26]. This study aims to explore the efficacy and safety of a novel dual oral regimen, combining pyrotinib with metronomic vinorelbine chemotherapy, for the treatment of HER2-positive advanced breast cancer patients who failed the trastuzumab therapy.
Materials and Methods
1. Study design and patients
This investigator-initiated, single-center, single-arm, open-label prospective phase II trial (NCT04903652) enrolled female patients aged 18 to 75, with histologically confirmed HER2-positive (defined by an immunohistochemistry score of 3+ and/or a positive fluorescence in situ hybridization test, as confirmed by investigators) recurrent/metastatic breast cancer who experienced disease progression (PD) during or after trastuzumab treatment (discontinued < 12 months prior) from the Tianjin Medical University Cancer Institute and Hospital. Eligibility criteria included an Eastern Cooperative Oncology Group performance status score of 0-2, an expected overall survival of ≥ 12 weeks, at least one measurable lesion per Response Evaluation Criteria in Solid Tumors (RECIST) ver. 1.1 and normal major organ function. Exclusion criteria comprised visceral crisis, conditions impacting oral medication intake or absorption, prior treatments for advanced/metastatic disease including radiotherapy, endocrine therapy, surgery (except local puncture), or targeted therapy. Other malignancies within 5 years, and current pregnancy or breastfeeding also led to exclusion.
2. Procedures
Eligible patients received oral pyrotinib 400 mg once daily and oral vinorelbine 40 mg three time a week for each 21-day cycle. Treatment was continued until PD, intolerable toxicity, or withdrawal of consent.
Every 8 weeks, patients underwent evaluation of tumor response via advanced computed tomography or magnetic resonance imaging, until PD or death, following RECIST ver. 1.1 guidelines. During the study, AEs were graded based on the National Cancer Institute Common Terminology Criteria for Adverse Events ver. 4.03.
Dose adjustments or delays were based on the highest grade of hematologic or non-hematologic toxicities observed in patients. Any treatment delay due to AEs shouldn’t exceed 3 weeks, with the subsequent chemotherapy cycle adjusted accordingly. Doses can be modified in response to various conditions such as specific absolute neutrophil count counts, febrile neutropenia, platelet levels, and durations of anemia or neurotoxicity. If a patient develops severe neutropenia in a treatment cycle, the drug dosage may be reduced for subsequent cycle. Each drug has a maximum allowance dose reduction limit; exceeding this limit may necessitate the patient’s withdrawal from the study. Once a dose is decreased, it should be consistently maintained in the following administrations.
3. Endpoints
The primary endpoint was PFS, defined as the period from the initiation of study treatment to either the first instance of PD or death from any cause. Secondary endpoints included the objective response rate (ORR), characterized as the ratio of patients achieving confirmed complete response (CR) or partial response (PR) as the best overall response, duration of response (time from first CR or PR to PD for patients with confirmed objective response), disease control rate (DCR) involving CR, PR, or stable disease, OS, and safety.
4. Statistical analysis
Drawing from the EMILIA study, the median PFS of the combined treatment of lapatinib and capecitabine was 6.4 months [27]. The goal of the study treatment was to extend the median PFS to 12.0 months. Assuming survival times follow an exponential distribution with a two-sided test at a significance level of 0.05, considering a 1-year enrollment period followed by a 1-year follow-up, the study aimed to attain a statistical power of 80% with a requirement of 20 observed events. Based on these considerations, the required sample size was calculated to be 32 patients. Accounting for a 10% potential dropout rate, the target sample size was set at 36 patients.
Efficacy and safety were assessed in all patients who received at least one dose of the study drug. Continuous variables were presented as median (range), while categorical variables were expressed as frequency (%). The 95% confidence intervals (CIs) for ORR and DCR were calculated using the Clopper-Pearson method. Median PFS and OS were estimated via the Kaplan-Meier method, with 95% CIs calculated using the Brookmeyer-Crowley method. Subgroup comparisons for PFS were conducted using the Cox proportional hazard regression model. For subgroup analysis, primary resistance to trastuzumab was defined as PD at the first radiological reassessment (typically conducted 8-12 weeks or within 3 months after initiating first-line trastuzumab with or without chemotherapy in the metastatic setting) or new recurrences diagnosed during or within 12 months after completing adjuvant trastuzumab treatment. Secondary resistance was defined as PD occurring after two or more lines of trastuzumab-containing regimens that initially achieved disease response or stabilization at the first radiological assessment [28]. All statistical analyses were performed by SAS ver. 9.4 (SAS Institute Inc., Cary, NC). A two-sided p-value of < 0.05 was deemed statistically significant.
Results
1. Patient characteristics
From October 21, 2019, to January 21, 2022, a total of 36 patients were prospectively enrolled. Baseline characteristics are presented in Table 1. All patients received at least one dose of study treatment and were included in the analysis of efficacy and safety. Of these patients, 19 (52.8%) had hormone receptor-positive disease, 23 (63.9%) had multifocal metastasis and 27 (75%) demonstrated hepatic metastatic involvement. Prior to study initiation, 23 (63.9%) had undergone trastuzumab treatment in advanced stage, and nine (25.0%) exhibited primary trastuzumab resistance. Additionally, 15 patients (41.7%) had been previously treated with lapatinib, and eight patients (22.2%) had received chemotherapy in three or more sequential lines.
Baseline characteristics
As of the data cutoff date on December 28, 2023, of 36 patients, 29 experienced PD or mortality, two lost follow-up, and five were still under the study treatment. With a median follow-up duration of 35 months, the median PFS was 13.5 months (95% CI, 8.33 to 18.5) (Fig. 1A). A total of 12 deaths were reported, and the OS data are currently immature. No patient achieved CR while 14 patients obtained PR, yielding an ORR of 38.9% (95% CI, 23.1 to 56.5), with a DCR of 83.3% (95% CI, 67.2 to 93.6).
Kaplan-Meier curves of progression-free survival (PFS) for human epidermal growth factor receptor 2–positive advanced breast cancer patients. (A) PFS curve for entire cohort (n=36). (B) PFS for subgroups with or without lung metastasis (median, 14.3 vs. 7.6 months; nominal p=0.037). (C) PFS for subgroups primarily or secondarily resistant to trastuzumab (median, 19.7 vs. 10.9 months; nominal p=0.207). (D) PFS for subgroups previously treated with trastuzumab (median: 13.6 months) in advanced or early disease stages (median, 13.9 vs. 11.8 months). (E) PFS for subgroups with or without previous lapatinib treatment (median, 8.3 vs. 15.3 months; nominal p=0.008).
The post-hoc subgroup analysis results are presented in Table 2. Notably, patients with lung metastases demonstrated a median PFS of 14.2 months, compared to 7.6 months for those without lung metastases (nominal p=0.037) (Fig. 1B). A median PFS of 19.7 months was observed in patients with primary resistance to trastuzumab, versus the secondary resistant population with a median PFS of 10.9 months (nominal p=0.207) (Fig. 1C). All patients underwent prior trastuzumab treatment. For patients who received trastuzumab treatment in the advanced stage, the median PFS reached 13.9 months; while those treated with trastuzumab in the early stage exhibited a median PFS of 11.8 months. And for the population with previous trastuzumab treatment in both advanced and early stages, the median PFS was 13.6 months (Fig. 1D). Of particular significance is that patients with prior treatment of lapatinib had a median PFS of 8.3 months, substantially shorter than the 15.3 months observed in lapatinib-naïve patients (nominal p=0.008) (Fig. 1E).
The post-hoc subgroup analysis
2. Safety
The most common treatment-related AEs of any grade were diarrhea (94.4%), decreased appetite (88.9%), and nausea (80.6%). Grade 3 AEs were observed in 17 patients, with diarrhea being the most common (10 patients, 27.8%), followed by vomiting (3 patients, 8.3%) and stomachache (2 patients, 5.6%). There were no grade 4/5 AEs (Table 3). No death due to AEs was reported. No new or unexpected AE was identified, and all AEs were manageable.
Summary of adverse events
Discussion
Anti-HER2 antibody-drug conjugates (ADCs) are currently the preferred regimen for patients previously treated with trastuzumab. The EMILIA study established the role of trastuzumab emtansine (T-DM1) in this population, showing a median PFS of 9.6 months and a median OS of 30.9 months [27]. Recently, trastuzumab deruxtecan (T-DXd) achieved amazing outcomes from the phase 3 DESTINY-Breast 03 study with a median PFS of 28.8 months (hazard ratio, 0.33; p < 0.0001) [29]. Both ADCs have been recommended as standard second and third lines of treatment by the National Comprehensive Cancer Network and European Society of Medical Oncology guidelines [3,30]. T-DM1 and T-DXd granted their approval in China in 2020 and 2023, respectively. However, their use was not yet common practice due to economic factors. As such, exploration of small molecule combination therapies is still necessary.
Pyrotinib is an oral, irreversible pan-HER TKI that irreversibly binds to EGFR, HER2, and HER4, thereby preventing downstream signaling and suppressing the growth and survival of tumor cells [31]. Data from a nationwide, prospective, real-world observational study showed that patients who received pyrotinib as a second-line therapy experienced a median PFS of 12.0 months, while those receiving it as a third or subsequent line of therapy had a median PFS of 6.4 months [32]. In the Phase III PHENIX trial, pyrotinib in combination with capecitabine achieved a median PFS of 11.1 months for trastuzumab-treated HER2-positive metastatic breast cancer [12]. Similarly, in the Phase III PHOEBE trial, this combination obtained a median PFS of 12.5 months in HER2-positive metastatic breast cancer, reducing the risk of disease progression or death by 61% compared to lapatinib combined with capecitabine [11]. In this phase II trial, the combination of pyrotinib and metronomic vinorelbine showed promising efficacy with a median PFS 13.5 (95% CI, 8.1 to 20.3) and a DCR of 83.3% (95% CI, 67.2 to 93.6) in HER2-positive advanced breast cancer after trastuzumab failure, exceeding the median PFS of EMILIA study [27], consistent with that of PHOEBE study [11].
The potential of pyrotinib to overcome trastuzumab resistance may explain the promising outcome in trastuzumab-treated HER2-positive breast cancer patients. There are several mechanisms, including the presence of HER2 carboxy-terminal fragment p95HER2 [33], HER2Δ16 variant lacking exon 16 [34], activation of alternative signaling pathways such as phosphoinositide 3-kinase/AKT/mammalian target of rapamycin and mitogen-activated protein kinase [35,36], overexpression of insulin-like growth factor-1 receptor, and amplification of EGFR or HER3 [6-8]. Additionally, immune suppression induction, vascular mimicry, breast cancer stem cells, and metabolic escape may also be involved. p95HER2, a truncated form of HER2 that lacks the extracellular domain necessary for trastuzumab binding, is responsive to lapatinib, suggesting that pan-HER TKIs can effectively target such resistant forms by also acting on other receptors like EGFR that increase with trastuzumab exposure [37,38]. In the PICTURE study, pyrotinib plus capecitabine achieved a median PFS of 11.8 months (95% CI, 8.4 to 15.1) in HER2-positive advanced breast cancer patients with primary resistance to trastuzumab [39]. Further supporting this, the PANDORA study reported that pyrotinib plus docetaxel as a first-line treatment achieved a median PFS of 20.8 months in trastuzumab-pretreated patients compared to 14.8 months in trastuzumab-naïve patients [40]. Subgroup analysis in our study revealed a median PFS of 19.7 months in patients with primary resistance to trastuzumab compared to 10.9 months in the secondary resistant population (nominal p=0.207), supporting the mechanism of pan-HER TKIs in overcoming primary resistance to trastuzumab.
Several studies have highlighted the effectiveness of metronomic vinorelbine in metastatic breast cancer, with favorable median PFS of 7.4-12 months and DCR of 50%-88% [25,41-43]. One of the standout attributes of metronomic vinorelbine is its low incidence of severe toxicity, even during long-term use [25,41-43]. In our study, the highest grade of diarrhea observed without primary prophylaxis was grade 3, with an incidence of 27.8%. Comparatively, even with primary prophylaxis, grade 4 diarrhea was observed in the PHENIX and PHOEBE studies [10-12], with grade ≥ 3 diarrhea incidences were 30.8% and 30.5%, respectively, with the combination of pyrotinib and capecitabine; the PHILA and PHEDRA studies [13,14] reported even higher grade ≥ 3 diarrhea incidences of 46.5% and 44.4%, respectively, with pyrotinib combined with trastuzumab and docetaxel. Reduced incidence of severe diarrhea could improve patient compliance to pyrotinib administration. High-dose chemotherapy often leads to the selection of chemo-resistant tumor cell clones, as the cytotoxic stress preferentially eliminates drug-sensitive cells. Metronomic dosing mitigates this risk by maintaining constant pressure on the tumor environment, reducing the risk of drug resistance. Additionally, low-dose chemotherapy targets endothelial cells, enhancing the antiangiogenic effect. More frequent dosing schedules have been associated with the activation of antitumor immune responses, ultimately synergizing with other drugs to increase antitumor efficacy [25]. This may explain the numerically slightly higher median PFS observed in our study. The efficacy and feasibility of metronomic chemotherapy combined with targeted therapy has been demonstrated with promising results observed in several clinical trials combining metronomic chemotherapy with anti-HER2 agents and antiangiogenics [42,44-47].
Future directions in treatment may involve combining ADCs with small-molecule inhibitors, potentially offering even greater benefits to patients. The HER2CLIMB-02 trial has confirmed the efficacy advantages of combining ADCs with TKIs [48]. Additionally, ongoing studies like the Alliance A011801 trial, which investigates post-neoadjuvant T-DM1 with tucatinib/placebo in patients with residual HER2-positive invasive breast cancer [49], and the HER2CLIMB-04 trial, a phase 2 open-label trial of tucatinib plus T-DXd in patients with HER2 positive unresectable locally advanced or metastatic breast cancer with and without brain metastases [50], are expected to provide further insights into these promising combinations.
There are several limitations in this study. Given single-arm design and small sample size of this study, all results should be interpreted with caution. Due to limited availability of T-DM1, T-DXd and pertuzumab during the study period and economic factors, no patients in our study had been treated with these ADCs and pertuzumab, which is quite different from the patient characteristics of global population, impacting the extrapolation and it is also not easy to compare with other global studies. Nonetheless, this dual oral regimen appears to be a feasible approach in this setting and warrants further study in larger randomized trials. The mechanisms of pyrotinib and metronomic vinorelbine suggest potential synergies. Future research delving into tumor angiogenesis, immune markers, and cancer stem cell clusters could provide further insight into the biologic interactions between these agents. As we chart the path ahead, refining the dosage and regimen of this combination will be paramount. The incorporation of other targeted agents, immunotherapies, or antiangiogenics in a three-drug protocol might further amplify the treatment’s efficacy.
In summary, this study provides promising clinical evidence for dual oral pyrotinib and metronomic vinorelbine HER2-positive advanced breast cancer after trastuzumab failure. Further research will be instrumental in perfecting this combination and elucidating its optimal role in the treatment of such patients.
Notes
Ethical Statement
The study was conducted in accordance with the Declarations of Helsinki and Good Clinical Practice and was approved by the ethics committee of Tianjin Medical University Cancer Institute and Hospital (approval number: E220691). Written informed consent was obtained from each patient. The study was registered with ClinicalTrials.gov, NCT04903652.
Author Contributions
Conceived and designed the analysis: Hao C, Wang X.
Collected the data: Shi Y, Tong Z, Li S, Liu X, Zhang L.
Contributed data or analysis tools: Shi Y, Tong Z, Li S, Liu X, Zhang L (Lan Zhang).
Performed the analysis: Zhang J, Meng W, Zhang L (Li Zhang).
Wrote the paper: Zhang J, Meng W, Zhang L (Li Zhang).
Conflicts of Interest
Conflict of interest relevant to this article was not reported.
Acknowledgements
We would like to acknowledge the patients and their families, the study investigators, and the clinical site staff. We thank Xuwei Fu (Department of Medical Affairs, Jiangsu Hengrui Pharmaceuticals Co., Ltd.) for her input in study design, data interpretation, and statistical support; and Yilan Wu (Department of Medical Affairs, Jiangsu Hengrui Pharmaceuticals Co., Ltd.) for medical writing assistance.